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Interstitial Lung Disease, Lung Cancer, Lung Transplantation, Pulmonary Vascular Disorders, and Sleep-disordered Breathing in AJRCCM in 2004

Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Denver Veterans Affairs Medical Center; Departments of Medicine and Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado; Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, United Kingdom

Correspondence and requests for reprints should be addressed to Edward Abraham, M.D., University of Colorado Health Sciences Center, Division of Pulmonary Sciences and Critical Care Medicine, 4200 East 9th Avenue, Box C272, Room 5503, Denver, CO 80262-0001. E-mail: edward.abraham{at}uchsc.edu

	INTERSTITIAL LUNG DISEASE

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Idiopathic Pulmonary Fibrosis
Histopathologic subtypes.
Contradictory data have been published regarding vascular remodeling in idiopathic pulmonary fibrosis (IPF). Ebina and coworkers (1) examined alveolar vascularity in surgical lung tissue from seven patients with usual interstitial pneumonia. Alveolar capillary endothelial cells were examined with antibodies for CD34, von Willebrand factor, and thrombomodulin. Alveolar capillaries with CD34-positive endothelial cells were increased in nonfibrotic lesions, with a subset immunoreactive for Ki-67, a marker of proliferation. Alveolar type II epithelial cells in close contact with increased capillary endothelial cells were intensively immunoreactive with the potent angiogenic factors vascular endothelial growth factor and interleukin 8. Vascular density gradually decreased as the degree of fibrosis increased. No vessels were seen inside fibroblastic foci. Venules with CD34-negative, but von Willebrand factor–positive endothelial cells were localized in the center of fibrotic lesions and were identified as postcapillary venules. Heterogeneous vascular remodeling was confirmed in usual interstitial pneumonia. The increase in CD34-positive capillaries in nonfibrotic lesions was believed to be related to subsequent events in the fibrotic process. The authors hypothesized that this may contribute to the regeneration of alveolar walls in IPF.

Biomarkers.
The effect of IFN- on the clinical course of IPF remains controversial. Strieter and colleagues (2) administered thrice-weekly IFN- (n = 17) or placebo (n = 15) for 6 months to patients with IPF. No significant difference was seen in clinical efficacy endpoints between the two groups. The primary endpoint (the change from baseline in mRNA transcription for transforming growth factor ß (TGF-ß) and connective tissue growth factor (CTGF) in transbronchial biopsies did not differ between the two groups. Several secondary endpoints did achieve statistical significance, including the upregulation of IFN-inducible T-cell- chemoattractant (ITAC)/CXCL11 in bronchoalveolar lavage fluid and in plasma with IFN- treatment. A favorable change in several other biomarkers of fibrosis approached significance. The authors suggest that IFN- therapy may affect biomarkers of fibrosis, angiogenesis, proliferation, immunomodulation, and antimicrobial activity.

Clinical assessment.
Bronchiolitis obliterans syndrome (BOS) is the main cause of graft loss and mortality after lung transplantation. Physiologic criteria have been used to define this syndrome. A recent expert panel proposed that a new stage be used (Stage 0-p) to define early change in allograft function. The BOS Stage 0-p has been defined as a 10 to 19% decrease in FEV₁ or a 25% or more decrease in mean forced expiratory flow during the middle half of the FVC (FEF_25–75%) from baseline. Hachem and colleagues (3) retrospectively examined serial spirometric studies in 203 double lung transplant recipients during a mean of 2.7 ± 1.7 years of observation. They noted that the FEV₁ BOS 0-p criterion exhibited a reasonable positive predictive value of 79% and a negative predictive value of 82% for the subsequent development of BOS Stage 1. Fifty-seven percent of patients that met FEV₁ BOS 0-p criteria progressed to BOS Stage 1 within 1 year. The FEF_25–75% criterion demonstrated lower operating characteristics. These data provide the first large study of the predictive criteria of the most recent physiologic criteria used to define BOS.

Cellular and molecular mechanisms, in vivo.
Several groups have suggested that community-acquired respiratory viral infections are associated with chronic graft dysfunction after lung transplantation. Khalifah and colleagues (4) performed a retrospective analysis of 228 consecutive lung transplant recipients during a mean follow-up of approximately 3 years. Twenty-one of the recipients experienced a community-acquired respiratory viral infection during follow-up; respiratory syncytial virus and parainfluenza virus were most frequently seen. In multivariable analysis, the presence of community-acquired respiratory viral infection and acute rejection were independently associated with the development of BOS and death. These data further support the importance of community-acquired respiratory viral infections in lung transplant recipients.

