Asthma, Airway Biology, and Nasal Disorders in AJRCCM 2001 

MARTIN J. TOBIN

Division of Pulmonary and Critical Care Medicine, Loyola University of Chicago Stritch School of Medicine and Hines Veterans Affairs Hospital, Hines, Illinois

	CONTENTS

TOP CONTENTS ASTHMA AND AIRWAY BIOLOGY ALLERGIC RHINITIS AND NASAL... REFERENCES

Asthma and Airway Biology (150)

    Genetics (5)

    Epidemiology (10)

    Airway Inflammation (33)

        Animal Models (8)

        Induced Sputum (4)

        Bronchial and Bronchoalveolar Specimens (7)

        Blood (4)

        Exhaled Nitric Oxide (4)

        Other Exhaled Markers (4)

        Review Articles (2)

    Airway Hyperreactivity (27)

        Animal Models: Antigen Challenge (10)

        Animal Models: Other Challenges and Mediators (3)

        Ex-vivo Studies (5)

        Early and Late Asthmatic Responses (3)

        Chemical and Antigen Challenge (3)

        Hyperventilation- and Exercise-Induced Asthma (2)

        Drugs (1)

    Other Pathophysiologic Mechanisms in Asthma (31)

        Tachykinins and Neural Activity (4)

        Deep Inspiration (4)

        Infection and Immunology (4)

        Airway Narrowing (1)

        Remodeling (17)

        Review Article (1)

    Treatment (30)

        Beta-agonists (4)

        Inhaled Glucocorticoids (6)

        Glucocorticoids (1)

        Theophylline (1)

        Leukotriene Inhibitors (1)

        Combination Regimens (4)

        Immunotherapy (2)

        Management Plans and Education (4)

        New Agents (7)

    Specific Clinical Scenarios (11)

        Nocturnal Asthma (2)

                Acute Severe and Fatal Asthma (2)

Severity and Chronicity (1)

        Gastroesophageal Reflux (1)

        Pregnancy (1)

        Dyspnea (1)

        Gas Exchange (1)

        Quality of Life (1)

        Psychopathology (1)

    Occupational Asthma (3)

        Laboratory Animal Workers (1)

        Prevalence and Severity (2)

Allergic Rhinitis and Nasal Disorders (7)

    Nasal Function (1)

    Inflammation and Hyperreactivity (4)

    Nasal Polyposis (2)

	ASTHMA AND AIRWAY BIOLOGY

TOP CONTENTS ASTHMA AND AIRWAY BIOLOGY ALLERGIC RHINITIS AND NASAL... REFERENCES

Genetics

Studies that show an association between asthma-related phenotypes and alleles within a specific gene have generally lacked statistical power. Hakonarson and coworkers (1) did a case-control study of phenotypes associated with asthma and 24 candidate genes in 94 patients with atopic asthma and 94 control subjects without atopy or asthma. Phenotypic information in the cases consisted of a physician diagnosis of asthma, skin reactivity to 12 aeroallergens, level of IgE, pulmonary function, and response to methacholine challenge. The targeted genes that were sequenced included the cytokine gene cluster on chromosome 5q31-33, the interleukin-4 receptor on chromosome 16p12, the high affinity IgE receptor  chain (Fc RI) on chromosome 11q13, and other genes encoding cytokines, chemokines, adhesion molecules, and various enzymes that are implicated in the pathogenesis of asthma. Forty-two single nucleotide polymorphisms (SNPs) were genotyped in the 24 genes, with an average minor allele frequency of 20.3% (asthma) and 20.7% (control). The allelic frequencies of the single nucleotide polymorphisms in the candidate genes did not differ between patients and control subjects. Linkage studies conducted in 269 patients with atopic asthma and in 230 of their unaffected relatives uncovered no evidence of linkage to markers associated with the 24 genes. The authors conclude that the study failed to produce evidence that variations within 24 candidate genes for atopy and asthma significantly influence the expression of phenotypes of atopic asthma or contribute to the susceptibility for developing atopic asthma. An editorial commentary by Weiss (2) accompanies this article.

In the promoter region of the gene encoding CD14 (a receptor for endotoxin), a transition of C-to-T at position 159 is associated with atopic phenotypes in American children. To determine whether or not the C allele of CD14/159 is associated with phenotypes of atopy and asthma, Koppelman and coworkers (3) studied 159 probands with asthma and 158 spouses as controls from an adult Dutch population in which linkage of IgE and bronchial hyper-responsiveness to chromosome 5q had been previously reported. Homozygotes for the C allele of CD14/159 had a higher number of positive skin tests, a higher level of serum IgE in subjects with positive skin tests, and more self-reported allergic symptoms as compared with subjects with the CT and TT alleles. The authors conclude that the C-to-T promoter polymorphism at position 159 in the CD14 gene results in the expression of a more severe atopic phenotype.

Two polymorphisms of the ₂-adrenergic receptor gene at codon 16 (arginine to glycine) and codon 27 (glutamine to glutamate) are thought to influence airway responsiveness. To assess the association of asthma with polymorphisms of the ₂-adrenergic receptor gene and cigarette smoking, Wang and coworkers (4) did a case-control study of 128 patients with asthma and 136 control subjects living in rural China. Genotyping revealed a marginal interaction between smoking and the ₂AR-16 genotype. Compared with individuals who were homozygous for the Gly-16 allele and who never smoked, the homozygotes for the Arg-16 alleles who ever smoked had an increased risk of asthma (odds ratio, 7.8). This association had a dose-dependent relationship to the number of cigarettes smoked. Asthma was not related with polymorphisms of the ₂-adrenergic receptor gene at position 27. The authors conclude that homozygotes for the Arg-16 allele who smoke cigarettes are at increased risk of developing asthma.

The major macromolecular components of mucus consist of mucin proteins that are encoded by various MUC genes. Using the BLAST search and DNA-sequencing approach, Chen and coworkers (5) identified an expressed sequence tag (EST) clone in mice that shows great similarity to the 3' end of the human MUC5B gene. The clone was named 3pmmuc5b-1. A subsequent search of the mouse genome database with this sequence identified two overlapping genomic clones that contained the sequence for both 3pmmuc5b-1 and the mouse Muc5ac gene. The genomic order of the mouse Muc gene is 5'-Muc5ac-Muc5b-3'. The results suggest that the newly identified EST clone, 3pmmuc5b-1, is part of the 3' portion of the mouse Muc5b gene. In situ hybridization demonstrated that the putative mouse Muc5b message was expressed in a restricted manner under the tongue and in the region of the submucosal glands of the trachea. In mice with ovalbumin-induced asthma, gene expression was greatly enhanced in airway surface epithelium and in submucosal glands. The authors conclude that the newly cloned mouse Muc5b gene could be used as a marker for studying aberrant gene expression in mouse models of airway diseases.

Epidemiology

To determine whether or not a diagnosis of asthma is associated with weight gain or physical activity, Beckett and coworkers (6) followed 4,547 young adults, 18 to 30 years of age at study entry, for 10 years. At study entry, a diagnosis of asthma was associated with center of the study, race, sex, low level of education, and active smoking, but not with exposure to environmental tobacco smoke. At baseline, asthma showed little association with body mass index. On follow-up, a new diagnosis of asthma showed a J-shaped pattern of association with body mass index among women, but not among men. (A J-shaped pattern occurs when a risk for the lowest quintile [lowest change in weight over 10 years] is slightly higher than for the second quintile, and when the risk for the three highest quintiles is more elevated.) A lower level of physical activity did not explain the association between the incidence of asthma and the gain in weight. The authors conclude that a gain in weight is associated with a new diagnosis of asthma in young women, and that a lower level of physical activity does not explain the association.

To determine the relationship between body weight and asthma, Celedon and coworkers (7) did a cross-sectional study of 7,109 adults from families of subjects with asthma in Anqing (a rural province in China). Criteria for asthma were a physician diagnosis of asthma plus airway responsiveness to methacholine (at 25 mg per ml or less) plus two or more respiratory symptoms or attacks of asthma. Criteria for symptomatic airway hyperresponsiveness were airway responsiveness to methacholine (at 8 mg per ml or less) plus two or more respiratory symptoms or attacks of asthma. After adjusting for intensity of cigarette smoking and other factors, multivariate analysis revealed that both being underweight and being overweight was associated with asthma in women, and that being underweight was associated with asthma in men. Compared with a body mass index (in kg per m²) of 21, the odds of symptomatic airway hyperresponsiveness was 2.5 times higher in men and 2 times higher in women for a body mass index of 16, and it was 2.3 times higher in both men and women for a body mass index of 30. The authors conclude that both being underweight and overweight is associated with an increased risk of asthma among adults in families of subjects with asthma that live in rural China.

To determine whether or not growing up on a farm protects against the development of allergy, Leynaert and coworkers (8) analyzed data from 6,251 randomly selected participants (aged 20 to 44 years) in the European Community Respiratory Health Survey. After adjusting for potential confounders, living on a farm during childhood was associated with a decrease in the risk of atopic sensitization as an adult (odds ratio, 0.76). Compared with other individuals, individuals growing up on a farm were less frequently sensitized to cats (odds ratio, 0.63) and Timothy grass (odds ratio, 0.68), and had a lower risk of nasal symptoms in the pollen season (odds ratio, 0.80). The authors conclude that growing up on a farm decreases the risk of atopy and hay fever in adulthood, suggesting that exposure to environmental factors in childhood may have a lifelong protective effect against the development of allergy.

In the developing countries, the move to cities is associated with a switch from biomass fuels (wood, charcoal, animal dung) to modern fuels (kerosene, gas, electricity). To assess the influence of exposure to modern fuels on the risk of allergy, Venn and coworkers (9) studied a random sample of individuals who live in Jimma, Ethiopia. Questionnaire information was collected from 9,844 adults and children, and allergy skin tests were done on 2,372 of the individuals. The use of any modern fuel was reported by 959 individuals (10%). Compared with the sole use of a biomass fuel, the use of a modern fuel was associated with an increased risk of allergic sensitization (odds ratio, 1.8), wheeze (odds ratio, 1.6), rhinitis (odds ratio, 2.1), and eczema (odds ratio, 2.8). The authors conclude that domestic combustion of modern fuels increases the risk of allergic sensitization and symptoms.

To determine the relationship between asthma or rhinitis and the reactivity of skin tests to aeroallergies in a rural area of mainland China, Celedon and colleagues (10) studied 10,009 members of 2,544 families selected on the basis that at least two siblings had physician-diagnosed asthma. Although 47% of the subjects were sensitized to at least one aeroallergen, only 3.5% reported symptoms of allergic rhinitis. Sensitization to dust mite, a perennial aeroallergen, was a predictor of asthma (odds ratio, 1.3) and rhinitis (odds ratio, 1.3), and sensitization to mold was a predictor of asthma (odds ratio, 1.6). Sensitization to silk, a seasonal aeroallergen, was the strongest predictor of rhinitis (odds ratio, 1.5). The authors conclude that sensitization to perennial aeroallergens is predictive of asthma among subjects in rural China who have a family history of asthma, and that allergic rhinitis is far less common in rural China as compared with the industrial world.

To determine whether or not indoor levels of common allergens influence sensitization and clinical activity of asthma, Dharmage and coworkers (11) studied 485 individuals. Fungal levels in air samples from bedrooms were associated with increased bronchial hyperreactivity. The level of ergosterol, an estimate of fungal biomass, in floor dust was a risk factor for sensitization to fungi and for having wheezed in the preceding year. A high level of Fel d 1 (cat allergen) in floor dust was associated with an increased risk of being sensitized to cats, and a high level of Fel d 1 in beds was associated with current asthma. None of the studied outcomes was related to the levels of Der p1, the house dust mite allergen, possibly because almost every participant was exposed to supranormal levels of this allergen. The authors conclude that exposure to fungal and cat allergens, but not to house dust mite allergen, has a significant influence on sensitization and the clinical activity of asthma in young adults.

