© 2004 American Thoracic Society
Asthma, Airway Biology, and Nasal Disorders in AJRCCM 2003Division of Pulmonary and Critical Care Medicine, Loyola University of Chicago Stritch School of Medicine and Hines Veterans Affairs Hospital, Hines, Illinois 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
Allergic Rhinitis and Nasal Disorders (4) Nasal Function (1) Inflammation and Hyperreactivity (3) Asthma and Airway Biology (82) Genetics (4) Epidemiology (7) Airway Inflammation (21) Animal Models (11) Bronchial and Bronchoalveolar Specimens (4) Blood (2) Exhaled Nitric Oxide (3) Other Exhaled Markers (1) Airway Hyperreactivity (18) Animal Models: Antigen Challenge (5) Animal Models: Other Challenges and Mediators (7) Chemical and Antigen Challenge (1) Hyperventilation- and Exercise-Induced Asthma (5) Other Pathophysiological Mechanisms in Asthma (13) Deep Inspiration (1) Infection and Immunology (4) Remodeling (8) Treatment (13) Glucocorticoids (3) Theophylline (1) Combination Regimens (4) Management Plans and Education (1) New Agents (4) Specific Clinical Scenarios (4) Acute Severe and Fatal Asthma (1) Pregnancy (1) Dyspnea (1) Radiology (1) Occupational Asthma (2)
Nasal Function Hypoxia is known to inhibit the activity and expression of ion-transport proteins of cultured alveolar epithelial cells. To determine whether in vivo hypoxia inhibits lung ion transport, Mairbaurl and coworkers (1) measured transepithelial nasal potentials before and during a stay at high altitude (4,559 m). In normoxia, total nasal potential was about 20% higher in 12 control subjects than in 10 mountaineers with a history of high-altitude pulmonary edema; the groups did not differ in nasal potentials that could be inhibited by amiloride. At high altitude, total nasal potential increased by 250% in both groups; nasal potential sensitive to amiloride decreased by about 80% solely in the control subjects, and the portion of nasal potential sensitive to chloride ion almost doubled. Because nasal dryness is common at high altitude, the effect of controlled humidity of 50% was also studied during normobaric hypoxia: no change was observed in total nasal potential or in the fractions sensitive to amiloride or chloride. The authors conclude that an increase in chloride secretion compensating for drying of the nasal mucosa is responsible for the transepithelial nasal potential at high altitude, and that changes in nasal potentials at high altitude reflect a specific response of the nasal mucosa and do not reflect the alveolar epithelium.
Secretoneurin is a neuropeptide potentially involved in the migration of eosinophils, monocytes, and dendritic cells, but whether it is present in human airway mucosa is not known. To investigate this issue, Korsgren and coworkers (2) obtained nasal mucosal biopsies and lavage fluids in 24 patients with allergic rhinitis before and during the birch pollen season. Immunohistochemical analysis revealed an abundance of nerves displaying secretoneurin immunoreactivity, mainly distributed around blood vessels and submucosal glands. Most nerve fibers containing vesicular acetylcholine transporter, tyrosine hydroxylase, calcitonin gene–related peptide, and vasoactive intestinal peptide were also secretoneurin-immunoreactive, indicating that secretoneurin is localized in cholinergic, adrenergic, and sensory nerves. Allergen exposure produced an increase in secretoneurin in lavage fluid. Levels of secretoneurin were not correlated with eosinophil cationic protein. The authors conclude that secretoneurin is widely found in nasal mucosal nerves of patients with allergic rhinitis and that allergen exposure increases the levels of secretoneurin in nasal fluid. To determine whether rhinitis is associated with hypertension, Kony and coworkers (3) studied 330 adults (aged 28 to 56 years) as part of the European Community Respiratory Health Survey. Systolic blood pressure was higher in men with rhinitis (diagnosed by questionnaire) than in men without rhinitis: 131 versus 124 mm Hg. After multivariate adjustment, hypertension (defined as systolic pressure of at least 140 mm Hg, and/or diastolic pressure of at least 90 mm Hg, and/or prescription of antihypertensive medications) was more frequent in men with rhinitis than in men without rhinitis (odds ratio, 2.6). In men, systolic pressure progressively increased on going from absence of rhinitis to seasonal rhinitis and then to perennial rhinitis. The authors conclude that rhinitis is associated with hypertension in men. Because hypertension has been reported to be associated with rhinitis, Heinrich and coworkers (4) reexamined the association by analyzing data from a population-based sample of 896 subjects participating in the European Respiratory Health Survey. After adjusting for age, body mass index, and smoking, neither systolic nor diastolic blood pressure was significantly different between men with rhinitis and men without rhinitis (assessed by questionnaire). Adjusted prevalence rate of hypertension did not differ between men with rhinitis and men without rhinitis. No association was found between hypertension and rhinitis in women. The authors conclude that hypertension is not associated with rhinitis.