Epithelial cell injury and repair are believed to be critical in the pathogenesis of interstitial lung disease. Lappi-Blanco and colleagues (5) used immunohistochemistry, in situ hybridization, and immunoelectron microscopy to study the expression of laminin-5₂, believed to be critical in promoting epithelial adhesion, in IPF and cryptogenic organizing pneumonia, disorders with divergent outcomes. Although reepithelialization was decreased in IPF, laminin-5₂ was synthesized by epithelial cells in either case.

Alterations in angiogenesis may underlie some of the abnormalities in IPF. Cosgrove and colleagues (6) noted that pigment epithelium–derived factor was increased in oligonucleotide microarray analysis of lungs of patients with IPF. Pigment epithelium–derived factor is a highly active angiostatic peptide, so the authors further examined the relationship between its expression and angiogenesis in fibroblastic foci. Decreased angiogenesis and increased pigment epithelium–derived factor were found to colocalize. Furthermore, the fibrogenic cytokine, TGF-ß1, which colocalized with pigment epithelium–derived factor, was shown to induce pigment epithelium–derived factor in cell culture. The authors postulated that TGF-ß1 and pigment epithelium–derived factor are pathogenic in the aberrant angiogenesis found in IPF.

Idiopathic interstitial pneumonias (IIPs) are poorly understood and often respond poorly to therapy. Choi and colleagues (7) examined microarray analyses of gene expression in usual interstitial pneumonia and studied the CC chemokine CCL7 further with real-time reverse transcriptase–polymerase chain reaction, immunohistochemistry, and ELISA. CCL7 expression is upregulated in the IIPs and derivative fibroblast cell lines. CCL5 can induce CCL7 in vitro. The authors concluded that CCL7 may be involved in the fibrotic processes underlying IIPs.

Idiopathic Interstitial Pneumonia
The diagnostic approach to IIPs has continued to evolve, with international expert guidelines recommending a dynamic interactive diagnostic process involving clinicians, radiologists, and pathologists. Flaherty and colleagues (8) examined such an iterative approach among three expert clinicians, two radiologists, and two pathologists in evaluating 58 consecutive patients with IIP. Data were reviewed by all participants in an incremental fashion. Interobserver agreement improved as additional data were provided and interaction occurred. This was particularly evident with the inclusion of histopathologic data. Patients with typical clinical and radiologic features of IPF may not require surgical lung biopsy, although in non-IPF IIPs, surgical lung biopsy frequently led to a change in final diagnosis. These data support that an iterative approach among expert diagnosticians may be an optimal diagnostic approach to IIPs.

Sarcoidosis
Genetics.
Susceptibility to sarcoidosis is linked to the HLA locus. Grunewald and colleagues (9) examined the association between various HLA class I and II alleles and disease course in a cohort of 166 Scandanavian patients with sarcoidosis. They found associations suggesting that both HLA class I and II polymorphisms are important in sarcoidosis and defined specific HLA haplotypes associated with good and bad prognoses.

CC10 (uteroglobin) has immunosuppressive actions. Thus, polymorphisms affecting CC10 expression are attractive candidate genes for sarcoidosis susceptibility. Ohchi and coworkers (10) examined the frequency of A38G polymorphisms of the CC10 gene in Japanese patients with sarcoidosis and control subjects from the Hokkaido region. The frequency of the A38 allele was found to be significantly increased in sarcoidosis. Furthermore, the authors demonstrated that bronchoalveolar lavage CC10 levels correlated with A38G genotype and showed that the polymorphism is functional in reporter gene assays.

Janssen and colleagues (11) followed up on the previously described report (10) that the A38 allele of the CC10 gene is increased in Japanese patients with sarcoidosis from the Hokkaido region and examined A38G allele frequencies in patients with sarcoidosis from the Netherlands and the Kyoto region of Japan. No significant differences in allele frequencies were found between cases and control subjects. The A38 allele was more frequent in the Hokkaido control subjects than the Kyoto control subjects. This study emphasizes the need to generalize genetic association studies cautiously in light of variations in polymorphism frequency in different populations.

Molecular mechanisms.
Phansalkar and coworkers (12) simultaneously measured the diffusing capacity for carbon monoxide, the diffusing capacity for nitric oxide, lung volumes, and cardiac output in patients with stage II–III sarcoidosis. They hypothesized that a strong relationship exists between diffusing capacity for carbon monoxide and membrane diffusing capacity for carbon monoxide and that microvascular recruitment in sarcoidosis is relatively normal. From these studies, they derived information on the alveolar pathophysiology of sarcoidosis.