To measure the incidence of asthma in Spain, Basagana and coworkers (12) did a follow-up study in 1998 and 1999 of 1,640 individuals who had previously participated in the European Community Respiratory Health Survey of 1991 to 1993. The subjects had been 20 to 44 years of age during the survey. Incident cases were defined as those who were free of asthma in 1991 to 1993 and who gave a positive answer to the question "have you ever had asthma" in 1998 to 1999. The incidence of asthma was 5.53 per 1,000 person years: 6.88 in women and 4.04 in men. The incidence was highest in the subjects who at the time of the baseline survey had bronchial hyperresponsiveness (incidence rate ratio, 3.85), positive IgE against Timothy grass (incidence rate ratio, 3.16), and who were women (incidence rate ratio, 1.80). No association was seen with total IgE, atopy, smoking, occupational exposure, or maternal asthma. The authors conclude that bronchial hyperresponsiveness and IgE reactivity to grass are the main determinants of new asthma in subjects who had not reported having asthma when assessed six years earlier.

Dietary antioxidants may protect against the development of asthma, but the evidence is weak. To investigate this relationship, Shaheen and coworkers (13) did a population-based study of 607 cases of asthma and 864 control subjects. After controlling for confounding variables, asthma was negatively associated with apple consumption (odds ratio per increase in frequency group, 0.89) and with the intake of selenium (odds ratio per quintile increase, 0.84). The severity of asthma was negatively associated with the consumption of red wine. The authors conclude that the associations between asthma with apples and red wine suggest that flavonoids and other dietary antioxidants may protect against asthma.

The association between cleanliness and the increase in asthma is debated by von Mutius (14) and Platts-Mills and colleagues (15), with rebuttals from each (16, 17).

Airway Inflammation

Animal models The eosinophilic inflammatory response in asthma is associated with protein nitration, which can be studied using immunostaining for 3-nitrotyrosine. In murine models of allergic asthma, Duguet and coworkers (18) investigated the relative contribution of eosinophil peroxidase and inducible nitric oxide synthase to protein nitration. Three strains of mice were sensitized and challenged intranasally with ovalbumin. Staining for 3-nitrotyrosine in eosinophils around the airways was much less in New Zealand White mice, which have a spontaneous deficiency of eosinophil peroxidase, as compared with A/J and C57BL/6J mice. Mice with a targeted deletion of inducible nitric oxide synthase and also wild-type control mice had similar staining for 3-nitrotyrosine. The authors conclude that protein nitration, after allergen challenge in a murine model of asthma, is dependent on eosinophil peroxidase in the eosinophils and it is not dependent on increased production of nitric oxide. An editorial commentary by Cross and colleagues (19) accompanies this article.

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Induced sputum To assess the safety and efficacy of sputum induction in patients with severe asthma, ten Brinke and coworkers (26) studied 93 patients with severe asthma. The patients were symptomatic despite using a regular inhaled glucocorticoid and a long-acting ₂-agonist for at least a year, and had received at least one course of an oral glucocorticoid in the preceding year. Patients with an FEV₁ of less than 50% of predicted were excluded. A strict protocol for inhaling 0.9, 3.0, and 4.5% saline generated an adequate sputum sample in 74% of the patients. A greater than 15% fall in FEV₁ accompanied the induction of sputum in 22% of the patients, and it occurred despite pretreatment with albuterol. The decrease in FEV₁ was associated with an increase in the use of ₂-agonists for rescue in the preceding two days (r_s = 0.51), a lower post-bronchodilator FEV₁ (r_s = 0.31), and a lower PC₂₀ on methacholine provocation (r_s = 0.52). The risk of excessive bronchoconstriction was increased 10.2-fold in the patients who recently used ₂- agonists as rescue medication. The authors conclude that sputum induction can be successful and safe in patients with severe asthma provided that a strict protocol is followed, and that the patients at greatest risk of excessive bronchoconstriction are those who used ₂-agonists for rescue in the preceding days.

Bronchial and bronchoalveolar specimens The cysteinyl-leukotrienes generated by 5-lipoxygenase in mast cells and eosinophils, and also the prostanoid products generated by the cyclooxygenase pathway in mast cells and Th2-lymphocytes, cause bronchoconstriction, leukocyte recruitment, and bronchial hyperresponsiveness in asthma. To characterize the cellular expression of the enzymes of these two pathways in the bronchial mucosa, Seymour and coworkers (30) did bronchial biopsies in 12 patients with atopic asthma both before and during seasonal exposure to birch pollen. During the pollen season, symptom scores for asthma increased by 3.8-fold, accompanied by a decrease in PEF and an increase in bronchial responsiveness to methacholine. Bronchial biopsies during the pollen season revealed two-fold increases in cells staining for 5-lipooxygenase, 5-lipooxygenase-activating protein, and leukotriene A₄ hydrolase, and a fourfold increase in leukotriene C₄ synthase (the terminal enzyme in the synthesis of cysteinyl-leukotriene). The increase in leukotriene C₄ activity was accompanied by a six-fold increase in the proportion of eosinophils staining for the enzyme. Macrophages were also increased, but mast cells and subsets of T lymphocytes did not change. Staining for enzymes of the cyclooxygenase pathway did not change during the pollen season. Morning PEF was correlated with the counts of cells staining for 5-lipooxygenase in biopsies both before (r = 0.59) and during (r = 0.65) the pollen season. The authors conclude that the bronchial mucosa of patients with asthma shows increased activity of enzymes of the 5-lipoxygenase pathway, but not of the cyclooxygenase pathway, during allergen exposure, and that the increased activity is mainly seen in airway eosinophils and macrophages.

Blood Interleukin-4 is central to the maturation of type 2 (Th2) helper T cells and IgE class switching. The splice variant of interleukin-4, IL-42, may be a functional antagonist of interleukin-4 that competes for receptor binding. Seah and coworkers (37) measured messenger RNA copy numbers of interleukin-4 and its splice variant in the peripheral blood monocytes of 9 patients who had chronic atopic asthma and high serum IgE titers, in 18 patients with tuberculosis (a disease involving a significant increase in type-2 cytokine expression, although type-1 cytokines constitute the dominant response), and in 18 healthy subjects. The median number of messenger RNA copy numbers of interleukin-4 in the patients with asthma was 2.8 logs higher as compared with the patients with tuberculosis, and 4.5 logs higher as compared with the healthy subjects. The expression of the splice variant of interleukin-4, IL-42, in cells from patients with asthma was similar to that seen in the cells from patients with tuberculosis. The ratio of interleukin-4 to its splice variant was 500 times higher in the patients with asthma than in patients with tuberculosis or the healthy subjects. The authors conclude that the low level of expression of the splice variant, IL-42, relative to the expression of interleukin-4 may be a factor in the pathogenesis of asthma.

Exhaled nitric oxide To assess the usefulness of exhaled nitric oxide in detecting and predicting loss of control in asthma, Jones and coworkers (41) withdrew inhaled glucocorticoid therapy from 78 patients with mild-to-moderate asthma. Over the subsequent six weeks, 60 patients (78%) experienced a deterioration in the control of their asthma, with a median time to loss of control of 17 days. Exhaled nitric oxide was repeated every week, and the change in its concentration was correlated with symptom score (r = 0.45), sputum eosinophils (r = 0.44), percent predicted FEV₁ (r = 0.35), and the dose of saline causing a 15% decrease in FEV₁ (PD₁₅; r = 0.45). Both single and repeated measurements of exhaled nitric oxide had positive predictive values of 80 to 90% for predicting loss of control. Sputum eosinophils and PD₁₅ for hypertonic saline had equivalent positive predictive values. The authors conclude that exhaled nitric oxide is as powerful as the analysis of induced sputum or an airway challenge with hypertonic saline in predicting the loss of asthma control, but is easier to perform. An editorial commentary by Kharitonov and Barnes (42) accompanies this article.

Other exhaled markers To investigate the relationship between exhaled carbon monoxide and airway inflammation, Khatri and coworkers (45) exposed eight patients with atopic asthma to a whole lung allergen challenge. At baseline, exhaled carbon monoxide was equivalent in the patients and in the control subjects: 1.9 versus 1.8 ppm. After the allergen challenge, the patients developed an immediate decrease in exhaled carbon monoxide (to 1.4 ppm) and it returned to baseline after 1 hour. At baseline, exhaled nitric oxide was higher in the patients as compared with the control subjects: 15 versus 7.3 ppb. All but one patient developed an increase in exhaled nitric oxide at three hours after allergen challenge. The authors conclude that allergen challenge produces an immediate decrease in exhaled carbon monoxide in patients with asthma and that the levels return to baseline during the late asthmatic response.

Review articles In a state-of-the-art review article, D'Ambrosio and colleagues (49) discuss the role of cytokines and their receptors in guiding the recruitment of T lymphocytes in lung inflammation.

Airway Hyperreactivity

Animal models: antigen challenge To determine the relative roles of isoforms of nitric oxide synthase in contributing to airway hyperresponsiveness, Samb and coworkers (51) studied lung homogenates and tracheal smooth muscle from guinea pigs immunized and repeatedly challenged with ovalbumin. Six hours after the preceding challenge, protein expression of nitric oxide synthase 1 (the neural isoform) was decreased in lung homogenates, and returned to baseline at 24 hours. Nitric oxide synthase 3 was not modified, and nitric oxide synthase 2 was undetectable. The decreased expression of nitric oxide synthase 1 was associated with a decrease in the conversion of L-[³H]arginine to L-[³H]citrulline and a decrease in the concentrations of nitrate and nitrite in the lung. The decreased expression of nitric oxide synthase 1 was accompanied by a decrease in exhaled nitric oxide and by the development of airway hyperresponsiveness to histamine. The authors conclude that ovalbumin stimulation in guinea pigs induces a transient decrease in the expression and activity of nitric oxide synthase 1, which probably participates in airway hyperresponsiveness.

Animal models: other challenges and mediators The M₂ muscarinic receptors, which are located on the postganglionic parasympathetic nerves, inhibit the release of acetylcholine and vagally induced bronchoconstriction. Antigen challenge causes dysfunction of the M₂ receptors in guinea pigs. To determine whether or not dexamethasone pretreatment would prevent M₂ receptor dysfunction, Evans and coworkers (61) sensitized guinea pigs to inhaled ovalbumin. Pretreatment with dexamethasone before the antigen challenge prevented the hyperreactivity to vagal stimulation, the loss of M₂ receptor function, and the recruitment of eosinophils to airway nerves, but it did not prevent the eosinophil influx into the airways. The authors conclude that dexamethasone prevents antigen-induced hyperreactivity by protecting M₂ muscarinic receptors from antagonism by eosinophil major basic protein, and that this protection is achieved by specifically inhibiting the recruitment of eosinophils to airway nerves.

Ex-vivo studies Because interleukin-13 and interleukin-4, type 2 (Th2) helper cytokines, are believed to be important in asthma, Laporte and coworkers (64) studied the effects of these two cytokines on cultured smooth-muscle cells from the human airway. Smooth-muscle cells expressed transcripts for interleukin 4, interleukin 13 receptor 1 and interleukin 13 receptor II, but not for the  chain of the interleukin 2 receptor. STAT-6, a transcription factor, was phosphorylated by both interleukin-4 (peaking at 15 minutes) and interleukin-13 (peaking at 1 hour). Both interleukin-13 and interleukin-4 also caused phosphorylation of extracellular signal-regulated kinase mitogen-activated protein (ERK MAP) kinase. The -adrenergic responsiveness of the smooth-muscle cells was decreased by interleukin-13, but not by interleukin 4. U0126, an inhibitor of MEK (the enzyme that phosphorylates extracellular signal regulated kinase), reduced the effect of interleukin-13 on -adrenergic responsiveness. The authors conclude that the direct effect of interleukin-13 on smooth-muscle cells may contribute to airway narrowing in patients with asthma.

Early and late asthmatic responses To determine whether or not inhaled glucocorticoids have a dose-dependent effect on airway responses to inhaled antigen, Inman and coworkers (69) did a double-blind crossover study of placebo versus three doses of mometasone furoate in 12 patients with mild asthma. The three doses (100, 200, and 800 µg daily) achieved equivalent reduction in the early asthmatic response and in allergen-induced hyperresponsiveness to methacholine. The late maximal fall in FEV₁ was 24% after placebo, which was reduced by mometasone in a dose-dependent manner: 12% for 100 µg, 11% for 200 µg, and 6% for 800 µg. The increase in sputum eosinophilia was 60 (× 10⁴ cells per ml) at 24 hours, and this was reduced by mometasone: 24 for 100 µg, 15 for 200 µg, and 6 for 800 µg. The authors conclude that inhaled mometasone furoate attenuates the early and late asthmatic responses, and that the detection of a dose-response effect for attenuating the late response may prove useful in evaluating the relative potency of inhaled glucocorticoids.