Genetics The ADAM33 gene, located on the short arm of chromosome 20, was recently identified as contributing to asthma. Because the earlier study was conducted exclusively in white subjects recruited from the United States and Britain, Lind and coworkers (5) investigated whether the ADAM33 gene is associated with asthma in Puerto Ricans (who have the highest asthma prevalence in the United States) and Mexicans (who have the lowest asthma prevalence). Genotyping of six single-nucleotide polymorphisms (SNPs) revealed no associations with asthma severity, bronchodilator response, or IgE levels. The transmission equilibrium test and genotyping of matched control samples (to permit case-control analyses) did not reveal significant associations in either the Puerto Rican or Mexican population. The authors conclude that the ADAM33 gene is not an important risk factor for asthma or for asthma-associated phenotypes in Mexicans or Puerto Ricans. Serum levels of eosinophil cationic protein, which is produced by activated eosinophils, reflect the degree of activation of the circulating pool of eosinophils. Because some patients with asthma do not have elevated levels of this protein, Noguchi and coworkers (6) screened 137 Japanese families (identified through children with asthma) for polymorphisms in the gene for eosinophil cationic protein. Three polymorphisms were identified: -393 C/T, -138C/A, and 124 Arg/Thr. The transmission disequilibrium test did not reveal an association between these polymorphisms and asthma. Serum levels of eosinophil cationic protein were lower in subjects with the -393T allele than in subjects with the -393C allele. Gel shift assay revealed that the C/eosinophil cationic protein is capable of binding the -393C/T polymorphic site. The authors conclude that a significant amount of the variance in baseline serum levels of eosinophil cationic protein can be explained by -393C/T polymorphism, although this polymorphism is not involved in the development of asthma. Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) M1 are detoxifying enzymes induced in response to oxidative stress, as occurs during ozone exposure. To examine the relationship between significant polymorphisms in NQO1 and GSTM1 and risk of asthma, David and coworkers (7) studied 218 case-parent triads in children from Mexico City (which has the highest ozone levels in North America). The Pro187Ser polymorphism in NQO1 was not associated with risk of asthma. Among subjects with homozygous deletion of GSTM1, carriers of a serine allele were at reduced risk of asthma as compared with Pro/Pro homozygotes. The authors conclude that children who live in an area with high exposure to ozone and who carry at least one NQO1 Ser allele and are homozygous for the GSTM1 deletion are at a decreased risk of asthma. Variation in levels of exhaled nitric oxide in patients with asthma may arise from sequence variants in the genes for nitric oxide synthase. To determine whether a sequence variant in the gene for endothelial nitric oxide synthase (NOS3), an enzyme constitutively expressed in endothelial cells, could explain some of the variation in exhaled nitric oxide, Storm van's Gravesande and coworkers (8) studied 73 patients with mild to moderate asthma. A strong association was found between exhaled nitric oxide and a known functional NOS3 missense sequence variant in the endothelial nitric oxide gene (G894T). Age- and sex-adjusted levels of exhaled nitric oxide were lowest in patients with the TT genotype (7.2 ppb) and higher in patients with either the GT genotype (17.1 ppb) or the GG genotype (12.1 ppb). The G894T DNA variant explained 16% of the residual variance in levels of exhaled nitric oxide. The authors conclude that a missense variant of the gene for endothelial nitric oxide synthase explains about one-sixth of the variation in levels of exhaled nitric oxide among patients with asthma.
Epidemiology To determine the magnitude and predictors for hospital readmission for childhood asthma, Bloomberg and coworkers (11) analyzed data from 8,761 children who experienced 14,905 admissions for asthma. During the 10-year period, 30% of children were admitted more than once. A multivariate model revealed that African-American children with Medicaid or no insurance had a higher rate of readmission than did African-American children with commercial insurance or white (or other ethnicity) children regardless of insurance (risk ratio, 1.28). The probability of readmission increased from 30% after the first admission to 46% after a second admission and to 59% after a third admission. The authors conclude that prior admission is a more powerful predictor for readmission for childhood asthma than are ethnicity, insurance status, or their combination. To determine whether parasitic infection decreases the risk of wheeze in young children, Dagoye and coworkers (12) did a nested case-control study based on data on 7,155 children aged 1 to 4 years living in urban and rural areas of Ethiopia. Infections with parasites was common: whipworm (Trichuris) (54%), roundworm (Ascaris) (38%), and hookworm (Ancylostoma spp.) (10%). Wheezing in the past year was more prevalent in urban children than in rural children (4.4% versus 2%), and was less prevalent in children infected with Ascaris (adjusted odds ratio, 0.5). A similar, although nonsignificant, association was found for hookworm (adjusted odds ratio, 0.6), but not for Trichuris. Skin sensitization with house dust mite (Dermatophagoides pteronyssinus) and cockroach (Blattella germanica) was more prevalent in rural than in urban children, and unrelated to wheeze. The authors conclude that Ascaris infection protects against wheeze in young Ethiopian children and that this effect is not mediated by inhibition of allergen sensitization. Home dampness is associated with lower respiratory symptoms in children. To determine whether in-home fungal concentrations can predict lower respiratory illnesses (croup, pneumonia, bronchitis, and bronchiolitis) in the first year, Stark and coworkers (13) studied a prospective birth cohort of 499 children of parents with asthma/allergies. After controlling for sex, presence of water damage, presence of visible mold/mildew, a winter birth, breastfeeding, and exposure to other children (through siblings), multivariate analyses revealed significant associations between lower respiratory illnesses and high