Epidemiology.
Sarcoidosis has long been assumed to be environmentally induced in genetically susceptible individuals, but the antigen(s) are not identified. In this collaborative epidemiologic investigation performed at 10 centers and including over 700 newly diagnosed patients with sarcoidosis, Newman and collaborators (13) identified several factors associated with sarcoidosis. Agricultural work, especially involving exposure to insecticides, and work environments with mildew or mold exposure were associated with significant increases in risk for development of sarcoidosis. Cigarette smoking was associated with a decreased risk. The authors concluded that no single exposure causes sarcoidosis. However, agricultural occupations, exposure to insecticides, or work with exposure to microbial bioaerosols may be associated with sarcoidosis.

Review.
A National Heart, Lung, and Blood Institute (NHLBI) workshop, summarized by Martin and colleagues (14), explored future directions in sarcoidosis research and suggested development of tissue banks, novel approaches to understanding genetic predisposition, further studies of immunopathogenesis, novel biologically based therapeutics, and further randomized controlled trials of therapy.

Hypersensitivity Pneumonitis
The lower incidence of hypersensitivity pneumonitis in smokers is a well-known clinical association. Blanchet and coworkers (15) examined whether nicotine might be responsible for this effect. Nicotine or vehicle was administered to mice either intranasally or intraperitoneally simultaneously with induction of a model of hypersensitivity pneumonitis. Lung inflammation, as measured by histology or bronchoalveolar lavage cell counts, was reduced in the nicotine-treated mice, as was mRNA for some inflammatory cytokines, including IFN-. The authors concluded that nicotine reduces some measures of inflammation in this model and suggest that nicotine treatment of hypersensitivity pneumonitis, as is done in ulcerative colitis, be considered.

	LUNG CANCER

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Diagnosis
Gene expression profiling of lung tumors may yield clinically useful information, including tumor classification, diagnosis, prognosis, and response to specific treatments. Most gene expression profiling has been done with surgically resected tissue, which is not the optimal method of tissue sampling for many clinical purposes. Borczuk and colleagues (16) demonstrated that useful gene expression profiling can be done with excess tissue from clinically indicated bronchial brushings or transthoracic needle aspirations. Histologic and prognostic class prediction models were devised, demonstrating the potential clinical and research utility of gene expression profiling using small excess tissue samples obtained for clinical purposes.

Gene expression profiling assesses the expression of tens of thousands of genes simultaneously and may yield highly accurate information on diagnosis, prognosis, and treatment response. Hofmann and coworkers (17) analyzed gene expression profiles of non–small cell lung cancer or lung metastasis specimens and normal lung. They hypothesized that the expression ratio of mRNAs for the receptor for advanced glycation end products and cyclin B2 was a powerful discriminator between normal lung and lung neoplasm. They then tested this prospectively in a different set of lung tumors using quantitative reverse transcriptase–polymerase chain reaction and validated the accuracy of this discriminator. Application of microarray-based gene expression data to develop expression ratio–based diagnostic tools may be economical and clinically useful.

Studies of Molecular Mechanisms
Current treatments for malignant pleural mesothelioma are inadequate. Ebstein and coworkers (18) have assessed a new strategy for dendritic cell–based immunotherapy, loading dendritic cells with apoptotic mesothelioma cells that were either heat shocked before induction of apoptosis or were not. Improved immune response to mesothelioma cells was obtained in the preparations, including dendritic cells loaded with heat shock protein 70 expressing mesothelioma cells.

Malignant and premalignant pulmonary epithelial tissues of current or ex-smokers exhibit multiple genetic alterations that drive the malignant process. Massion and colleagues (19) examined the expression of phosphatidylinositol 3-kinase and phospho-Akt, two members of a critical pathway regulating susceptibility to apoptosis, in lung cancer and premalignant bronchial epithelium. They demonstrated frequent amplification of the gene encoding a subunit of phosphatidylinositol 3-kinase and frequent presence of a downstream metabolite, phospho-Akt, in tumors and in the higher grades of premalignant dysplasia, suggesting diagnostic and potential therapeutic strategies for both chemotherapy and chemoprevention.