Chemical and antigen challenge To determine whether or not a bronchial challenge with adenosine 5'-monophosphate (AMP) is more closely associated with airway inflammation as compared with methacholine, van den Berge and coworkers (72) studied 120 patients with asthma. In a stepwise multiple linear regression model, 18% of the variance in the PC₂₀ for methacholine (the provocative concentration producing a 20% fall in FEV₁) was explained by FEV₁ (as percent predicted), and 23% of the variance was explained when peripheral blood monocytes, an independent predictor, were added to the model. In contrast, 25% of the variance in the PC₂₀ for AMP was explained by the percentage of eosinophils in induced sputum, and 36% of the variance was explained when FEV₁ (as percent predicted), an independent predictor, was added to the model. The authors conclude that a challenge with AMP more closely reflects airway inflammation as compared with a challenge with methacholine. An editorial commentary by Cockcroft (73) accompanies this article.

Hyperventilation- and exercise-induced asthma To determine whether or not nitric oxide is involved in the pathogenesis of thermally induced asthma, Kotaru and coworkers (75) studied 13 patients with asthma and 10 healthy subjects. The subjects performed isocapnic hyperpnea while breathing frigid air. Five minutes after hyperpnea, FEV₁ fell by 28% in the patients with asthma and by 4% in the healthy subjects. During hyperpnea, the volume of exhaled nitric oxide rose in both groups, but the patients exhaled almost twice as much nitric oxide as compared with the control subjects. The increase in nitric oxide in the patients continued into the recovery period, and exhaled nitric oxide rose as airflow limitation developed. The authors conclude that nitric oxide plays an important role in thermally induced asthma.

Drugs The effect of estrogen therapy in patients with asthma is controversial. To investigate the mechanisms whereby estrogen influences airway reactivity, Degano and coworkers (77) compared the effect of physiologic doses of 17 -estradiol versus placebo in oophorectomized female rats. In in vivo studies, the airways of estrogen-treated rats had about one-sixth the responsiveness to inhaled acetylcholine as compared with placebo-treated rats. In ex vivo studies of isolated tracheal segments, estrogen increased the contractile response to acetylcholine but not the response to carbachol. The difference in contractile responsiveness between the estrogen and placebo treated rats was abolished by either physostigmine, a cholinesterase inhibitor, or by removing the epithelium. The activity of acetylcholinesterase was 1.4 times greater in homogenates of the whole trachea from the estrogen-treated rats than that of the placebo-treated rats. This difference disappeared when the epithelium of the trachea was removed. The authors conclude that estradiol decreases the responsiveness of the airways to acetylcholine and that the effect is partly dependent on increased activity of acetylcholinesterase in the epithelium.

Other Pathophysiologic Mechanisms in Asthma

Tachykinins and neural activity The tachykinin, neurokinin A, is a powerful bronchoconstrictor that acts mainly on neurokinin 2 receptors. Amadesi and coworkers (78) determined whether or not activation of the neurokinin 1 receptor causes motor responses in isolated medium-size (2-5 mm) human bronchi. A selective agonist of the neurokinin 1 receptor, [Sar⁹, Met(O₂)¹¹]SP, contracted about 60% of the isolated bronchial rings. Two antagonists of the neurokinin 1 receptor, CP-999,994 and SR 140,333, reduced the contraction. The effect of the agonist was independent of the release of acetylcholine and histamine and their epithelial removal, and the contraction was not affected by inhibition of nitric oxide synthase and cyclooxygenase. The agonist caused increases in inositol phosphate, and these increases were blocked by SR 140,333 in medium and small-size (about 1 mm in diameter) bronchi and by a cyclooxygenase inhibitor in small but not in medium-size bronchi. The authors conclude that the neurokinin 1 receptors mediate bronchoconstriction in a large proportion of medium-size human bronchi, apparently through direct activation of smooth muscle receptors and release of inositol phosphate.

Deep inspiration A deep inhalation both reverses and prevents against bronchoconstriction in healthy subjects, but the bronchoprotector effect is impaired in patients with asthma. To determine whether or not the impaired bronchoprotector effect is related to the degree of bronchial hyperresponsiveness, Scichilone and coworkers (82) studied 10 healthy subjects, 12 patients with asthma and moderate-to-severe bronchial hyperresponsiveness, 14 patients with asthma and mild-to- borderline hyperresponsiveness, and 10 patients with allergic rhinitis and mild-to-borderline hyperresponsiveness. In the absence of a deep inhalation, a single challenge with methacholine produced equivalent decreases in FEV₁ in the four groups. Taking a deep inhalation before methacholine had a bronchoprotector effect only in the healthy subjects. Taking a deep inhalation after methacholine had a bronchodilator effect in all four groups, and the effect was strongest in the healthy subjects. The authors conclude that the failure of a deep inhalation to protect against bronchoconstriction is related to bronchial hyperresponsiveness rather than to a clinical diagnosis of asthma, and that the dissociation between bronchoprotection and bronchoconstriction suggests that the two effects involve different mechanisms.

Infection and immunology Chronic infection with Chlamydia pneumoniae has been linked with the severity of asthma. Black and coworkers (86) did a double-blind trial of roxithromycin, a macrolide, in 232 patients with asthma who had high titers of antibodies to C. pneumoniae (IgG, IgA or both). At the end of six weeks, PEFR in the evening was 12 liters per minute higher in the patients receiving roxithromycin as compared with the patients receiving placebo. PEFR in the morning did not differ between the groups, and no differences were found at either three or six months after completing the treatment. The authors conclude that six weeks of treatment with roxithromycin leads to improvement in asthma control, but the benefit is not sustained. An editorial commentary by Johnston (87) accompanies this article.

Airway narrowing Methacholine causes greater airway narrowing in immature rabbits than in mature rabbits. To better understand the underlying mechanisms, Duguet and coworkers (90) used video microscopy to measure dynamic narrowing of intraparenchymal airways after maximal stimulation with methacholine. Compared with explants from mature rabbits, explants from immature rabbits showed 24% greater narrowing of the airways and a 65% increase in the peak velocity of shortening. In both groups, a greater velocity of shortening resulted in greater airway narrowing. The authors conclude that a lower elastic load limits the shortening of airway smooth muscle in immature rabbits.

Remodeling Remodeling of the airways in patients with asthma is partly characterized by an increase in the amount of smooth muscle in the airway wall. To determine whether or not patients with asthma have a different pattern of proliferation of smooth-muscle cells as compared with other individuals, Johnson and coworkers (91) obtained airway smooth muscles from 12 patients with asthma and 10 patients with pulmonary disorders other than asthma. On being cultured over seven days, the asthmatic cells proliferated at a faster pace and in greater number as compared with the nonasthmatic cells. On the first day, the amount of tritiated thymidine incorporated into cells was 3.2 times greater in the asthmatic cells as compared with the nonasthmatic cells. On flow cytometric analysis of DNA content, the proportion of cells in the G₂ + M phase was about twice as high in the asthmatic cells. The authors conclude that airway smooth-muscle cells of patients with asthma show greater proliferation when cultured as compared with cells from patients with other diseases.

Review article In a pulmonary perspective, Fahy and O'Byrne (108) advocate that the term "reactive airways disease" be abandoned.

Treatment

Beta-agonists To determine the effect of the long-acting ₂-agonist, salmeterol, on airway inflammation, Calhoun and coworkers (109) did a double-blind crossover trial in 13 patients with allergic asthma controlled by short-acting ₂-agonists on an as-needed basis. Bronchoalveolar lavage was performed at five minutes and at 48 hours after a segmental allergen challenge. Salmeterol improved FEV₁, but it had no effect on the early or late cellular and inflammatory response to allergen challenge, with the exception of a decrease in the release of superoxide and a decrease in the level of interleukin-4 in baseline samples. The authors conclude that salmeterol does not have a positive or negative effect on airway inflammation induced by segmental allergen challenge.

Inhaled glucocorticoids To identify patients with asthma who do not tolerate a reduction in inhaled glucocorticoids, Leuppi and coworkers (113) studied 50 patients taking a median glucocorticoid dose of 1,000 µg daily, in whom they tried to cut the dose by half every 8 weeks. Seven patients decreased the dose to zero, 39 patients suffered an exacerbation, and four dropped out. Predictors of an exacerbation during weaning of glucocorticoids included: hyperresponsiveness to both histamine and mannitol at baseline; hyperresponsiveness to mannitol as the dose was being decreased; and age greater than 40 years. An increase in sputum eosinophils before a failed reduction of glucocorticoids (but not at baseline) also predicted an exacerbation. Symptoms, spirometry and exhaled nitric oxide did not predict exacerbations. The authors conclude that airway hyperresponsiveness and sputum eosinophils help predict which patients will develop an exacerbation of asthma as the dose of inhaled glucocorticoids is decreased.

Glucocorticoids Because damage and denudation of the airway epithelium is a prominent feature of asthma, Dorscheid and coworkers (119) determined whether or not glucocorticoids can cause cell death of airway epithelium. In a culture of primary epithelial cells of the central airway (cell line 1HAEo^-), apoptosis occurred in a time-dependent and concentration- dependent manner with dexamethasone, beclomethasone, budesonide, or triamcinolone. Cell death occurred through disruption of mitochondrial polarity with extrusion of cytochrome c and the subsequent activation of caspase-9, followed by the downstream activation of caspase proteases. Inhibitors of caspase activity blocked the cell death, as did overexpression of the apoptosis regulators Bcl-2 or Bcl-x_L. The authors conclude that glucocorticoids induce apoptotic cell death of airway epithelium, raising the possibility that glucocorticoid therapy may contribute to the shedding and denudation of the airway epithelium in patients with asthma.

Theophylline Because theophylline may have anti-inflammatory actions, Lim and coworkers (120) did a double-blind, crossover study of the effect of a low dose theophylline (250 mg twice daily) on eosinophilic inflammation in 15 patients with mild asthma. Compared with placebo, theophylline (serum level, 6.1 mg per liter) for five weeks produced a 29% decrease in sputum eosinophils, a 50% decrease in eosinophils in bronchoalveolar fluid, and a 34% decrease in eosinophils in airway biopsies. Exhaled nitric oxide and lung function did not change. The authors conclude that a low dose of theophylline decreases eosinophilic inflammation in the airways of patients with asthma but it does not alter exhaled nitric oxide.

Leukotriene inhibitors The cysteinyl leukotrienes exert most of their bronchoconstrictive and proinflammatory effects through activating the cysteinyl leukotriene 1 receptor. Figueroa and coworkers (121) described the distribution of this receptor in the lung and peripheral blood cells of healthy subjects. The receptor was expressed in eosinophils, monocyte/macrophages, B lymphocytes, and CD34⁺ granulocytic precursor cells. In the lung, the receptor was found in smooth-muscle cells and in macrophages. The authors conclude that the expression of the cysteinyl leukotriene 1 receptor in the lung is consistent with the actions of receptor antagonists against bronchoconstriction and inflammation.

Combination regimens To compare the efficacy of a combination product, fluticasone proprionate (100 µg) and salmeterol (50 µg), inhaled twice daily through a Diskus device, with that of a leukotriene receptor antagonist, montelukast (10 mg orally once daily), Calhoun and coworkers (122) did a double-blind study in 423 patients with asthma who were symptomatic while receiving short-acting ₂-agonists. The study lasted 12 weeks. Compared with the montelukast group, the patients receiving the combination of fluticasone and salmeterol had greater increases in morning FEV₁ (0.54 versus 0.27 liter), morning PEF (90 versus 34 liters per minute), evening PEF (70 versus 31 liters per minute), percentage of symptom-free days (49 versus 22%), percentage of rescue-free days (5 versus 26%), and percentage of nights without awakenings (23 versus 16%). Compared with montelukast, the fluticasone-salmeterol combination produced decreases in asthma symptom score (1 versus 0.6), use of albuterol for rescue (3.3 versus 1.9 puffs per day), and number of exacerbations (0 versus 11). The authors conclude that the combination of fluticasone and salmeterol into a single device was more effective than montelukast in terms of pulmonary function, asthma symptoms, use of albuterol for rescue, number of asthmatic exacerbations, and patient satisfaction score.

Immunotherapy The role of immunotherapy in the management of allergic asthma is debated by Bousquet (126) and Adkinson (127), with rebuttals from each (128, 129).