levels (more than 90th percentile) of airborne Penicillium (relative risk, 1.73), dust-borne Cladosporium (relative risk, 1.52), Zygomycetes (relative risk, 1.96), and Alternaria (relative risk, 1.51). On multivariate analysis, lower respiratory illnesses were associated with households that had any fungal level above the 90th percentile (relative risk, 1.86). The authors conclude that exposure to high levels of fungi in the home increase the risk of wheezing and nonwheezing lower respiratory illnesses during infancy. To determine the association between day care attendance in the first year of life and asthma and wheezing over the first 6 years of life, Celedon and coworkers (14) followed from birth 453 children with and without a maternal history of asthma. Day care in the first year of life was inversely associated with eczema (odds ratio, 0.3). Day care attendance in the first year of life was associated with a decreased risk of asthma (odds ratio, 0.3) and recurrent wheezing (odds ratio, 0.3) at 6 years of age, and with a decreased risk of wheezing after 4 years of age among children without a maternal history of asthma. Among children with a maternal history of asthma, day care in early life did not have a protective effect on asthma or recurrent wheezing at 6 years of age, but was instead associated with an increased risk of wheezing in the first 6 years of life. The authors conclude that a maternal history of asthma influences the relationship between day care–related exposure and childhood asthma. In a cohort of children with asthma from 12 Southern California communities, McConnell and coworkers (15) investigated the relationship between bronchitic symptoms and ambient particulate matter, particulate elemental and organic carbon, nitrogen dioxide, and other gaseous pollutants. Symptoms (assessed by questionnaire every year between 1996 and 1999) were associated with yearly variability of particulate matter with aerodynamic diameter less than 2.5 µm (odds ratio, 1.41), nitrogen dioxide (odds ratio, 1.07), organic carbon (odds ratio, 1.41), nitrogen dioxide (odds ratio, 1.07), and ozone (odds ratio, 1.06). The within-community associations were stronger in magnitude than the between-community associations. The effects of yearly variation of organic carbon and nitrogen dioxide were only modestly reduced after adjusting for other pollutants. The effects of all other pollutants were reduced after adjusting for organic carbon and nitrogen dioxide. The authors conclude that previous cross-sectional studies may have underestimated the effects of organic carbon and nitrogen dioxide on chronic bronchitic symptoms in children with asthma.
Airway Inflammation To determine the role of endogenous histamine in the recruitment of eosinophils and airway hyperresponsiveness, Koarai and coworkers (17) used knockout mice with disruption of the gene for L-histidine decarboxylase. In wild-type mice sensitized to ovalbumin, inhalation of ovalbumin caused accumulation of eosinophils in the lung, enhanced proliferation of eosinophils in the bone marrow, and increased airway hyperresponsiveness to methacholine. In the knockout mice, airway hyperresponsiveness to methacholine was not altered, but eosinophil proliferation in the bone marrow and eosinophil recruitment to the lung was significantly reduced. Induction of P-selectin in the lung after ovalbumin challenge was also decreased in the knockout mice. The authors conclude that endogenous histamine is involved in the accumulation of eosinophils in the airways after allergic challenge, possibly acting in the bone marrow and producing P-selectin in the airways, and that airway hyperresponsiveness occurs independently of airway eosinophilia. To examine the proinflammatory and antiinflammatory actions of nitric oxide in bronchial asthma, Jibiki and coworkers (18) studied molecular mechanisms for the activation of activator protein-1 (by nitric oxide) in human bronchial epithelial cells. The reactive nitrogen–generating species, NOR-1, induced the activation of activator protein-1, and this activation was attenuated by a nitric oxide scavenger (carboxyl-PTIO) and by transient transfection of the dominant negative form of apoptosis signal–regulating kinase 1. The reactive nitrogen–generating species, NOR-1, phosphorylated apoptosis signal–regulating kinase 1, c-Jun-NH2–terminal kinase (JNK), and p38 mitogen–activated protein kinase. In stable endothelial cells of the porcine artery transfected with apoptosis signal–regulating kinase 1, activity of activator protein-1 and phosphorylation of c-Jun-NH2–terminal kinase and p38 mitogen–activated protein kinase were depressed. The authors conclude that nitric oxide is capable of inducing the activation of activator protein-1 in bronchial epithelial cells and that the cascade of apoptosis signal–regulating kinase 1 and p38 mitogen–activated protein kinase and c-Jun-NH2–terminal kinase is involved in the activation. Because allergen-specific immunotherapy is not available for latex allergy, Hardy and coworkers (19) developed a mouse model of allergen to latex glove allergen, Hev b 5. Mice were immunized with the allergen and the response was compared with the response achieved with ovalbumin immunization. Immunization with Hev b 5 or glove extract elicited hallmarks of pulmonary Type 2 (Th2) helper T cell immune responses: increased serum antigen-specific IgE; eosinophilic infiltrates in lungs; increased interleukin-5 in bronchoalveolar fluid; and mucus hypersecretion by epithelial cells in the airways. The responses were comparable to those achieved by ovalbumin. The authors conclude that the mouse model will enable research into the pulmonary inflammation caused by the major latex glove allergen, Hev b 5. In a mouse model of lung inflammation induced by immunization with ovalbumin, Koo and coworkers (20) investigated the action of compound A, a nonpeptidyl small-molecule antagonist of very late antigen-4. Intratracheal administration of compound A achieved good occupancy of blood cell receptors for about 8 hours. Intranasal administration achieved dose-dependent inhibition of eosinophilia in bronchiolar lavage fluid; intravenous administration of compound A did not have this effect. Specific staining of major basic protein of eosinophils revealed peribronchiolar infiltration of eosinophils; some eosinophils were also positive for nitrotyrosine. The deposition of major