Treatment
A significant proportion of patients with lung cancer develop airway obstruction from tumor resulting in diminished terminal quality of life. Miyazawa and colleagues (20) prospectively studied 64 such patients using helical computed tomography (CT), bronchoscopy, endobronchial ultrasound, ultrathin bronchoscopy, and pulmonary function testing to determine optimal strategies for stent placement. When stents were placed based on choke point determination, symptomatic and physiologic results were excellent. In some cases, the choke point migrated distally to a segment of airway weakened by tumor destruction of cartilage; secondary stenting was effective in these cases. These studies refine the strategy for optimal placement of airway stents in selected patients with lung cancer.

	LUNG TRANSPLANTATION

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Obliterative Bronchiolitis
The clinical significance of minimal acute rejection (A₁ histology) after lung transplantation has remained controversial. Hopkins and colleagues (21) prospectively examined 1,159 transbronchial biopsies in 184 recipients over a 6-year period. Two hundred seventy-nine biopsies in 128 patients exhibited findings of A₁ histology. Sixty-four of 255 surveillance biopsies with A₁ histology progressed to higher grade rejection within 3 months of follow-up. Seventy-eight patients experienced two or more A₁ biopsies in the first 12 months after transplantation. BOS developed in 68% of these patients compared with 43% of patients with less than one A₁ biopsy. As such, a statistically significantly greater development of BOS was noted in patients with multiple episodes of minimal acute rejection. These data suggest that a cavalier approach to the management of minimal acute rejection may not be appropriate.

Rejection
In a state of the art review, Kotloff and colleagues (22) provided a comprehensive review of the pulmonary complications frequently noted after solid organ and hematopoetic stem cell transplantation.

Immunology and Biochemistry
Reimplantation injury remains a common clinical hurdle in lung transplantation. The proinflammatory effects of tumor necrosis factor have been implicated in this process. Goto and coworkers (23) examined the role of inhibiting tumor necrosis factor –converting enzyme (TACE), which mediates cleavage of membrane-associated tumor necrosis factor to its bioactive soluble form, in a rat model of lung transplantation. Inhibition of TACE attenuated endothelial and alveolar septal damage as well as neutrophil accumulation. Bronchoalveolar levels of monocyte chemoattractant protein-1 (MCP-1), cytokine-induced neutrophil chemoattractant-1 (CINC-1), high mobility group box protein-1 (HMGB-1), soluble E-cadherin, and neutrophil elastase activity were also decreased with TACE inhibition. The authors concluded that TACE mediates a critical step in the genesis of post-transplantation acute lung injury.

Pulmonary Function
Concern regarding the physiologic and clinical implications of native lung hyperinflation in patients with emphysema undergoing single lung transplantation has been longstanding. De Groote and colleagues (24) provided an innovative study merging imaging and physiologic testing in defining the movement of the chest wall and mediastinum in eight patients with emphysema after single lung transplant. Using optoelectronic plethysmography, the authors confirmed that the functional residual capacity and total lung capacity in the native and transplanted hemithoraces were identical. In addition, changes in CO₂-induced hyperpnea and FVC maneuvers were similar. Using dynamic CT, the authors documented displacement of the mediastinum toward the native lung during tidal and full inspiration, and toward the graft during tidal and forced expiration.

	PULMONARY VASCULAR DISORDERS

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Pulmonary Hypertension
Molecular and pathophysiologic mechanisms.
Pulmonary hypertension (PH) is a significant complication of fibrotic lung diseases. Leuchte and colleagues (25) identified moderate to severe PH in 11 of 39 patients with fibrotic lung diseases (28 of 39 with IPF). No difference in lung function parameters was noted between patients with and without PH, although the former did exhibit a lower 6-minute walk distance. Similarly, no differences were seen between patients with and without IPF. Plasma brain natriuretic peptide levels were significantly higher in patients with PH; a threshold level of 33 pg/ml for brain natriuretic peptide exhibited a sensitivity of 1.0 and specificity of 0.89 for identifying PH. These data suggest that plasma brain natriuretic peptide may serve as a reasonable screening test for identifying PH in patients with fibrotic lung disease.

Sildenafil, an oral phosphodiesterase type-5 inhibitor, and beraprost, an oral prostacyclin analog, induce pulmonary vasorelaxation through different mechanisms. Itoh and coworkers (26) studied each of these agents alone or in combination in a monocrotaline model of pulmonary vasculopathy in rats. Three weeks after monocrotaline injection, there was significant development of PH, which was attenuated with sildanefil and beraprost treatment. The combination of these two led to additive effects in hemodynamics, physiology, morphometry, and plasma cAMP and cGMP levels. All rats treated with combination therapy survived, suggesting the amelioration of PH. These data suggest that combination therapy may be a novel approach to the management of PH.