Management plans and education The use of asthma management plans is becoming popular, but their impact is unknown. To address this issue, Abramson and coworkers (130) identified 89 patients who died from asthma and 322 control subjects who had presented with acute severe asthma. A questionnaire was administered to 222 control subjects and to 51 of the next-of-kin of the patients who had died from asthma. Smoking, drinking, and family problems were more likely among patients dying of asthma than among the controls. The risk of death from asthma was reduced by use of a peak flow meter in the preceding year (odds ratio, 0.65), a written action plan (odds ratio, 0.29), and use of oral glucocorticoids during preceding month (odds ratio, 0.71). The risk of death was increased by use of a nebulizer for symptomatic relief in preceding month (odds ratio, 4.3). The blood level of albuterol was 2.5 times higher in 35 patients dying of asthma as compared with 229 control subjects. The authors conclude that the more widespread use of a written management plan, closer supervision of patients, and decreased reliance on -agonists should reduce asthma mortality. An editorial commentary by Beasley and Crane (131) accompanies this article.

New agents Exposure to mycobacteria appears to suppress the development of asthma because mycobacteria induces a strong type 1 (Th1) helper T cell response that may downregulate the Th2-driven allergic processes in asthma. In 43 patients with moderately severe asthma, Shirtcliffe and coworkers (134) did a randomized trial of placebo versus two vaccines derived from Mycobacterium vaccae, a nonpathogenic mycobacterium. The three groups had equivalent responses in eosinophils, levels of IgE, T cell proliferative and cytokine responses, and markers of asthma severity. The authors conclude that a low dose vaccine derived from Mycobacterium vaccae has no effect on the severity of asthma.

Specific Clinical Scenarios

Nocturnal asthma The alternative form of the glucocorticoid receptor, GR, is believed to compete with and to antagonize the effects of the active receptor, GR. To determine the role of the alternative receptor in nocturnal asthma, Kraft and colleagues (141) did bronchoalveolar lavages at 4:00 P.M. and 4:00 A.M. in 10 patients with nocturnal asthma (24% fall in FEV₁) and in 7 patients with non-nocturnal asthma (5% fall in FEV₁). Dexamethasone suppressed the in vitro proliferation of lymphocytes similarly at 4:00 A.M. and 4:00 P.M. in the two groups. Dexamethasone caused less suppression of interleukin-8 and tumor necrosis factor- production by macrophages at 4:00 A.M. in the patients with nocturnal asthma; suppression was equal at both times in the patients with non-nocturnal asthma. Expression of glucocorticoid  receptor and interleukin-13 were increased at night, but only in the patients with nocturnal asthma; the addition of antibodies to interleukin-13 decreased the expression of the glucocorticoid receptor  by the macrophages. The authors conclude that the airway macrophages of patients with nocturnal asthma exhibit a circadian variation in steroid responsiveness that is associated with increased expression of the inhibitory glucocorticoid receptor and that this altered responsiveness is modulated by interleukin-13.

Acute severe and fatal asthma O'Sullivan and coworkers (143) investigated the association of CD8+ T lymphocytes and viral infection with fatal asthma. Seven patients with fatal asthma had 11 times more CD8+ cells expressing the activation marker CD25 as compared with seven individuals without lung disease. Seven patients with asthma who died of unrelated causes had 3.6 times more CD8+ cells expressing the activation marker CD25. Expression of perforin, which mediates destruction of virus-infected cells, was five times higher in the patients with fatal asthma as compared with the control subjects. The ratio of interferon- to interleukin-4 in the patients with fatal asthma was less than half of the ratio found in the control subjects. Viral genome for rhinovirus was found in the lung tissue of three of the seven patients with fatal asthma, and two of these patients also had detectable respiratory syncytial virus. Viral genome for respiratory syncytial virus was detected in five of the seven patients with nonfatal asthma, but in none of the control subjects. The authors conclude that patients with fatal asthma have an aberrant population of activated cytotoxic CD8+ T cells but a similar rate of viral infection as compared with patients with nonfatal asthma.

Severity and chronicity To determine the prevalence of persistent airflow limitation (defined as post bronchodilator FEV₁ or FEV₁/VC of less than 75% of predicted), ten Brinke (145) studied 132 patients with severe asthma. All patients had experienced an exacerbation of asthma treated with oral glucocorticoid in the preceding year or were taking prednisone. Persistent airflow limitation was found in 49% of the patients; these patients had a post bronchodilator FEV₁ of 58% of predicted, as compared with 96% of predicted in the remaining patients. On multiple logistic regression analysis, persistent airflow limitation was associated with sputum eosinophils of at least 2% (odds ratio, 7.7), PC₂₀ for histamine of 1 mg per ml or less (odds ratio, 3.9), and onset of asthma at 18 years or older (odds ratio, 3.3). Only sputum eosinophilia was independently associated with the persistent airflow limitation. The authors conclude that persistent airflow limitation is common in patients with severe asthma and is most strongly associated with sputum eosinophilia.

Gastroesophageal reflux To determine the prevalence of upper respiratory symptoms in patients with symptomatic gastroesophageal reflux, Theodoropoulos and coworkers (146) distributed a questionnaire to 74 subjects with heartburn and monitored their esophageal pH for 24 hours. The 52 subjects with reflux disease had 80% higher scores for upper respiratory symptoms as compared with the 22 subjects with normal esophageal pH or a group of 74 healthy subjects. Scores on the questionnaire were related to the number of reflux episodes per 24 hours (r = 0.47). Laryngeal symptoms for five or more days per month were reported by 75% of the subjects with upper gastroesophageal reflux, by 68% of subjects with lower reflux, by 36% of subjects with normal esophageal pH, and by 9% of healthy subjects. Nasal symptoms for five or more days per month were reported by 69% of the subjects with upper reflux, 50% of subjects with lower reflux, 31% of subjects with normal pH, and 14% of healthy subjects. The authors conclude that upper respiratory symptoms are frequent among subjects with symptomatic gastroesophageal reflux diagnosed by esophageal pH monitoring.

Pregnancy Babies born to women with asthma have a low birth weight. To determine whether or not vascular abnormalities in the placenta might contribute to impaired fetal growth, Clifton and coworkers (147) studied 83 pregnant women with asthma and 28 women without asthma. At 18 weeks gestation, women with moderate or severe asthma had lower velocities of blood flow through the umbilical artery, as measured by Doppler ultrasound; flow velocity was also decreased in women using inhaled glucocorticoids. At 30 weeks gestation, flow velocity did not differ between women with asthma and women without asthma. After delivery, the placentae of women with moderate or severe asthma showed less vascular dilation in response to corticotrophin-releasing hormonea potent vasodilator that acts via the nitric oxide pathway. The vasoconstrictor responses to prostaglandin F₂ and potassium chloride were also reduced in the placentae of women with moderate or severe asthma. The authors conclude that vascular function of the placenta is abnormal in women with asthma and speculate that a decrease in fetal blood flow may contribute to the low birth weight of infants born to mothers with asthma.

Dyspnea Patients with asthma who have a poor perception of airway narrowing are predisposed to undertreatment. To determine the interaction between inhaled glucocorticoids and ₂-agonists on the ability to perceive airway narrowing, Bijl-Hofland and coworkers (148) did a 12-week double-blind study of albuterol, formoterol or placebo in 64 patients with asthma (FEV₁, 87% of predicted). One year later, the same treatments were repeated in combination with beclomethasone diproprionate. The ability to perceive a 20% decrease in FEV₁ induced by histamine was assessed every 4 weeks. The slope of sensory perception (Borg) versus the percentage fall in FEV₁ was 0.0074 in the patients treated with the long-acting ₂-agonist, formoterol, and the slope increased to 0.0065 when the inhaled glucocorticoid was added. Enhanced perception was not seen in patients treated with a short-acting ₂-agonist. The authors conclude that the addition of inhaled glucocorticoids in patients receiving a long-acting ₂-agonist enhances the ability of patients with asthma to detect narrowing of the airway induced by histamine.

Gas exchange Using the multiple inert gas elimination technique, Echazarreta and coworkers (149) studied gas exchange in 13 patients with mild asthma who inhaled leukotriene D₄. The bronchial challenge produced a decrease in FEV₁ of 32% and a decrease in PO₂ from 93 to 68 mm Hg. The hypoxemia was accompanied by worsening of the ventilation-perfusion ratio, as reflected by a 59% increase in the dispersions of pulmonary blood flow and a 65% increase in the dispersions of alveolar ventilation. Intrapulmonary shunt or dead space did not change. Although the changes in gas exchange paralleled the changes in lung mechanics, the two sets of functions did not directly correlate with each other. The authors conclude that inhaled leukotriene induces marked alterations in pulmonary gas exchange in patients with asthma.

Quality of life To determine how traditional measures of asthma severity (based on symptoms, lung function, and use of rescue medications) relate to a measure of health-related quality of life, Moy and coworkers (150) analyzed data from two clinical trials. One trial was done in patients with mild asthma, and the second trial was done in patients with moderate-to-severe asthma. Lung function did not predict the quality of life, measured by a questionnaire developed by Juniper, at any level of asthma severity, whereas the intensity of dyspnea predicted the quality of life at all levels of severity. The use of rescue -agonists independently predicted the quality of life in the patients with mild asthma, but not in patients with moderate-to-severe asthma. As asthma status improved from moderate-to-severe to mild-to-moderate, the use of rescue -agonists predicted the quality of life. The authors conclude that conventional clinical variables (symptoms, lung function, rescue medication) predict the quality of life differently depending on the level of asthma severity.

Psychopathology To determine whether or not psychopathology in patients with severe asthma predisposes them to increased use of health care resources, ten Brinke and colleagues (151) studied 98 patients with difficult-to-control asthma. All patients had required at least one course of high-dose oral glucocorticoids in the preceding year or were receiving maintenance glucocorticoid therapy. Psychopathology was identified as a score of at least 6 on a 12-point questionnaire. Of the 98 patients, 21% scored 6 or higher (median 8) and the remainder had a median score of 0. The two groups did not differ in measures of demography or lung function. Patients with psychopathology had more frequent visits to a general practitioner (odds ratio, 5.9), emergency visits (odds ratio, 5.3), exacerbations (odds ratio, 12.4), hospital admissions (odds ratio 4.8), and need for mechanical ventilation (odds ratio, 6.9) as compared with patients without psychopathology. The authors conclude that the morbidity and costs of severe asthma may be related to psychological dysfunction rather than to asthma per se.

Occupational Asthma

Laboratory animal workers To determine the incidence and host determinants of occupational asthma in laboratory animal workers, Gautrin and coworkers (152) prospectively followed 417 apprentices over 8 to 44 months. Probable occupational asthma developed in 28 apprentices, giving an incidence of 2.7% (28 per 1,043 person-years). The risk of probable occupational asthma was associated with baseline skin test reactivity to pets (relative risk, 4.1) and bronchial hyperresponsiveness (relative risk, 2.5); a lower FEV₁ had an apparent protective effect (relative risk, 0.58). The authors conclude that the incidence of probable occupational asthma is high among apprentices exposed to laboratory animals, and that pre-existing airway hyperresponsiveness and sensitization to pets pose an increased risk.

Prevalence and severity Because the fraction of asthma attributable to occupation is poorly defined, Karjalainen and coworkers (153) studied the entire population of 25- to 59-year-old individuals employed in Finland between 1986 to 1998. There were 49,575 incident cases of asthma. The attributable fraction of asthma related to occupation was 29% in men and 17% in women. The risk was increased particularly in agricultural, manufacturing, and service occupations. The authors conclude that occupational factors play a larger role in the onset of asthma among adults than is generally recognized.

	ALLERGIC RHINITIS AND NASAL DISORDERS

TOP CONTENTS ASTHMA AND AIRWAY BIOLOGY ALLERGIC RHINITIS AND NASAL... REFERENCES

Nasal Function

A major function of the nose is to warm and humidify air. In four groups of subjects, Assanasen and coworkers (155) delivered cold, dry air to the nose and measured the temperature and humidity of air as it entered and left the nasal cavity. The conditioning capacity of the nose was measured in terms of the total water gradient. Compared with 15 healthy subjects, the water gradient was decreased by 18% in 15 patients with seasonal allergic rhinitis outside of the allergy season and by 18% in 15 patients with asthma. The gradient was normal in 15 patients with perennial allergic rhinitis who had chronic nasal inflammation. In patients with asthma, the water gradient was inversely correlated with a score of asthma severity (r = 0.77). The authors conclude that the nose of patients with asthma and of patients with seasonal allergic rhinitis has a decreased capacity to condition cold, dry air.