basic protein and nitrotyrosine at the base of the perivascular endothelium indicated degranulation of eosinophils. The authors conclude that intranasal administration of compound A, an antagonist of very late antigen-4, decreased eosinophils and their activation products in a model of lung inflammation. To determine the role of cyclooxygenase-1 and cyclooxygenase-2 in modulating Th2 response in the allergic airway, Carey and coworkers (21) studied ovalabumin-induced airway allergy in mice with genetic deficiency of each enzyme. The airways of mice lacking cyclooxygenase 1 (COX-1-/-) contained increased numbers of CD4+ and CD8+ T cells, exaggerated levels of the Th2 cytokines, interleukin-4, -5, and -13, and increased levels of eotaxin and thymus- and activation-regulated chemokine. The COX-1-/- mice also exhibited greater allergen-induced bronchoconstriction. Compared with wild-type mice, both the COX-1-/- and COX-2-/- mice displayed increased levels of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in the lung. The authors conclude that genetic deficiency of cyclooxygenase-1, but not of cyclooxygenase-2, modulates T cell recruitment, secretion of Th2 cytokines, and airway caliber in the allergic airway. Chiang and coworkers (22) investigated the effect of dendritic cell-based immunotherapy in modulating the immune response of allergic disease in mice. Dendritic cells were first incubated for 48 hours with ovalbumin, ovalbumin plus ribavirin, or ovalbumin plus one of two oligodeoxynucleotides containing an immunostimulatory DNA sequence (ODN 1826 or ODN 1745). The cells were then injected intravenously into four groups of mice. Seven days later, all mice were immunized with intraperitoneal ovalbumin. Ribavirin and ODN 1826 increased the synthesis of interleukin-12 and inhibited the production of interleukin-10. ODN 1826 also enhanced the expression of B7.1, B7.2, and major histocompatibility complex I and II molecules. Dendritic cells modulated by ribavirin and ODN 1826 downregulated Th2 immune response in vivo and alleviated airway inflammation. The authors conclude that dendritic cells modulated with ribavirin or an oligodeoxynucleotide containing an immunostimulatory DNA sequence can decrease airway inflammation. The macrolide, rapamycin, has immunosuppressive properties and also inhibits smooth muscle proliferation. Fujitani and Trifilieff (23) compared the effects of SAR 943, a rapamycin derivative, and budesonide in a murine model of airway inflammation. In ovalbumin-sensitized mice, allergen challenge induced increases in interleukin-5, interleukin-4, eosinophils, neutrophils, lymphocytes, cellular fibronectin, lung epithelial cell proliferation, mucus hypersecretion, and hyperreactivity to methacholine. All of these variables were inhibited equally by SAR 943 and budesonide when given intranasally 1 hour before and 24 hours after aerosol challenge. In a primary culture of smooth muscle cells from the human airway, SAR 943 caused dose-dependent inhibition of cell proliferation induced by epidermal growth factor, but did not affect basal proliferation. SAR had no effect on a human bronchial epithelial cell line. The authors conclude that a rapamycin derivative, SAR 943, is as effective as budesonide in inhibiting both lung inflammation and remodeling in a murine model of asthma.
To investigate the effects of macrolide antibiotics on mucus hypersecretion, Shimizu and coworkers (24) induced hypertrophy and metaplasia of goblet cells in the nasal epithelium by intranasal instillation of ovalbumin in ovalbumin-sensitized rats and by instillation of lipopolysaccharide. Oral clarithromycin inhibited the mucus production induced by ovalbumin and lipopolysaccharide (ampicillin and josamycin had no effect). Clarithromycin and erythromycin inhibited mucus secretion that occurred spontaneously or in response to tumor necrosis factor- In a state of the art review article, Kinnula and Crapo (25) discuss superoxide dismutase in lung disease. In a pulmonary perspective, Turino and Cantor (26) discuss the role of hyaluronan in respiratory injury and repair.
Bronchial and bronchoalveolar specimens. In 52 patients with mild-to-moderate asthma, Sont and coworkers (28) compared fully automated image analysis of bronchial biopsy tissue with interactive digital cell counting and semiquantitative scoring of cytokine expression. Fully automated CD3+ cell counts showed perfect repeatability (r = 1.0) and were linearly correlated with the interactive procedure (r = 0.98). Automated densitometry showed perfect repeatability (r = 1.0) and a reasonable relationship with semiquantitative scoring of protein and messenger RNA expression (r = 0.43 to 0.89). Automated and semiquantitative assessments of changes in cytokine expression during 2 years of follow up were correlated (r = 0.40 to 0.84). The authors conclude that fully automated cell counts and densitometric analyses of bronchial biopsy tissue from patients with asthma are unbiased and decrease the variability in measures of inflammation. Fabbri and coworkers (29) asked, "Do patients with fixed airway obstruction have distinct pathologic and functional characteristics depending on whether they have asthma or COPD?". Twenty-seven patients with COPD and 19 patients with asthma had similar FEV1 (56% predicted in both groups) and airway hyperresponsiveness to methacholine (concentration producing a 20% decrease in FEV1: 2.8 versus 1.2 mg/ml). Compared with the patients who had COPD, the patients with asthma had more eosinophils in peripheral blood, sputum, bronchoalveolar lavage, and airway mucosa; fewer neutrophils in sputum and bronchoalveolar lavage; a higher CD4+/CD8+ ratio of T cells infiltrating the airway mucosa; and a thicker reticular layer of the epithelial basement membrane. The patients with asthma had lower residual volume, higher diffusing capacity, higher exhaled nitric oxide, less emphysema on computed tomography, and greater responsiveness to bronchodilators and glucocorticoids. The authors conclude that patients with asthma and COPD have distinct pathologic and functional characteristics even when the degree of airway obstruction is equivalent. In a report from an international workshop, Jeffery and colleagues (30) describe the methods used for the assessment of endobronchial biopsies in clinical research, and the application of these methods in studies of pathogenesis and treatment.