Oxidative stress has been suggested in patients with severe PH. Bowers and colleagues (27) examined lung tissue from 20 patients with PH (13 primary, 7 secondary) and lung tissue from control subjects. By combining immunohistochemistry (8-hydroxy guanine, nitrotyrosine), protein measurement (manganese-containing superoxide dismutase), and mass spectroscopy (various eicosanoid metabolites), this group was able to demonstrate that oxidative stress can be documented in lung tissue of patients with severe PH. In addition, lung tissue from patients under chronic prostacyclin infusion therapy exhibited lower concentrations of eicosanoid metabolites. Whether ischemia/reperfusion or inflammation, or both, contribute to this oxidative stress remains conjectural.

Pulmonary vascular remodeling has been well described in humans and in animal models of chronic hypoxia. Unfortunately, the role of oxygen deprivation or associated erythrocytosis has remained controversial. Hasegawa and colleagues (28) studied transgenic mice that constitutively overexpress human erythropoietin gene in an oxygen-independent manner. These mice exhibited impressive polycythemia and pulmonary artery pressures in vivo. Importantly, the transgenic mice, in contrast to wild-type mice, showed reduced thickness of the pulmonary arterial vessels, elevated prostacyclin production, and stronger endothelial nitric oxide synthase expression. In isolated, blood-free perfused lungs, transgenic mice exhibited lower pulmonary artery pressures than wild-type mice. These data suggest that the increased hematocrit and blood viscosity lead to the PH seen in vivo in this transgenic mouse model.

A link between 5-hydroxytryptamine (5-HT) and PH, particularly in response to chronic hypoxia, has been suggested. Welsh and colleagues (29) determined that 5-HT has a comitogenic effect with serum to produce enhanced proliferation of rat pulmonary artery fibroblasts from chronically hypoxic rats. In addition, the data presented suggest that the 5-HT_2A receptor may be responsible for hypoxia-associated 5-HT proliferation noted in this model. Furthermore, this study demonstrated that the 5-HT_2A receptor signals via p38 mitogen-activated protein kinase, and that the 5-HT transporter is important in the mitogenic response. The authors speculate that HT_2A receptor antagonists could have a therapeutic role in modulating pulmonary artery fibroblast proliferation in PH.

Endothelial dysfunction is believed to be a crucial event in the onset and progression of PH. Murata and colleagues (30) examined the effect of dexamethasone on hypoxia-induced dysfunction of the pulmonary endothelium in organ-cultured rabbit intrapulmonary arteries. The authors confirmed that dexamethasone inhibited hypoxia-induced impairment of endothelial-dependent relaxation, cGMP accumulation, and the increase in intracellular Ca²⁺ level under substance P-stimulated conditions. Dexamethasone treatment also restored decreased endothelium-dependent relaxation. Additional mechanistic studies confirmed that the beneficial effects of dexamethasone on chronic hypoxia-induced endothelial dysfunction were related to a protective effect on endothelial nitric oxide production.

Abnormalities of TGF-ß signaling have been linked to the development of PH. Richter and coworkers (31) examined the cellular pattern and expression intensity of TGF-ß signaling molecules in normal human pulmonary arteries and pulmonary arteries from patients with emphysema or idiopathic PH. Using immunohistochemistry and quantitative morphometry, the authors demonstrated that endothelial cells lining normal or remodeled pulmonary arteries expressed all TGF-ß signaling molecules. Interestingly, core endothelial cells of plexiform lesions in idiopathic PH failed to express these molecules. As such, these data confirm that pulmonary artery endothelial cells have active TGF-ß signaling, whereas the loss of such signaling may contribute to abnormal endothelial growth in plexiform lesions.

C-type natriuretic peptide acts as a local regulator of vascular tone and remodeling, while exhibiting antiinflammatory and antithrombotic effects in blood vessels. Itoh and colleagues (32) confirmed that C-type natriuretic peptide infusion attenuated the development of monocrotaline-induced PH in rats. This infusion enhanced Ki-67, a marker for endothelial cell proliferation, and augmented lung tissue content of endothelial nitric oxide synthase. Furthermore, C-type natriuretic peptide infusion suppressed apoptosis of pulmonary endothelial cells, decreased monocyte/macrophage infiltration, and inhibited expression of plasminogen activator inhibitor type 1. It also improved survival rate. Beneficial effects were also seen when C-type natriuretic peptide was infused in established PH.