Inflammation and Hyperreactivity

In 10 patients with allergic rhinitis, Terada and coworkers (156) investigated the role of eotaxin (a potent eosinophil chemoattractant that belongs to the class of C-C chemokines) in causing eosinophil inflammation. Allergen challenge produced parallel increases in eosinophil counts, levels of eosinophil protein X, and eotaxin in nasal lavage fluid. The level of eotaxin was correlated with the eosinophil count (r = 0.73) and with the level of eosinophil protein X (r = 0.67). Among eosinophil chemoattractants, eotaxin had the most potent effect on the migration of eosinophils through endothelial cells taken from microvessels of the nose. This migration was blocked by a monoclonal antibody directed against the eotaxin receptor, CCR-3. The authors conclude that eotaxin plays an important role in mediating eosinophil-dependent inflammation in the nasal mucosa and that blocking eotaxin or its receptor might be effective in the treatment of allergic rhinitis.

To determine the role of mast cells and basophils in allergic inflammation, Braunstahl and coworkers (157) studied eight healthy subjects and eight patients with allergic rhinitis who did not have asthma. Segmental bronchoprovocation delivered through a bronchoscope produced an increase in basophils in the bronchial and nasal mucosa, a decrease in mast cells in the nasal mucosa (as reflected by decreased staining for tryptase and chymase), a decrease in the number of basophils in the blood, and an increase in serum interleukin-5 in the patients with allergic rhinitis. No changes were seen in the control subjects. The authors conclude that segmental bronchoprovocation reduces the number of mast cells in the nose of nonasthmatic patients with allergic rhinitis as a result of degranulation, and that it also causes an influx of basophils from the bloodstream into the nasal and bronchial mucosae. An editorial commentary by Togias (158) accompanies this article.

To determine the influence of atopy on the inflammatory response to an upper respiratory infection, Corne and colleagues (159) did nasal lavage in 23 atopic and 21 nonatopic subjects who caught the common cold. During the acute phase, both groups had increased levels of interleukin-1, interleukin-6, interleukin-8, tumor necrosis factor-, RANTES (regulated on activation, normal T cell expressed and secreted), secretory intercellular adhesion molecule 1, myeloperoxidase, eosinophilic cationic protein, interleukin-10, and interferon-. The atopic subjects had higher levels of histamine and lower levels of interleukin-10. At convalescence, the levels of interleukin-1, interleukin-6, secretory intercellular adhesion molecule 1, eosinophilic cationic protein, RANTES, and albumin were higher in the atopic subjects. An upper respiratory virus was detected in 61% of the total group during the acute stage and in 4% during convalescence. The authors conclude that viral-induced inflammatory changes in the nose last longer in atopic subjects as compared with nonatopic subjects, and that the longer duration may be secondary to decreased production of the anti-inflammatory cytokine, interleukin-10.

The CD80 and CD86 stimulatory molecules appear to vary in their ability to differentiate and maintain type 1 (Th1) and type 2 (Th2) helper T cells. To study the role of CD80 and CD86 in the initiation phase and the exacerbation phase of allergic rhinitis, Okano and coworkers (160) studied BALB/c mice in which they induced allergic rhinitis by the repeated administration of Schistosoma mansoni egg antigen. Intranasal challenge with the antigen elicited nasal eosinophilia and a strong Th2 response that included the production of specific IgE, interleukin-4, and interleukin-5 by nasal lymphocytes. The induction phase of these manifestations was blocked by an antibody against CD80, but not by an antibody against CD86. During the effector phase, the simultaneous blockade of both CD80 and CD86 partially inhibited the nasal eosinophilia and the production of IgE and IgG₁, whereas blockade of either CD80 or CD86 failed to inhibit these responses. The authors conclude that CD80 contributes to the induction phase in a mouse model of allergic rhinitis, and that both CD80 and CD86 stimulatory molecules are involved in the exacerbation phase of the disorder.

Nasal Polyposis

Patients with nasal polyposis and asymptomatic bronchial hyperresponsiveness display eosinophilic bronchial inflammation similar to that in patients with asthma, whereas patients with nasal polyposis who do not have bronchial hyperresponsiveness do not display this type of inflammation. To better understand this phenomenon, Lamblin and coworkers (161) studied three groups of patients with nasal polyposis: 11 patients without bronchial hyperreactivity, eight with asymptomatic hyperreactivity, and nine with coexistent asthma. The patients with coexistent asthma had higher numbers of cells in the bronchial submucosa that were positive for interleukin-5 protein, interleukin-5 messenger RNA, and eotaxin, as compared with the other two groups. The patients with asymptomatic hyperreactivity had more cells positive for interleukin-5 protein as compared with the patients without hyperreactivity, whereas the two groups had similar numbers of cells positive for interleukin-5 messenger RNA and eotaxin. Only the patients with asthma had increased levels of interleukin-5 in bronchial lavage. The authors conclude that interleukin-5 contributes to the bronchial hyperreactivity, whether symptomatic or asymptomatic, that occurs in some patients with nasal polyposis.

Nitric oxide plays a major role in host defenses through its bacteriostatic action, and the concentration of nitric oxide is especially high in the paranasal sinuses (5-20 parts per billion) because of poor air circulation. Superoxide ion produced by eosinophils of nasal polyps can inactivate nitric oxide, and vice versa. To evaluate this interaction, Pasto and coworkers (162) measured superoxide production in fragments of polyps taken from 24 patients. Superoxide production varied widely among the patients, and was related to eosinophilic infiltration (r = 0.67). A nitric oxide donor, DETANONOate, achieved a concentration of nitric oxide that was equivalent to that in the normal paranasal sinuses and the donor inhibited the production of superoxide anion in a dose-dependent fashion. The authors conclude that the concentration of nitric oxide in the paranasal sinuses is within a range that suppresses the production of superoxide anion by phagocytes in nasal polyps.

	Footnotes

Correspondence and requests for reprints should be addressed to Martin J. Tobin, M.D., Division of Pulmonary and Critical Care Medicine, Hines Veterans Affairs Hospital, Route 111N., Hines, IL 60141. E-mail: mtobin2{at}lumc.edu

Acknowledgments: Supported by a Merit Review grant from the Veterans Affairs Research Service.

	References

TOP CONTENTS ASTHMA AND AIRWAY BIOLOGY ALLERGIC RHINITIS AND NASAL... REFERENCES

1. Hakonarson H, Bjornsdottir US, Ostermann E, Arnason T, Adalsteinsdottir AE, Halapi E, Shkolny D, Kristjansson K, Gudnadottir SA, Frigge ML, et al . Allelic frequencies and patterns of single-nucleotide polymorphisms in candidate genes for asthma and atopy in Iceland. Am J Respir Crit Care Med 2001; 164: 2036-2044 [Abstract/Free Full Text].

2. Weiss ST. Association studies in asthma genetics. Am J Respir Crit Care Med 2001; 164: 2014-2015 [Free Full Text].

3. Koppelman GH, Reijmerink NE, Colin SO, Howard TD, Whittaker PA, Meyers DA, Postma DS, Bleecker ER. Association of a promoter polymorphism of the CD14 gene and atopy. Am J Respir Crit Care Med 2001; 163: 965-969 [Abstract/Free Full Text].

4. Wang Z, Chen C, Niu T, Wu D, Yang J, Wang B, Fang Z, Yandava CN, Drazen JM, Weiss ST, et al . Association of asthma with ₂-adrenergic receptor gene polymorphism and cigarette smoking. Am J Respir Crit Care Med 2001; 163: 1404-1409 [Abstract/Free Full Text].

5. Chen Y, Zhao YH, Wu R. In silico cloning of mouse Muc5b gene and upregulation of its expression in mouse asthma model. Am J Respir Crit Care Med 2001; 164: 1059-1066 [Abstract/Free Full Text].

6. Beckett WS, Jacobs DR Jr,, Yu X, Iribarren C, Williams OD. Asthma is associated with weight gain in females but not males, independent of physical activity. Am J Respir Crit Care Med 2001; 164: 2045-2050 [Abstract/Free Full Text].

7. Celedon JC, Palmer LJ, Litonjua AA, Weiss ST, Wang B, Fang Z, Xu X. Body mass index and asthma in adults in families of subjects with asthma in Anqing, China. Am J Respir Crit Care Med 2001; 164: 1835-1840 [Abstract/Free Full Text].

8. Leynaert B, Neukirch C, Jarvis D, Chinn S, Burney P, Neukirch F. Does living on a farm during childhood protect against asthma, allergic rhinitis, and atopy in adulthood? Am J Respir Crit Care Med 2001; 164: 1829-1834 [Abstract/Free Full Text].

9. Venn AJ, Yemaneberhan H, Bekele Z, Lewis SA, Parry E, Britton J. Increased risk of allergy associated with the use of kerosene fuel in the home. Am J Respir Crit Care Med 2001; 164: 1660-1664 [Abstract/Free Full Text].

10. Celedon JC, Palmer LJ, Weiss ST, Wang B, Fang Z, Xu X. Asthma, rhinitis, and skin test reactivity to aeroallergens in families of asthmatic subjects in Anqing, China. Am J Respir Crit Care Med 2001; 163: 1108-1112 [Abstract/Free Full Text].

11. Dharmage S, Bailey M, Raven J, Mitakakis T, Cheng A, Guest D, Rolland J, Forbes A, Thien F, Abramson M, et al . Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure. Am J Respir Crit Care Med 2001; 164: 65-71 [Abstract/Free Full Text].

12. Basagana X, Sunyer J, Zock JP, Kogevinas M, Urrutia I, Maldonado JA, Almar E, Payo F, Anto JM. Incidence of asthma and its determinants among adults in Spain. Am J Respir Crit Care Med 2001; 164: 1133-1137 [Abstract/Free Full Text].

13. Shaheen SO, Sterne JA, Thompson RL, Songhurst CE, Margetts BM, Burney PG. Dietary antioxidants and asthma in adults. Population-based case-control study. Am J Respir Crit Care Med 2001; 164: 1823-1828 [Abstract/Free Full Text].

14. von Mutius E. The increase in asthma can be ascribed to cleanliness. Am J Respir Crit Care Med 2001; 164: 1106-1107 [Free Full Text].

15. Platts-Mills TA, Woodfolk JA, Sporik RB. The increase in asthma cannot be ascribed to cleanliness. Am J Respir Crit Care Med 2001; 164: 1107-1108 [Free Full Text].

16. von Mutius E. Rebuttal. Am J Respir Crit Care Med 2001; 164: 1108-1109 .

17. Platts-Mills TA, Woodfolk JA, Sporik RB. Rebuttal. Am J Respir Crit Care Med 2001; 164: 1109 [Free Full Text].

18. Duguet A, Iijima H, Eum SY, Hamid Q, Eidelman DH. Eosinophil peroxidase mediates protein nitration in allergic airway inflammation in mice. Am J Respir Crit Care Med 2001; 164: 1119-1126 [Abstract/Free Full Text].

19. Cross CE, van der Vliet A, Eiserich JP. Peroxidases wheezing their way into asthma. Am J Respir Crit Care Med 2001; 164: 1102-1103 [Free Full Text].

20. Lavoie JP, Maghni K, Desnoyers M, Taha R, Martin JG, Hamid QA. Neutrophilic airway inflammation in horses with heaves is characterized by a Th2-type cytokine profile. Am J Respir Crit Care Med 2001; 164: 1410-1413 [Abstract/Free Full Text].

21. Wollin L, Uhlig S, Nusing R, Wendel A. Granulocyte-macrophage colony-stimulating factor amplifies lipopolysaccharide-induced bronchoconstriction by a neutrophil- and cyclooxygenase 2-dependent mechanism. Am J Respir Crit Care Med 2001; 163: 443-450 [Abstract/Free Full Text].

22. Maus U, Huwe J, Maus R, Seeger W, Lohmeyer J. Alveolar JE/MCP-1 and endotoxin synergize to provoke lung cytokine upregulation, sequential neutrophil and monocyte influx, and vascular leakage in mice. Am J Respir Crit Care Med 2001; 164: 406-411 [Abstract/Free Full Text].