Blood.
The transcription factor, nuclear factor-
Exhaled nitric oxide. To measure fractions of exhaled nitric oxide in intubated, mechanically ventilated patients, Tornberg and coworkers (34) developed a method for obtaining multiple single-breath measurements at preset expiratory flows. A suction ejection system connected to a restriction valve was used to obtain multiple single-breath exhalations. Intubation produced a 50% decrease in the fraction of exhaled nitric oxide and a 36% decrease in the airway wall transfer rate of nitric oxide. Neither the fraction of nitric oxide originating in alveoli or in airway wall epithelium was affected by intubation. The peak concentration of nitric oxide after 20 seconds of apnea was similar to the value of nitric oxide calculated as originating in the airway wall epithelium. The authors conclude that the vacuum aspiration method for multiple single-breath measurements in mechanically ventilated patients enables the calculation of alveolar and bronchial fractions of nitric oxide. To determine whether endogenous endothelium-dependent vasoactive substances cause release of nitric oxide that can be detected in exhaled air, Malmstrom and coworkers (35) administered intravenously various pharmacologic compounds in anesthetized pigs and humans. Administration of acetylcholine, bradykinin, substance P, endothelin-1, and nitroglycerine produced dose-dependent increases of exhaled nitric oxide in pigs. Each compound caused a highly individual and reproducible release pattern. Angiotensin converting enzyme inhibition enhanced the release of nitric oxide induced by bradykinin. Endothelin receptor antagonism reduced the response of exhaled nitric oxide to endothelin-1. Atropine abolished the response to acetylcholine. Inhibition of nitric oxide synthase abolished the basal levels of exhaled nitric oxide and also decreased the exhaled nitric oxide response to all compounds except nitroglycerine. In six human subjects, acetylcholine evoked a dose-dependent increased in exhaled nitric oxide. The authors conclude that release of nitric oxide in response to endogenous vasoactive compounds can be measured online in exhaled air.
Other exhaled markers.
Airway Hyperreactivity To determine whether strains of mice differ in their susceptibility to asthmatic-type responses, Shinagawa and Kojima (38) screened four strains of mice (A/J, BALB/c, C57BL/6, and C3H/HeJ) by giving antigen into the nose and assessing the evoked response. Continuous eosinophilic inflammation was observed only in A/J mice, and not in the other three strains. Twelve weeks after antigen exposure, the A/J mice exhibited features characteristic of airway remodeling (airway wall thickening and increased collagen deposition). The A/J mice exhibited persistent airway hyperresponsiveness after chronic exposure to the antigen. The BALB/c mice exhibited less eosinophilic inflammation, collagen deposition, and airway wall thickening than did the A/J mice, and airway hyperresponsiveness was absent. The C57BL/6 and C3H/HeJ mice exhibited no eosinophilic inflammation, airway wall thickening, or airway hyperresponsiveness; deposition of collagen was slightly increased. In the A/J mice, antigen challenge by inhalation (after ovalbumin/alum immunization) led to only a transient increase in eosinophils and less airway wall thickening, indicating the importance of the protocol used. The authors conclude that use of the A/J strain of mice and delivering antigen by nasal instillation is the preferred mouse model for studying mechanisms underlying asthma. An editorial commentary by Shore (39) accompanies this article.
Long-term exposure to allergen can attenuate inflammation and revert airway hyperreactivity to normal responsiveness. Cui and coworkers (40) developed a model of this reversal by administering multiple daily airway challenges to ovalbumin-sensitized and challenged mice. The reversal in inflammation and airway hyperresponsiveness was associated with a transition from Th2 to Th1 cytokine profile in bronchoalveolar fluid. Transfer of cells from mice exposed to long-term allergen challenges into hyperreactive mice induced normal airway responsiveness, indicating that active suppression was responsible for the reversal of the hyperresponsiveness; the transfer of cells did not affect eosinophil airway inflammation. After suppression of airway responsiveness (by long-term allergen challenge), hyperresponsiveness could be reestablished by depleting Because complement anaphylatoxins (C3a and C5a) are thought to contribute to the development of allergic asthma in mice, Taube and coworkers (41) investigated the effects of inhibiting complement activation after sensitization (but before allergen challenge) on the development of allergic airway inflammation and airway hyperresponsiveness. Complement activation was prevented with complement receptor–related gene y (Crry) fused to the IgG1 hinge, CH2 and CH3 domains (Crry-Ig), which accelerates decay in both the classic and alternative pathways of complement, and is also a cofactor for the cleavage of C3b and C4b mediated by factor I. After mice had been sensitized with ovalbumin (Days 1 and 14), Crry-Ig was administered. When the mice were subsequently challenged with ovalbumin, Crry-Ig prevented the development of airway hyperresponsiveness, decreased airway and lung eosinophilia, decreased lung lymphocytes, decreased interleukin-4, interleukin-5, and interleukin-13 in bronchoalveolar fluid, and decreased serum-specific IgE and IgG1. The authors conclude that inhibition of the classic and alternative pathways of complement decreases airway inflammation and prevents the development of airway hyperreactivity when sensitized mice are challenged with ovalbumin.