Bosentan has been successfully used to treat PH in humans. Few data have been available examining its in vitro mechanism of action, however. Kunichika and colleagues (33) examined the effect of bosentan on human pulmonary artery smooth muscle cells from normal subjects and patients with idiopathic PH. Bosentan inhibited endothelin-1 (ET-1), as well as platelet-derived growth factor, mediated pulmonary artery smooth muscle cell proliferation. The effects of bosentan on platelet-derived growth factor–mediated proliferation was much greater in cells from patients with PH than normal subjects. Furthermore, data presented suggest that ET-1 and platelet-derived growth factor–mediated pulmonary artery smooth muscle cell proliferation is associated with upregulation of transient receptor potential channel 6; this process was downregulated by bosentan. These data provide a mechanistic correlate to the clinical efficacy reported for this ET receptor blocker in humans with PH.

Lung tissue of patients with PH is difficult to obtain. Bull and colleagues (34) used oligonucleotide microarrays to detect gene expression differences in a surrogate tissue, peripheral blood mononuclear cells, between patients with PH and control patients. Unsupervised clustering revealed that the patterns of gene expression in patients with PH were more closely related to each other than to that in control subjects. Using training and test set analysis, the predictive value of gene expression patterns was validated. Supervised clustering revealed that genes involved in inflammation, stress response, and intracellular signaling exhibit different expression in PH. No statistically robust differences in gene expression between primary and secondary PH were found, but the relatively small sample size may have contributed to this failure.

Treatment.
ET is a potent, endogenous peptide with vasoconstrictor, mitogenic, and profibrotic effects. Two distinct ET receptor isoforms have been identified (ET_A and ET_B); activation of ET_A facilitates vasoconstriction and proliferation of vascular smooth muscle. An ET_A/ET_B receptor blocker has been approved for use in human PH. Barst and colleagues (35) examined the effect of two doses of sitaxsentan, a more selective, potent ET_A receptor antagonist versus placebo for 12 weeks in 178 patients with idiopathic, connective tissue–related, or congenital systemic-to-pulmonary shunt–related PH. The primary endpoint (% predicted peak O₂) improved modestly with high-dose, but not low-dose, sitaxsentan in contrast to placebo. Importantly, numerous clinically relevant secondary endpoints (6-minute walk distance, several pulmonary hemodynamic measurements, and New York Heart Association (NYHA) functional status) improved with both doses of active drug in contrast to placebo. Safety profiles were similar for both doses of sitaxsentan. These data suggest that selective ET_A receptor blockade may serve as a novel therapy of human PH.

Sildenafil, an oral phosphodiesterase type-5 inhibitor, is currently being investigated for the treatment of PH in humans. The chronic effects of this agent remain unclear. Schermuly and colleagues (36) examined the effects of sildenafil administration from Weeks 2 through 4 and, in separate experiments, from Days 28 through 42 after monocrotaline administration in rats. Sildenafil administration attenuated PH and right ventricular remodeling compared with monocrotaline-treated control animals. In addition, fewer animals died when treated with sildanefil from Days 28 through 42 in contrast to monocrotaline-treated control animals. These data suggest that, in an experimental model of PH, sildanefil exhibits an acute vasodilatory and antiremodeling effect.

PH has been reported to complicate infection with HIV. Sitbon and colleagues (37) reported an open-labeled, 16-week study of bosentan in 16 patients with HIV-associated PH. Improvement was reported in 6-minute walk distance, NYHA class, hemodynamics, Doppler-echocardiographic variables, and health status. Bosentan administration was well tolerated, with no negative impact on control of HIV infection or unexpected hepatic toxicity. This small, uncontrolled study supports the use of this ET antagonist in HIV-associated PH.

Thromboembolic Disorders
The diagnosis of pulmonary embolism remains a clinically challenging problem. Previous attempts to diagnose pulmonary embolism using radiolabeled, anti-fibrin–specific antibodies and nuclear imaging have been unimpressive. Morris and colleagues (38) combined the techniques of radiolabeled, "deimmunized," murine antihuman D-dimer antibody fragments, which quickly clear from the circulation, and single photon emission CT in a canine model of pulmonary embolism. In five dogs, this technique detected all clots 0.4 g or greater with an optimal imaging time of 4 hours. These data suggest that nuclear medicine techniques may be a useful technique for detecting pulmonary embolism.