23. Suto A, Nakajima H, Kagami SI, Suzuki K, Saito Y, Iwamoto I. Role of CD4⁺ CD25⁺ regulatory T cells in T helper 2 cell-mediated allergic inflammation in the airways. Am J Respir Crit Care Med 2001; 164: 680-687 [Abstract/Free Full Text].

24. Schmidlin F, Amadesi S, Vidil R, Trevisani M, Martinet N, Caughey G, Tognetto M, Cavallesco G, Mapp C, Geppetti P, et al . Expression and function of proteinase-activated receptor 2 in human bronchial smooth muscle. Am J Respir Crit Care Med 2001; 164: 1276-1281 [Abstract/Free Full Text].

25. Ezeamuzie CI, Sukumaran J, Philips E. Effect of wortmannin on human eosinophil responses in vitro and on bronchial inflammation and airway hyperresponsiveness in Guinea pigs in vivo. Am J Respir Crit Care Med 2001; 164: 1633-1639 [Abstract/Free Full Text].

26. ten Brinke A, de Lange C, Zwinderman AH, Rabe KF, Sterk PJ, Bel EH. Sputum induction in severe asthma by a standardized protocol. Predictors of excessive bronchoconstriction. Am J Respir Crit Care Med 2001; 164: 749-753 [Abstract/Free Full Text].

27. Fahy JV, Boushey HA, Lazarus SC, Mauger EA, Cherniack RM, Chinchilli VM, Craig TJ, Drazen JM, Ford JG, Fish JE, et al . Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study. Am J Respir Crit Care Med 2001; 163: 1470-1475 [Abstract/Free Full Text].

28. Alexis NE, Hu SC, Zeman K, Alter T, Bennett WD. Induced sputum derives from the central airways. Confirmation using a radiolabeled aerosol bolus delivery technique. Am J Respir Crit Care Med 2001; 164: 1964-1970 [Abstract/Free Full Text].

29. Tamaoki J, Kondo M, Kuroda H, Aoshiba K, Takeyama K, Nakata J, Nagai A. Validity and safety of sputum induction by inhaled uridine 5'- triphosphate. Am J Respir Crit Care Med 2001; 164: 378-381 [Abstract/Free Full Text].

30. Seymour ML, Rak S, Åberg D, Riise GC, Penrose JF, Kanaoka Y, Frank AK, Holgate ST, Sampson AP. Leukotriene and prostanoid pathway enzymes in bronchial biopsies of seasonal allergic asthmatics. Am J Respir Crit Care Med 2001; 164: 2051-2056 [Abstract/Free Full Text].

31. Van Den Toorn LM, Overbeek SE, De Jongste JC, Leman K, Hoogsteden HC, Prins JB. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2001; 164: 2107-2113 [Abstract/Free Full Text].

32. Benayoun L, Letuve S, Druilhe A, Boczkowski J, Dombret MC, Mechighel P, Megret J, Leseche G, Aubier M, Pretolani M. Regulation of peroxisome proliferator-activated receptor gamma expression in human asthmatic airways: relationship with proliferation, apoptosis, and airway remodeling. Am J Respir Crit Care Med 2001; 164: 1487-1494 [Abstract/Free Full Text].

33. Lilly CM, Nakamura H, Belostotsky OI, Haley KJ, Garcia-Zepeda EA, Luster AD, Israel E. Eotaxin expression after segmental allergen challenge in subjects with atopic asthma. Am J Respir Crit Care Med 2001; 163: 1669-1675 [Abstract/Free Full Text].

34. Krug N, Tschernig T, Erpenbeck VJ, Hohlfeld JM, Kohl J. Complement factors c3a and c5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma. Am J Respir Crit Care Med 2001; 164: 1841-1843 [Abstract/Free Full Text].

35. Ordonez CL, Khashayar R, Wong HH, Ferrando R, Wu R, Hyde DM, Hotchkiss JA, Zhang Y, Novikov A, Dolganov G, et al . Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am J Respir Crit Care Med 2001; 163: 517-523 [Abstract/Free Full Text].

36. Takeyama K, Fahy JV, Nadel JA. Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am J Respir Crit Care Med 2001; 163: 511-516 [Abstract/Free Full Text].

37. Seah GT, Gao PS, Hopkin JM, Rook GA. Interleukin-4 and its alternatively spliced variant (IL-42) in patients with atopic asthma. Am J Respir Crit Care Med 2001; 164: 1016-1018 [Abstract/Free Full Text].

38. Stirling RG, van Rensen EL, Barnes PJ, Chung KF. Interleukin-5 induces CD34(+) eosinophil progenitor mobilization and eosinophil CCR3 expression in asthma. Am J Respir Crit Care Med 2001; 164: 1403-1409 [Abstract/Free Full Text].

39. Oshikawa K, Kuroiwa K, Tago K, Iwahana H, Yanagisawa K, Ohno S, Tominaga SI, Sugiyama Y. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am J Respir Crit Care Med 2001; 164: 277-281 [Abstract/Free Full Text].

40. Kurashima K, Fujimura M, Myou S, Kasahara K, Tachibana H, Amemiya N, Ishiura Y, Onai N, Matsushima K, Nakao S. Effects of oral steroids on blood cxcr3+ and ccr4+ t cells in patients with bronchial asthma. Am J Respir Crit Care Med 2001; 164: 754-758 [Abstract/Free Full Text].

41. Jones SL, Kittelson J, Cowan JO, Flannery EM, Hancox RJ, McLachlan CR, Taylor DR. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001; 164: 738-743 [Abstract/Free Full Text].

42. Kharitonov SA, Barnes PJ. Does exhaled nitric oxide reflect asthma control? Yes, it does! Am J Respir Crit Care Med 2001; 164: 727-728 [Free Full Text].

43. Lehtimaki L, Kankaanranta H, Saarelainen S, Hahtola P, Jarvenpaa R, Koivula T, Turjanmaa V, Moilanen E. Extended exhaled NO measurement differentiates between alveolar and bronchial inflammation. Am J Respir Crit Care Med 2001; 163: 1557-1561 [Abstract/Free Full Text].

44. Weicker S, Karachi TA, Scott JA, McCormack DG, Mehta S. Noninvasive measurement of exhaled nitric oxide in a spontaneously breathing mouse. Am J Respir Crit Care Med 2001; 163: 1113-1116 [Abstract/Free Full Text].

45. Khatri SB, Ozkan M, McCarthy K, Laskowski D, Hammel J, Dweik RA, Erzurum SC. Alterations in exhaled gas profile during allergen-induced asthmatic response. Am J Respir Crit Care Med 2001; 164: 1844-1848 [Abstract/Free Full Text].

46. Corradi M, Montuschi P, Donnelly LE, Pesci A, Kharitonov SA, Barnes PJ. Increased nitrosothiols in exhaled breath condensate in inflammatory airway diseases. Am J Respir Crit Care Med 2001; 163: 854-858 [Abstract/Free Full Text].

47. Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med 2001; 163: 1693-1722 [Free Full Text].

48. Mutlu GM, Garey KW, Robbins RA, Danziger LH, Rubinstein I. Collection and analysis of exhaled breath condensate in humans. Am J Respir Crit Care Med 2001; 164: 731-737 [Free Full Text].

49. D'Ambrosio D, Mariani M, Panina-Bordignon P, Sinigaglia F. Chemokines and their receptors guiding T lymphocyte recruitment in lung inflammation. Am J Respir Crit Care Med 2001; 164: 1266-1275 [Free Full Text].

50. Salvi SS, Babu KS, Holgate ST. Is asthma really due to a polarized T cell response toward a helper T cell type 2 phenotype? Am J Respir Crit Care Med 2001; 164: 1343-1346 [Free Full Text].

51. Samb A, Pretolani M, Dinh-Xuan AT, Ouksel H, Callebert J, Lisdero C, Aubier M, Boczkowski J. Decreased pulmonary and tracheal smooth muscle expression and activity of type 1 nitric oxide synthase (nNOS) after ovalbumin immunization and multiple aerosol challenge in guinea pigs. Am J Respir Crit Care Med 2001; 164: 149-154 [Abstract/Free Full Text].

52. Iijima H, Duguet A, Eum SY, Hamid Q, Eidelman DH. Nitric oxide and protein nitration are eosinophil dependent in allergen-challenged mice. Am J Respir Crit Care Med 2001; 163: 1233-1240 [Abstract/Free Full Text].

53. Silverman ES, De Sanctis GT, Boyce J, Maclean JA, Jiao A, Green FH, Grasemann H, Faunce D, Fitzmaurice G, Shi GP, et al . The transcription factor early growth-response factor 1 modulates tumor necrosis factor-, immunoglobulin E, and airway responsiveness in mice. Am J Respir Crit Care Med 2001; 163: 778-785 [Abstract/Free Full Text].

54. Ramos-Barbon D, Suzuki M, Taha R, Molet S, Issekutz TB, Hamid Q, Martin JG. Effect of ₄-integrin blockade on CD4+ cell-driven late airway responses in the rat. Am J Respir Crit Care Med 2001; 163: 101-108 [Abstract/Free Full Text].

55. Kanehiro A, Ikemura T, Makela MJ, Lahn M, Joetham A, Dakhama A, Gelfand EW. Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. Am J Respir Crit Care Med 2001; 163: 173-184 [Abstract/Free Full Text].

56. Vanacker NJ, Palmans E, Kips JC, Pauwels RA. Fluticasone inhibits but does not reverse allergen-induced structural airway changes. Am J Respir Crit Care Med 2001; 163: 674-679 [Abstract/Free Full Text].

57. Tomkinson A, Cieslewicz G, Duez C, Larson KA, Lee JJ, Gelfand EW. Temporal association between airway hyperresponsiveness and airway eosinophilia in ovalbumin-sensitized mice. Am J Respir Crit Care Med 2001; 163: 721-730 [Abstract/Free Full Text].

58. Wohlsen A, Uhlig S, Martin C. Immediate allergic response in small airways. Am J Respir Crit Care Med 2001; 163: 1462-1469 [Abstract/Free Full Text].

59. Shimizu T, Hirano H, Shimizu S, Kishioka C, Sakakura Y, Majima Y. Differential properties of mucous glycoproteins in rat nasal epithelium. A comparison between allergic inflammation and lipopolysaccharide stimulation. Am J Respir Crit Care Med 2001; 164: 1077-1082 [Abstract/Free Full Text].

60. Kanehiro A, Lahn M, Makela MJ, Dakhama A, Fujita M, Joetham A, Mason RJ, Born W, Gelfand EW. Tumor necrosis factor- negatively regulates airway hyperresponsiveness through T cells. Am J Respir Crit Care Med 2001; 164: 2229-2238 [Abstract/Free Full Text].

61. Evans CM, Jacoby DB, Fryer AD. Effects of dexamethasone on antigen-induced airway eosinophilia and M₂ receptor dysfunction. Am J Respir Crit Care Med 2001; 163: 1484-1492 [Abstract/Free Full Text].

62. Scuri M, Abraham WM, Botvinnikova Y, Forteza R. Hyaluronic acid blocks porcine pancreatic elastase (PPE)-induced bronchoconstriction in sheep. Am J Respir Crit Care Med 2001; 164: 1855-1859 [Abstract/Free Full Text].

63. Uller L, Persson CG, Kallstrom L, Erjefalt JS. Lung tissue eosinophils may be cleared through luminal entry rather than apoptosis. Effects of steroid treatment. Am J Respir Crit Care Med 2001; 164: 1948-1956 [Abstract/Free Full Text].

64. Laporte JC, Moore PE, Baraldo S, Jouvin MH, Church TL, Schwartzman IN, Panettieri RA Jr,, Kinet JP, Shore SA. Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med 2001; 164: 141-148 [Abstract/Free Full Text].

65. Hallsworth MP, Moir LM, Lai D, Hirst SJ. Inhibitors of mitogen-activated protein kinases differentially regulate eosinophil-activating cytokine release from human airway smooth muscle. Am J Respir Crit Care Med 2001; 164: 688-697 [Abstract/Free Full Text].

66. Amrani Y, Moore PE, Hoffman R, Shore SA, Panettieri RA. Interferon- modulates cysteinyl leukotriene receptor-1 expression and function in human airway myocytes. Am J Respir Crit Care Med 2001; 164: 2098-2101 [Abstract/Free Full Text].

67. Accomazzo MR, Rovati GE, Vigano T, Hernandez A, Bonazzi A, Bolla M, Fumagalli F, Viappiani S, Galbiati E, Ravasi S, et al . Leukotriene D₄-induced activation of smooth-muscle cells from human bronchi is partly Ca⁺⁺-independent. Am J Respir Crit Care Med 2001; 163: 266-272 [Abstract/Free Full Text].