Animal models: other challenges and mediators. Viral infection can cause dysfunction of M2 muscarinic receptors (of parasympathetic nerves) leading to increased release of acetylcholine and airway hyperreactivity. The role of CD8+ T cells in airway hyperreactivity and M2 receptor dysfunction induced by parainfluenza virus infection was studied by Adamko and coworkers (44) in guinea pigs. Depletion of CD8+ T cells prevented the M2 receptor dysfunction and airway hyperreactivity in guinea pigs sensitized to ovalbumin; it had no effect in nonsensitized guinea pigs. Sensitization increased the number of eosinophils in close relation to airway nerves. (When activated, the airway nerves release major basic protein, which binds to and blocks the M2 muscarinic receptors). Viral infection decreased the number of tissue eosinophils, likely reflecting degranulation; this effect was prevented by depletion of CD8+ T cells. The authors conclude that CD8+ T cells play a role in the virus-induced dysfunction of M2 muscarinic receptors and airway hyperreactivity in ovalbumin-sensitized guinea pigs (but not in nonsensitized guinea pigs), secondary to degranulation of eosinophils near the airway nerves. Induction of anesthesia with a single volatile anesthetic can cause cough, secretion, and airway obstruction in children. In 4- to 5-week-old guinea pigs anesthetized with urethane, Mutoh and Tsubone (45) studied the effect of two volatile anesthetics, halothane and sevoflurane, on the responsiveness of C-fiber afferents recorded from the internal carotid branch of the superior laryngeal nerve. Halothane caused twice as much responsiveness to capsaicin (injected into the left atrium or delivered by nebulization to the larynx) or laryngeal hyperinflation as did sevoflurane; baseline activity was unaffected. The authors conclude that the sensitivity of C-fiber afferents to chemical and mechanical stimuli in young guinea pigs is enhanced more by halothane than by sevoflurane. Dopamine D2–like receptors are known to inhibit the activity of dopaminergic neurons in the ventral tegmental area of the brain, and stimulation of dopamine D2–like receptors attenuates the afferent responses of the carotid chemoreceptors to hypoxia. Lin and coworkers (46) asked, "Does activation of dopamine D2–like receptors inhibit the hyperresponsiveness of pulmonary C fibers induced by inflammatory mediators?". In anesthetized, open-chest rats, a constant infusion of prostaglandin E2 significantly enhanced the response of C-fiber afferents to capsaicin injection. Pretreatment with quinpirole, an antagonist of D2-like receptors, caused marked attenuation of the hyperresponsiveness to capsaicin at 20 minutes, and the inhibitory action persisted for more than 90 minutes. The effect of quinpirole was dose-dependent. The effect was antagonized by pretreatment with domperidone, a D2-like receptor antagonist (administered 10 minutes before quinpirole). In separate experiments, prostaglandin E2 augmented the response of C fibers to injections of phenyl biguanide and lactic acid, and constant-pressure lung inflation; these potentiating responses were also reduced by quinpirole. The effect of quinpirole was equally effective in inhibiting the increase in excitability of pulmonary C fibers induced by alveolar hypercapnia or a constant infusion of adenosine. The authors conclude that activation of dopamine D2–like receptors attenuates the hyperresponsiveness of pulmonary C fibers to both chemical stimuli and lung inflation. To determine the role of neurokinins in the development of hyperventilation-induced bronchoconstriction, Freed and coworkers (47) used bronchoscopy to measure peripheral airway resistance and the production and release of eicosanoids in anesthetized dogs. Pretreatment with antagonists of neurokinin-1 and neurokinin-2 receptors reduced hyperventilation-induced bronchoconstriction by about 50%; the combined antagonism virtually abolished the airway reactivity to neurokinin A, partially reduced the response to substance P, and had little effect on the response to hypertonic saline. Blockade of the neurokinin receptors did not affect cell profiles, prostaglandin D2, or cysteinyl leukotrienes in bronchoalveolar fluid after hyperventilation. The authors conclude that neurokinin receptors modulate hyperventilation-induced bronchoconstriction and do so in part via eicosanoid production and release. In mice, Martin and coworkers (48) investigated the effect of exposure to chlorine gas on airway inflammation and hyperresponsiveness, and the role of oxidative mechanisms in the response. A 5-minute exposure to 400 or 800 ppm of chlorine caused increases in airway hyperresponsiveness 24 hours later. Responsiveness after inhaling 400 ppm of chlorine returned to normal by 2 days, but was again elevated at 7 days. Exposure to 800 ppm caused loss of airway epithelium, patchy alveolar damage, proteinaceous exudates, and inflammatory cells within alveolar walls. Macrophages, granulocytes, epithelial cells, and nitrate/nitrite levels were increased in lung lavage fluid. Expression of inducible nitric oxide synthase was increased, and lung proteins were oxidized. Exposure to 800 ppm was associated with staining of epithelial cells and alveolar macrophages for 3-nitrotyrosine residues. Inhibition of inducible nitric oxide synthase abrogated the changes in responsiveness induced by chlorine. The authors conclude that exposure to chlorine gas causes functional and pathological changes in the airways induced by oxidative stress and that inducible nitric oxide synthase contributes to the airway hyperresponsiveness.
Chemical and antigen challenge.