Hereditary Hemorrhagic Telangiectasia
Hereditary hemorrhagic telangiectasia can be complicated by devastating neurologic complications, two thirds of which are caused by pulmonary arteriovenous malformations. Transcatheter ablation techniques make the detection of pulmonary arteriovenous malformations a practical issue for the preventive health care of patients with hereditary hemorrhagic telangiectasia, but the best method of diagnosis is unclear. Cottin and colleagues (39) retrospectively analyzed various techniques for the detection of pulmonary arteriovenous malformations in 105 patients with hereditary hemorrhagic telangiectasia, using pulmonary angiography or contrast CT as the gold standards. Dyspnea, chest radiograph, shunt fraction–measured breathing 100% O₂, contrast echocardiography, and radionucleotide perfusion scanning were assessed. Contrast echocardiography in the supine position was most sensitive (93%). The authors conclude that a diagnostic strategy of either contrast echocardiography or CT scan with contrast was the most effective.

Sickle Cell Disease
It has been suggested that sickle cell disease is associated with a "proinflammatory state" and that this predisposes patients with sickle cell disease to the acute chest syndrome in response to trigger factors. To determine whether a proinflammatory state truly exists in sickle cell disease, Holtzclaw and coworkers (40) studied the effects of intraperitoneal endotoxin (LPS) in transgenic sickle and control mice. Sickle mice at baseline differed from control mice only by the presence of elevated levels of circulating lymphocytes and soluble vascular cell adhesion molecule 1. In response to the LPS challenge, sickle mice showed significant increases in mortality and airway tone, as well as in serum and bronchoalveolar lavage levels of the cytokines tumor necrosis factor , interleukin 1ß, and soluble vascular cell adhesion molecule 1, compared with control mice. Microarray analysis 4 hours after LPS identified 413 genes differently expressed in sickle mice compared with only 7 in the control mice. Light microscopy did not reveal any difference in the lung parenchyma between the two groups. These data suggest that sickle red blood cells confer a subclinical proinflammatory state and that the enhanced response to an inflammatory insult in sickle cell disease could play a role in the increased susceptibility to pulmonary dysfunction.

Reviews
In an occasional essay, Fishman (41) focused on the control of normal and hypertensive pulmonary circulations and advances that have occurred over the last century.

	SLEEP-DISORDERED BREATHING

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Epidemiology
The relationship between obstructive sleep apnea (OSA) and obesity is complex. Palmer and colleagues (42) performed the first whole genome analysis of linkage of these two traits in African American subjects. African Americans appear to have more severe OSA than do whites, so this is a particularly important population on which to focus linkage studies. Apnea hypopnea index (AHI) and body mass index (BMI) were measured. A candidate region on 8q was significantly linked to AHI with a lod score of 1.29. BMI was linked to regions on 8q (lod = 2.56) and 4q (lod = 2.63). Adjustment of AHI linkage for BMI did not greatly reduce linkage, but adjustment of BMI linkage for AHI did, suggesting that OSA may modulate obesity significantly. The BMI linkage to 4q substantiates a similar finding in a linkage analysis of type II diabetes mellitus and obesity in African Americans, which supports the generalizability of the finding.

In a pulmonary perspective, Weese-Mayer and coworkers (43) reviewed the exciting progress in congenital central hypoventilation, including both clinical and molecular features, as well as the mutations in the PHOX2b transcription.

Because the prevalence of sleep-disordered breathing (SDB; AHI 5/hour of recording time) and OSA hypopnea syndrome (AHI 5/hour + daytime hypersomnolence) is not known in Indians, Udwadia and coworkers (44) took a sample of 658 urban Indian males from Bombay (Mumbai) visiting a hospital clinic for a routine health examination who then completed questionnaires regarding snoring and symptoms of OSA hypoventilation syndrome. A subset of 258 who were identified for snoring underwent overnight monitoring of cardiopulmonary variables at home from which the AHI was estimated. SDB and OSA hyperventilation syndrome were found in 19.5 and 7.5% of subjects, respectively. Factors associated with the presence of SDB and OSA hyperventilation syndrome included high BMI, increased neck circumference, diabetes, snoring, unrefreshing sleep, recurrent awakenings, daytime hypersomnolence, and fatigue. The authors concluded that SDB and OSA hyperventilation syndrome are common in urban Indian males, and their prevalence may be higher than in Western countries. However, caution must be exercised in accepting the latter conclusion because subjects sought medical attention and were not a random sample of the Indian male population.