68. Pype JL, Xu H, Schuermans M, Dupont LJ, Wuyts W, Mak JC, Barnes PJ, Demedts MG, Verleden GM. Mechanisms of interleukin 1- induced human airway smooth muscle hyporesponsiveness to histamine. Involvement of p38 MAPK NF-B. Am J Respir Crit Care Med 2001; 163: 1010-1017 [Abstract/Free Full Text].

69. Inman MD, Watson RM, Rerecich T, Gauvreau GM, Lutsky BN, Stryszak P, O'Byrne PM. Dose-dependent effects of inhaled mometasone furoate on airway function and inflammation after allergen inhalation challenge. Am J Respir Crit Care Med 2001; 164: 569-574 [Abstract/Free Full Text].

70. Gauvreau GM, Parameswaran KN, Watson RM, O'Byrne PM. Inhaled leukotriene E₄, but not leukotriene D₄, increased airway inflammatory cells in subjects with atopic asthma. Am J Respir Crit Care Med 2001; 164: 1495-1500 [Abstract/Free Full Text].

71. Brannan JD, Anderson SD, Gomes K, King GG, Chan HK, Seale JP. Fexofenadine decreases sensitivity to and montelukast improves recovery from inhaled mannitol. Am J Respir Crit Care Med 2001; 163: 1420-1425 [Abstract/Free Full Text].

72. van den Berge M, Meijer RJ, Kerstjens HA, de Reus DM, Koeter GH, Kauffman HF, Postma DS. PC₂₀ adenosine 5'-monophosphate is more closely associated with airway inflammation in asthma than PC₂₀ methacholine. Am J Respir Crit Care Med 2001; 163: 1546-1550 [Abstract/Free Full Text].

73. Cockcroft DW. How best to measure airway responsiveness. Am J Respir Crit Care Med 2001; 163: 1514-1515 [Free Full Text].

74. van den Berge M, Kerstjens HA, Meijer RJ, de Reus DM, Koeter GH, Kauffman HF, Postma DS. Corticosteroid-induced improvement in the PC₂₀ of adenosine monophosphate is more closely associated with reduction in airway inflammation than improvement in the PC₂₀ of methacholine. Am J Respir Crit Care Med 2001; 164: 1127-1132 [Abstract/Free Full Text].

75. Kotaru C, Coreno A, Skowronski M, Ciufo R, McFadden ER Jr.. Exhaled nitric oxide and thermally induced asthma. Am J Respir Crit Care Med 2001; 163: 383-388 [Abstract/Free Full Text].

76. Davis MS, Freed AN. Repeated hyperventilation causes peripheral airways inflammation, hyperreactivity, and impaired bronchodilation in dogs. Am J Respir Crit Care Med 2001; 164: 785-789 [Abstract/Free Full Text].

77. Degano B, Prevost MC, Berger P, Molimard M, Pontier S, Rami J, Escamilla R. Estradiol decreases the acetylcholine-elicited airway reactivity in ovariectomized rats through an increase in epithelial acetylcholinesterase activity. Am J Respir Crit Care Med 2001; 164: 1849-1854 [Abstract/Free Full Text].

78. Amadesi S, Moreau J, Tognetto M, Springer J, Trevisani M, Naline E, Advenier C, Fisher A, Vinci D, Mapp C, et al . NK1 receptor stimulation causes contraction and inositol phosphate increase in medium-size human isolated bronchi. Am J Respir Crit Care Med 2001; 163: 1206-1211 [Abstract/Free Full Text].

79. Graham RM, Friedman M, Hoyle GW. Sensory nerves promote ozone-induced lung inflammation in mice. Am J Respir Crit Care Med 2001; 164: 307-313 [Abstract/Free Full Text].

80. Kajekar R, Rohde HK, Myers AC. The integrative membrane properties of human bronchial parasympathetic ganglia neurons. Am J Respir Crit Care Med 2001; 164: 1927-1932 [Abstract/Free Full Text].

81. Widdicombe J. The race to explore the pathway to cough: who won the silver medal? Am J Respir Crit Care Med 2001; 164: 729-730 [Free Full Text].

82. Scichilone N, Permutt S, Togias A. The lack of the bronchoprotective and not the bronchodilatory ability of deep inspiration is associated with airway hyperresponsiveness. Am J Respir Crit Care Med 2001; 163: 413-419 [Abstract/Free Full Text].

83. King GG, Moore BJ, Seow CY, Pare PD. Airway narrowing associated with inhibition of deep inspiration during methacholine inhalation in asthmatics. Am J Respir Crit Care Med 2001; 164: 216-218 [Abstract/Free Full Text].

84. Brown RH, Scichilone N, Mudge B, Diemer FB, Permutt S, Togias A. High-resolution computed tomographic evaluation of airway distensibility and the effects of lung inflation on airway caliber in healthy subjects and individuals with asthma. Am J Respir Crit Care Med 2001; 163: 994-1001 [Abstract/Free Full Text].

85. Lutchen KR, Jensen A, Atileh H, Kaczka DW, Israel E, Suki B, Ingenito EP. Airway constriction pattern is a central component of asthma severity: the role of deep inspirations. Am J Respir Crit Care Med 2001; 164: 207-215 [Abstract/Free Full Text].

86. Black PN, Blasi F, Jenkins CR, Scicchitano R, Mills GD, Rubinfeld AR, Ruffin RE, Mullins PR, Dangain J, Cooper BC, et al . Trial of roxithromycin in subjects with asthma and serological evidence of infection with Chlamydia pneumoniae. Am J Respir Crit Care Med 2001; 164: 536-541 [Abstract/Free Full Text].

87. Johnston SL. Is Chlamydia pneumoniae important in asthma? The first controlled trial of therapy leaves the question unanswered. Am J Respir Crit Care Med 2001; 164: 513-514 [Free Full Text].

88. Gencay M, Rudiger JJ, Tamm M, Soler M, Perruchoud AP, Roth M. Increased frequency of Chlamydia pneumoniae antibodies in patients with asthma. Am J Respir Crit Care Med 2001; 163: 1097-1100 [Abstract/Free Full Text].

89. Poirier CD, Inhaber N, Lalonde RG, Ernst P. Prevalence of bronchial hyperresponsiveness among HIV-infected men. Am J Respir Crit Care Med 2001; 164: 542-545 [Abstract/Free Full Text].

90. Duguet A, Wang CG, Gomes R, Ghezzo H, Eidelman DH, Tepper RS. Greater velocity and magnitude of airway narrowing in immature than in mature rabbit lung explants. Am J Respir Crit Care Med 2001; 164: 1728-1733 [Abstract/Free Full Text].

91. Johnson PR, Roth M, Tamm M, Hughes M, Ge Q, King G, Burgess JK, Black JL. Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med 2001; 164: 474-477 [Abstract/Free Full Text].

92. Ward C, Johns DP, Bish R, Pais M, Reid DW, Ingram C, Feltis B, Walters EH. Reduced airway distensibility, fixed airflow limitation, and airway wall remodeling in asthma. Am J Respir Crit Care Med 2001; 164: 1718-1721 [Abstract/Free Full Text].

93. Orsida BE, Ward C, Li X, Bish R, Wilson JW, Thien F, Walters EH. Effect of a long-acting ₂-agonist over three months on airway wall vascular remodeling in asthma. Am J Respir Crit Care Med 2001; 164: 117-121 [Abstract/Free Full Text].

94. Boushey H, Lee TH, Perruchoud AP, Wanner A. Purpose of the conference. Am J Respir Crit Care Med 2001; 164: S25 [Free Full Text].

95. Caughey GH. Chairman's Summary. Mechanisms of airway remodeling. Am J Respir Crit Care Med 2001; 164: S26-S27 [Free Full Text].

96. Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 2001; 164: S28-S38 [Abstract/Free Full Text].

97. McDonald DM. Angiogenesis and remodeling of airway vasculature in chronic inflammation. Am J Respir Crit Care Med 2001; 164: S39-S45 [Abstract/Free Full Text].

98. Fahy JV. Remodeling of the airway epithelium in asthma. Am J Respir Crit Care Med 2001; 164: S46-S51 [Abstract/Free Full Text].

99. Sommerhoff CP. Mast cell tryptases and airway remodeling. Am J Respir Crit Care Med 2001; 164: S52-S58 [Abstract/Free Full Text].

100. Warburton D, Tefft D, Mailleux A, Bellusci S, Thiery JP, Zhao J, Buckley S, Shi W, Driscoll B. Do lung remodeling, repair, and regeneration recapitulate respiratory ontogeny? Am J Respir Crit Care Med 2001; 164: S59-S62 [Abstract/Free Full Text].

101. Black JL, Roth M, Lee J, Carlin S, Johnson PR. Mechanisms of airway remodeling. Airway smooth muscle. Am J Respir Crit Care Med 2001; 164: S63-S66 [Abstract/Free Full Text].

102. Zhu Z, Lee CG, Zheng T, Chupp G, Wang J, Homer RJ, Noble PW, Hamid Q, Elias JA. Airway inflammation and remodeling in asthma. Lessons from interleukin 11 and interleukin 13 transgenic mice. Am J Respir Crit Care Med 2001; 164: S67-S70 [Abstract/Free Full Text].

103. Hogg JC. Role of latent viral infections in chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med 2001; 164: S71-S75 [Abstract/Free Full Text].

104. Miaestrelli P, Saetta M, Mapp CE, Fabbri LM. Remodeling in response to infection and injury. Airway inflammation and hypersecretion of mucus in smoking subjects with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164: S76-S80 [Abstract/Free Full Text].

105. Clement A, Henrion-Caude A, Besnard V, Corroyer S. Role of cyclins in epithelial response to oxidants. Am J Respir Crit Care Med 2001; 164: S81-S84 [Abstract/Free Full Text].

106. Yoneda K, Peck K, Chang MM, Chmiel K, Sher YP, Chen J, Yang PC, Chen Y, Wu R. Development of high-density DNA microarray membrane for profiling smoke- and hydrogen peroxide-induced genes in a human bronchial epithelial cell line. Am J Respir Crit Care Med 2001; 164: S85-S89 [Abstract/Free Full Text].

107. Tschumperlin DJ, Drazen JM. Mechanical stimuli to airway remodeling. Am J Respir Crit Care Med 2001; 164: S90-S94 [Abstract/Free Full Text].

108. Fahy JV, O'Byrne PM. "Reactive airways disease". A lazy term of uncertain meaning that should be abandoned. Am J Respir Crit Care Med 2001; 163: 822-823 [Free Full Text].

109. Calhoun WJ, Hinton KL, Kratzenberg JJ. The effect of salmeterol on markers of airway inflammation following segmental allergen challenge. Am J Respir Crit Care Med 2001; 163: 881-886 [Abstract/Free Full Text].

110. Fishwick D, Bradshaw L, Macdonald C, Beasley R, Gash D, Bengtsson T, Bondesson E, Borgstrom L. Cumulative and single-dose design to assess the bronchodilator effects of ₂-agonists in individuals with asthma. Am J Respir Crit Care Med 2001; 163: 474-477 [Abstract/Free Full Text].

111. Derom E, Borgstrom L, Van Schoor J, Lofroos AB, Pauwels R. Lung deposition and protective effect of terbutaline delivered from pressurized metered-dose inhalers and the Turbuhaler in asthmatic individuals. Am J Respir Crit Care Med 2001; 164: 1398-1402 [Abstract/Free Full Text].

112. Kips JC, Pauwels RA. Long-acting inhaled ₂-agonist therapy in asthma. Am J Respir Crit Care Med 2001; 164: 923-932 [Free Full Text].

113. Leuppi JD, Salome CM, Jenkins CR, Anderson SD, Xuan W, Marks GB, Koskela H, Brannan JD, Freed R, Andersson M, et al . Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001; 163: 406-412 [Abstract/Free Full Text].

114. Gibson PG, Saltos N, Fakes K. Acute anti-inflammatory effects of inhaled budesonide in asthma: a randomized controlled trial. Am J Respir Crit Care Med 2001; 163: 32-36 [Abstract/Free Full Text].

115. Ahrens RC, Teresi ME, Han SH, Donnell D, Vanden Burgt JA, Lux CR. Asthma stability after oral prednisone: a clinical model for comparing inhaled steroid potency. Am J Respir Crit Care Med 2001;164:1138-1145.