Hyperventilation- and exercise-induced asthma. Eucapnic voluntary hyperpnea has been recommended for identifying exercise-induced bronchoconstriction, but it requires relatively complex equipment. The validity of an osmotic aerosol, mannitol, as a surrogate was assessed by Holzer and coworkers (52) in 50 elite summer sport athletes, 27 of whom had been previously diagnosed as having asthma. Twenty-five subjects had a positive response to eucapnic voluntary hyperpnea (mean fall in FEV1, 25%), 26 subjects had a positive response to mannitol, and 24 subjects had positive responses to both challenges. When compared against eucapnic voluntary hyperpnea as a reference standard, inhalation of mannitol had a sensitivity of 96% and a specificity of 92%. The authors conclude that the response to inhaled mannitol is both sensitive and specific for detecting the response to eucapnic voluntary hyperpnea in elite swimmers. To determine whether variables measured from exhaled condensates are influenced by presence or absence of a nose clip, Vass and coworkers (53) studied 25 healthy volunteers and 8 patients with allergic rhinitis. The volume of condensate was higher when subjects inhaled and exhaled through the mouth (with a nose clip) than when they inhaled through the nose and exhaled through the mouth (without nose clip): 2,321 versus 1,746 µl. Levels of adenosine, ammonia, and thromboxane B2 were equivalent by the two routes in both healthy subjects and patients with rhinitis. The authors conclude that use of a nose clip results in an exhaled condensate of greater volume, but it does not influence the level of inflammatory mediators. In a pulmonary perspective, Boulet (54) discusses asymptomatic airway hyperresponsiveness.
Other Pathophysiological Mechanisms in Asthma
Infection and immunology. In 100 patients admitted to hospital with an acute exacerbation of asthma, Lieberman and coworkers (58) studied the role of four atypical pathogens. Serologic evidence of acute infection with Mycoplasma pneumoniae was found in 18% of the patients and in 3% of the control group; 56% of this subgroup had evidence of acute infection with a second pathogen (usually a virus). Acute infections with Chlamydia pneumoniae were present in 8% of the patients and in 6% of the control group, and acute infections with Legionella spp. were present in 5% of the patients and in 3% of the control group; evidence of infection with Coxiella burnettii was not found in either group. The authors conclude that infection with M. pneumoniae is associated with hospitalization for an acute exacerbation of asthma.
Viruses cause most exacerbations of asthma and rhinovirus is the most common. Because decreased generation of interferon-
Remodeling. Remodeling of the airway wall occurs in adult patients with asthma and thickening of the reticular basement membrane is pathognomonic of asthma. Payne and coworkers (62) asked, "Do children with asthma display thickening of the reticular basement membrane?". They studied endobronchial biopsies from 19 children with difficult asthma, 10 children without asthma, 10 adults with mild asthma, 6 adults who had been intubated for life-threatening asthma, and 8 healthy adults. Thickness of the reticular basement membrane in children with asthma (median, 8.2 µm) was similar to that in adults with mild asthma (8.1 µm) and adults with life-threatening asthma (7.2 µm), and thicker than that in healthy children (4.4 µm) or healthy adults (4.9 µm). The authors conclude that thickening of the reticular basement membrane in children with difficult asthma is similar to that found in adults with asthma. To determine whether inhaled glucocorticoid alters the vascular component of airway remodeling, Chetta and coworkers (63) did a randomized, double-blind, parallel-group study of low-dose (100 µg twice daily) and high-dose (500 µg twice daily) fluticasone propionate in 30 patients with mild-to-moderate asthma. At baseline, bronchial biopsies revealed an increase in the number of vessels and vascular area in patients with asthma as compared with eight healthy subjects. In patients with asthma, the number of vessels correlated with vascular area (r = 0.58) and with the number of mast cells (r = 0.67). Both low- and high-dose fluticasone propionate decreased symptoms, bronchial responsiveness to methacholine, and inflammatory cells. Only the high dose of fluticasone propionate caused a decrease in the number of vessels, the vascular area, and thickness of the basement membrane. The authors conclude that a high dose of fluticasone propionate (500 µg twice daily) over 6 weeks alters airway remodeling consequent to a decrease in submucosal vascularity and thickness of the basement membrane. Studies of hypervascularity of the bronchial wall in the airway remodeling of asthma have been confined to biopsy specimens. To investigate subepithelial vessels in a less invasive manner, Tanaka and coworkers (64) used a novel, high-magnification bronchovideoscope in 24 patients with stable asthma, 13 patients with COPD, and 12 healthy control subjects. In patients with asthma, the redness of the bronchial mucosa seen on conventional bronchoscopy was found to be caused by a fine vascular network. The density of subepithelial vessels, in terms of both area and length, was greater in patients with asthma than in patients with COPD or the healthy subjects. The increase in subepithelial vessels was equivalent in 8 steroid-naive and 16 patients with asthma receiving inhaled glucocorticoids. The authors conclude that patients with asthma have increased subepithelial microvessels in the tracheal mucosa and these vessels are present even in newly diagnosed patients. Transforming growth factor-ß is implicated in the remodeling of asthma: levels are increased in bronchial fluid, gene expression is increased in bronchial tissue, and the growth factor increases the release of collagen from airway smooth muscle. Burgess and coworkers (65) examined whether transforming growth factor-ß induces expression and release of connective tissue growth factor in smooth muscle cells of the human airway. Transforming growth factor-ß induced both messenger RNA (38-fold increase at 24 hours versus 14-fold increase at time zero) and protein production (68-fold versus 4-fold increase) for connective tissue growth factor. The response was greater in airway smooth muscle cultured from patients with asthma than in airway smooth muscle from subjects without asthma. The authors conclude that messenger RNA and protein of connective tissue growth factor are found in smooth muscle cells of the human airway and that transforming growth factor-ß enhances gene expression for this growth factor in smooth muscle cells of patients with asthma. Mechanical distortion of blood vessels is known to activate endothelial cells. To determine whether airway distension with the application of PEEP promotes leukocyte recruitment, Lim and Wagner (66) used intravital microscopy in rat tracheas. Normal mechanical ventilation produced no change in leukocyte rolling velocity and the number of adherent cells over 2 hours. Ventilation with PEEP of 8 cm H2O for 1 hour caused a decrease in leukocyte rolling velocity and an increase in adhesion. PEEP did not alter leukocyte recruitment in the mesenteric circulation. Application of PEEP distal to the site of measurement in the airway did not induce leukocyte recruitment. Pretreatment with endothelin receptor and selectin inhibitors blocks the effect of PEEP on leukocyte recruitment. The authors conclude that airway distension induced by PEEP leads to inflammatory leukocyte trafficking in the airways. An editorial commentary by Uhlig (67) accompanies this article.
Treatment The actions of glucocorticoids are determined in part by the type 2 isoform of 11ß-hydroxysteroid dehydrogenase. In a line of human bronchial epithelial cells (BEAS-2B), Suzuki and coworkers (70) determined whether inhibition of this enzyme potentiates the inhibitory action of dexamethasone on release of interleukin-8 and whether the enzyme is upregulated during prolonged treatment with dexamethasone. Carbenoxolone, an inhibitor of 11ß-hydroxysteroid dehydrogenase, increased the potency of dexamethasone almost 10-fold. Incubation of the epithelial cells with increasing concentrations of dexamethasone for up to 72 hours led to considerable increases in messenger RNA and protein levels of the enzyme. Prolonged treatment with dexamethasone increased the activity of the enzyme in a dose- and time-dependent fashion. The authors conclude that bronchial epithelial cells autoregulate the bioactive levels of glucocorticoids by inducing expression of 11ß-hydroxysteroid dehydrogenase type 2 and that this enzyme may locally regulate the action of inhaled glucocorticoids.
Theophylline.
Combination regimens.
In 28 patients with mild asthma, O'Sullivan and coworkers (74) determined whether adding montelukast (10 mg at night) would have an additional effect over inhaled fluticasone propionate (100 µg twice a day) on airway inflammation. Patients received inhaled fluticasone propionate plus montelukast for 8 weeks, and were then crossed over to the alternate treatment for another 8 weeks. After 8 weeks there were no differences in percent-predicted FEV1 or the dose of histamine producing a 20% decrease in FEV1. Both treatment arms achieved equivalent decreases in T cells, CD45RO+, mast cells, activated eosinophils in bronchial biopsies, and percentage area stained for interferon- To determine whether the addition of a leukotriene receptor antagonist is beneficial in patients being treated with an optimal dose of inhaled glucocorticoid alone or inhaled glucocorticoid combined with a long-acting ß2-agonist, Currie and coworkers (75) did a double-blind controlled trial in 22 patients with mild-to-moderate asthma. Compared with a 2-week run-in consisting of a combination of fluticasone propionate (250 µg) and salmeterol (50 µg), delivered as 1 puff twice daily, the addition of montelukast (10 mg daily) achieved a reduction in inflammatory mediators, although lung function was not affected. Compared with the fluticasone–salmeterol run-in, the addition of montelukast decreased blood eosinophils, decreased exhaled nitric oxide, decreased the recovery time after adenosine monophosphate challenge, and increased the threshold of adenosine monophosphate. The authors conclude that the addition of montelukast to an inhaled glucocorticoid (alone or in combination with a long-acting ß2-agonist) produced a decrease in surrogate markers of inflammation without having a beneficial effect on lung function.
Management plans and education.
New agents. In 26 patients with severe persistent asthma being treated with oral or high-dose inhaled glucocorticoids, Kips and coworkers (79) did a double-blind randomized trial of increasing doses of an antibody directed against interleukin-5 (SCH55700). Intravenous administration of the antibody achieved dose-dependent decreases in circulating eosinophils. Eosinophils remained depressed at 30 days after a dose of 1 mg per kg: 0.07 versus 0.23 x 109 per liter at baseline. Administration of 0.3 mg per kg produced a significant increase in FEV1 at 24 hours. Adverse effects were not noted. The authors conclude that SCH55700 is a biologically active antibody against interleukin-5 that can be safely used in patients with severe asthma. An editorial commentary by Kay and Menzies-Gow (80) accompanies this article.
Specific Clinical Scenarios
Pregnancy.
Dyspnea.
Radiology.
Occupational Asthma The American Thoracic Society (86) presents a statement from the first Jack Pepys Occupational Asthma Symposium.
Supported by a Merit Review grant from the Veterans Affairs Research Service Conflict of Interest Statement: M.J.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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ALLERGIC RHINITIS AND NASAL...
in airway epithelial cells (NCI-H292 cells or human nasal epithelial cells). Expression of MUC5AC messenger RNA was also inhibited. The authors conclude that the macrolide antibiotics, clarithromycin and erythromycin, directly inhibit the secretion of mucus by airway epithelial cells. 
and late release of pulmonary and activation-regulated chemokine. Both Th1- and Th2-attracting chemokines were induced, but the resulting effect was increased chemotactic activity of Th2 cells and not of Th1 cells. Diesel induced a late increase in the expression of the Th1-associated CXC receptor 3 and CC receptor 5. Upregulation of T cell CXC receptor 3 was not associated with increased migration to its ligands. The authors conclude that diesel, even in the absence of allergen, amplifies Th2 immune response and that it also increases late Th1-associated chemoreceptor expression. 
B, is inactive when it is bound to its inhibitory protein, I
T cells, especially V