116. Grunberg K, Sharon RF, Sont JK, In't Veen JCCM, Van Schadewijk WA, De Klerk EP, Dick CR, Van Krieken JH, Sterk PJ. Rhinovirus-induced airway inflammation in asthma: effect of treatment with inhaled corticosteroids before and during experimental infection. Am J Respir Crit Care Med 2001;164:1816-1822.

117. Vagaggini B, Taccola M, Conti I, Carnevali S, Cianchetti S, Bartoli ML, Bacci E, Dente FL, Di Franco A, Giannini D, et al . Budesonide reduces neutrophilic but not functional airway response to ozone in mild asthmatics. Am J Respir Crit Care Med 2001; 164: 2172-2176 [Abstract/Free Full Text].

118. Pedersen S. Do inhaled corticosteroids inhibit growth in children? Am J Respir Crit Care Med 2001; 164: 521-535 [Free Full Text].

119. Dorscheid DR, Wojcik KR, Sun S, Marroquin B, White SR. Apoptosis of airway epithelial cells induced by corticosteroids. Am J Respir Crit Care Med 2001; 164: 1939-1947 [Abstract/Free Full Text].

120. Lim S, Tomita K, Carramori G, Jatakanon A, Oliver B, Keller A, Adcock I, Chung KF, Barnes PJ. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 2001; 164: 273-276 [Abstract/Free Full Text].

121. Figueroa DJ, Breyer RM, Defoe SK, Kargman S, Daugherty BL, Waldburger K, Liu Q, Clements M, Zeng Z, O'Neill GP, et al . Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am J Respir Crit Care Med 2001; 163: 226-233 [Abstract/Free Full Text].

122. Calhoun WJ, Nelson HS, Nathan RA, Pepsin PJ, Kalberg C, Emmett A, Rickard KA, Dorinsky P. Comparison of fluticasone propionate-salmeterol combination therapy and montelukast in patients who are symptomatic on short-acting ₂-agonists alone. Am J Respir Crit Care Med 2001; 164: 759-763 [Abstract/Free Full Text].

123. O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T, Svensson K, Tattersfield A. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001; 164: 1392-1397 [Abstract/Free Full Text].

124. Kips JC. Treating asthma, or is simple too simple? Am J Respir Crit Care Med 2001; 164: 1336-1338 [Free Full Text].

125. Wilson SJ, Wallin A, Della-Cioppa G, Sandstrom T, Holgate ST. Effects of budesonide and formoterol on NF-B, adhesion molecules, and cytokines in asthma. Am J Respir Crit Care Med 2001; 164: 1047-1052 [Abstract/Free Full Text].

126. Bousquet J. Immunotherapy is clinically indicated in the management of allergic asthma. Am J Respir Crit Care Med 2001; 164: 2139-2140 [Free Full Text].

127. Adkinson NF Jr.. Immunotherapy is not clinically indicated in the management of allergic asthma. Am J Respir Crit Care Med 2001; 164: 2140-2141 [Free Full Text].

128. Bousquet J. Rebuttal. Am J Respir Crit Care Med 2001; 164: 2141-2142 [Free Full Text].

129. Adkinson NF Jr.. Rebuttal. Am J Respir Crit Care Med 2001; 164: 2142 [Free Full Text].

130. Abramson MJ, Bailey MJ, Couper FJ, Driver JS, Drummer OH, Forbes AB, McNeil JJ, Haydn WE. Are asthma medications and management related to deaths from asthma? Am J Respir Crit Care Med 2001; 163: 12-18 [Abstract/Free Full Text].

131. Beasley R, Crane J. Reducing asthma mortality with the asthma self-management plan system of care. Am J Respir Crit Care Med 2001; 163: 3-4 [Free Full Text].

132. Cote J, Bowie DM, Robichaud P, Parent JG, Battisti L, Boulet LP. Evaluation of two different educational interventions for adult patients consulting with an acute asthma exacerbation. Am J Respir Crit Care Med 2001; 163: 1415-1419 [Abstract/Free Full Text].

133. Macklem PT. Ann Woolcock 1937-2001: An Appreciation. Am J Respir Crit Care Med 2001; 163: 1041 [Free Full Text].

134. Shirtcliffe PM, Easthope SE, Cheng S, Weatherall M, Tan PL, Le Gros G, Beasley R. The effect of delipidated deglycolipidated (DDMV) and heat-killed Mycobacterium vaccae in asthma. Am J Respir Crit Care Med 2001; 163: 1410-1414 [Abstract/Free Full Text].

135. Ali S, Leonard SA, Kukoly CA, Metzger WJ, Wooles WR, McGinty JF, Tanaka M, Sandrasagra A, Nyce JW. Absorption, distribution, metabolism, and excretion of a respirable antisense oligonucleotide for asthma. Am J Respir Crit Care Med 2001; 163: 989-993 [Abstract/Free Full Text].

136. Kolb M, Inman M, Margetts PJ, Galt T, Gauldie J. Budesonide enhances repeated gene transfer and expression in the lung with adenoviral vectors. Am J Respir Crit Care Med 2001; 164: 866-872 [Abstract/Free Full Text].

137. Platts-Mills TA. The role of immunoglobulin E in allergy and asthma. Am J Respir Crit Care Med 2001; 164: S1-S5 .

138. Schulman ES. Development of a monoclonal anti-immunoglobulin E antibody (omalizumab) for the treatment of allergic respiratory disorders. Am J Respir Crit Care Med 2001; 164: S6-S11 [Abstract/Free Full Text].

139. Busse WW. Anti-immunoglobulin E (omalizumab) therapy in allergic asthma. Am J Respir Crit Care Med 2001; 164: S12-S17 [Abstract/Free Full Text].

140. Casale TB. Anti-immunoglobulin E (omalizumab) therapy in seasonal allergic rhinitis. Am J Respir Crit Care Med 2001; 164: S18-S21 [Abstract/Free Full Text].

141. Kraft M, Hamid Q, Chrousos GP, Martin RJ, Leung DY. Decreased steroid responsiveness at night in nocturnal asthma. Is the macrophage responsible? Am J Respir Crit Care Med 2001; 163: 1219-1225 [Abstract/Free Full Text].

142. Kraft M, Pak J, Martin RJ, Kaminsky D, Irvin CG. Distal lung dysfunction at night in nocturnal asthma. Am J Respir Crit Care Med 2001; 163: 1551-1556 [Abstract/Free Full Text].

143. O'Sullivan S, Cormican L, Faul JL, Ichinohe S, Johnston SL, Burke CM, Poulter LW. Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death. Am J Respir Crit Care Med 2001; 164: 560-564 [Abstract/Free Full Text].

144. Kepley CL, McFeeley PJ, Oliver JM, Lipscomb MF. Immunohistochemical detection of human basophils in postmortem cases of fatal asthma. Am J Respir Crit Care Med 2001; 164: 1053-1058 [Abstract/Free Full Text].

145. ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. Factors associated with persistent airflow limitation in severe asthma. Am J Respir Crit Care Med 2001; 164: 744-748 [Abstract/Free Full Text].

146. Theodoropoulos DS, Ledford DK, Lockey RF, Pecoraro DL, Rodriguez JA, Johnson MC, Boyce HW Jr.. Prevalence of upper respiratory symptoms in patients with symptomatic gastroesophageal reflux disease. Am J Respir Crit Care Med 2001; 164: 72-76 [Abstract/Free Full Text].

147. Clifton VL, Giles WB, Smith R, Bisits AT, Hempenstall PA, Kessell CG, Gibson PG. Alterations of placental vascular function in asthmatic pregnancies. Am J Respir Crit Care Med 2001; 164: 546-553 [Abstract/Free Full Text].

148. Bijl-Hofland ID, Cloosterman SG, Folgering HT, van Den Elshout FJ, van Weel C, van Schayck CP. Inhaled corticosteroids, combined with long-acting ₂-agonists, improve the perception of bronchoconstriction in asthma. Am J Respir Crit Care Med 2001; 164: 764-769 [Abstract/Free Full Text].

149. Echazarreta AL, Dahlen B, Garcia G, Agusti C, Barbera JA, Roca J, Dahlen SE, Rodriguez-Roisin R. Pulmonary gas exchange and sputum cellular responses to inhaled leukotriene D₄ in asthma. Am J Respir Crit Care Med 2001; 164: 202-206 [Abstract/Free Full Text].

150. Moy ML, Israel E, Weiss ST, Juniper EF, Dube L, Drazen JM. Clinical predictors of health-related quality of life depend on asthma severity. Am J Respir Crit Care Med 2001; 163: 924-929 [Abstract/Free Full Text].

151. ten Brinke A, Ouwerkerk ME, Zwinderman AH, Spinhoven P, Bel EH. Psychopathology in patients with severe asthma is associated with increased health care utilization. Am J Respir Crit Care Med 2001; 163: 1093-1096 [Abstract/Free Full Text].

152. Gautrin D, Infante-Rivard C, Ghezzo H, Malo JL. Incidence and host determinants of probable occupational asthma in apprentices exposed to laboratory animals. Am J Respir Crit Care Med 2001; 163: 899-904 [Abstract/Free Full Text].

153. Karjalainen A, Kurppa K, Martikainen R, Klaukka T, Karjalainen J. Work is related to a substantial portion of adult-onset asthma incidence in the Finnish population. Am J Respir Crit Care Med 2001; 164: 565-568 [Abstract/Free Full Text].

154. Zock JP, Sunyer J, Kogevinas M, Kromhout H, Burney P, Anto JM. Occupation, chronic bronchitis, and lung function in young adults. An international study. Am J Respir Crit Care Med 2001; 163: 1572-1577 [Abstract/Free Full Text].

155. Assanasen P, Baroody FM, Naureckas E, Solway J, Naclerio RM. The nasal passage of subjects with asthma has a decreased ability to warm and humidify inspired air. Am J Respir Crit Care Med 2001; 164: 1640-1646 [Abstract/Free Full Text].

156. Terada N, Hamano N, Kim WJ, Hirai K, Nakajima T, Yamada H, Kawasaki H, Yamashita T, Kishi H, Nomura T, et al . The kinetics of allergen-induced eotaxin level in nasal lavage fluid: its key role in eosinophil recruitment in nasal mucosa. Am J Respir Crit Care Med 2001; 164: 575-579 [Abstract/Free Full Text].

157. Braunstahl GJ, Overbeek SE, Fokkens WJ, Kleinjan A, McEuen AR, Walls AF, Hoogsteden HC, Prins JB. Segmental bronchoprovocation in allergic rhinitis patients affects mast cell and basophil numbers in nasal and bronchial mucosa. Am J Respir Crit Care Med 2001; 164: 858-865 [Abstract/Free Full Text].

158. Togias A. Systemic cross-talk between the lung and the nose. Am J Respir Crit Care Med 2001; 164: 726-727 [Free Full Text].

159. Corne JM, Lau L, Scott SJ, Davies R, Johnston SL, Howarth PH. The relationship between atopic status and IL-10 nasal lavage levels in the acute and persistent inflammatory response to upper respiratory tract infection. Am J Respir Crit Care Med 2001; 163: 1101-1107 [Abstract/Free Full Text].

160. Okano M, Azuma M, Yoshino T, Hattori H, Nakada M, Satoskar AR, Harn DA Jr,, Nakayama E, Akagi T, Nishizaki K. Differential role of CD80 and CD86 molecules in the induction and the effector phases of allergic rhinitis in mice. Am J Respir Crit Care Med 2001; 164: 1501-1507 [Abstract/Free Full Text].

161. Lamblin C, Bolard F, Gosset P, Tsicopoulos A, Perez T, Darras J, Janin A, Tonnel AB, Hamid Q, Wallaert B. Bronchial interleukin-5 and eotaxin expression in nasal polyposis. Relationship with (a)symptomatic bronchial hyperresponsiveness. Am J Respir Crit Care Med 2001; 163: 1226-1232 [Abstract/Free Full Text].

162. Pasto M, Serrano E, Urocoste E, Barbacanne MA, Guissani A, Didier A, Delisle MB, Rami J, Arnal JF. Nasal polyp-derived superoxide anion: dose-dependent inhibition by nitric oxide and pathophysiological implications. Am J Respir Crit Care Med 2001; 163: 145-151 [Abstract/Free Full Text].