Kim and associates (45) administered questionnaires on sleep disorders to 5,020 South Korean men and women between the ages of 40 and 69 years. Of these, 457 underwent overnight polysomnography. They found that OSA, defined as an AHI of 5 or greater per hour of sleep, was present in 27% of men and 16% of women. The prevalence of OSA syndrome (AHI 5/hour + a symptom of excessive daytime sleepiness) was 4.5% in men and 3.2% in women. Male sex and increasing BMI were significant risk factors for OSA, and hypertension was significantly associated with OSA. An interesting finding was that, unlike in predominantly white populations, most subjects in this study who had OSA were not obese. Therefore, OSA is common in South Korean men and women, and its prevalence is similar to that reported in Western countries, despite a markedly lower BMI in subjects found to have OSA in the present study. This finding suggests that factors other than obesity play a more important role in the causation of OSA in Asian than in white subjects.

Howard and colleagues (46) measured the prevalence of excessive sleepiness and OSA, and assessed accident risk factors in 2,342 Australian commercial vehicle drivers and another 161 drivers among 244 invited to undergo polysomnography. More than half (59.6%) of drivers had SDB and 15.8% had OSA plus excessive daytime sleepiness. Twenty-four percent of drivers had excessive sleepiness. Increasing sleepiness was related to an increased accident risk, but sleepiness was more closely related to short sleep time than to the presence of OSA. The sleepiest 5% of drivers had an increased risk of an accident (odds ratio 1.91, p = 0.02, and odds ratio 2.23, p < 0.01, respectively), adjusted for established risk factors. There was an increased accident risk with narcotic analgesic use (odds ratio 2.40, p < 0.01) and antihistamine use (odds ratio 3.44, p = 0.04). However, there was no significant increased risk of accidents associated with the presence of OSA. The authors conclude that chronic excessive sleepiness and SDB are common in Australian commercial vehicle drivers, and that accident risk was related to increasing chronic sleepiness, as well as to antihistamine and narcotic analgesic use. An equally important conclusion is that OSA appears not to constitute an important risk for traffic accidents in commercial truck drivers.

Detecting OSA in commercial drivers may be important because OSA may increase their risk of sleepiness-related accidents. Gurubhagavatula and colleagues (47) prospectively compared accuracies of five strategies in excluding the presence of severe OSA and, secondarily, any sleep apnea among 406 commercial drivers using polysomnography as the criterion standard. They found that a two-stage approach with symptoms plus BMI for everyone, followed by oximetry for a subset, was highly successful, with 91% sensitivity and specificity, and a negative likelihood ratio of 0.10. The authors concluded that two-stage screening may be a convenient, cost-effective means of excluding severe OSA among commercial drivers. However, because commercial truck drivers generally have far fewer accidents per mile and hours driven than noncommercial drivers, it is not clear that OSA has the same implication for motor vehicle accident risk as it does in the general noncommercial driving population. It is therefore not clear that widespread screening to truck drivers would be an effective means of reducing motor vehicle accident risk.

In a pulmonary perspective, Flemons and coworkers (48) examined capacity to perform polysomnographic studies for diagnosing sleep apnea versus demand for such studies in the United Kingdom, Belgium, Australia, the United States, and Canada.

Risk Factors
Franklin and coworkers (49) studied the relationship of habitual snoring with active and passive tobacco smoking in a population-based sample of 15,555 randomly selected men and women who answered a postal questionnaire. Habitual snoring was more prevalent among current smokers (24.0%, p < 0.0001) and ex-smokers (20.3%, p < 0.0001) than in never-smokers (13.7%). Snoring was also more prevalent in never-smokers exposed to passive smoking at home on a daily basis than in never-smokers without this exposure (19.8 vs. 13.3%, p < 0.0001). The frequency of habitual snoring increased with the amount of tobacco smoked. Active smoking and passive smoking were related to snoring, independently of obesity, sex, center, and age. Smoking accounted for 17.1% of the attributable risk of habitual snoring, obesity for 4.3%, and passive smoking for 2.2%. The greater attributable risk for snoring associated with smoking than with obesity was probably related to the much higher prevalence of smoking than of obesity in this population. The authors concluded that current and past smoking, as well as passive smoking, are significant contributors to habitual snoring in the general population. This finding may be because of smoking-induced upper airway inflammation and irritation or to nicotine withdrawal at sleep onset causing destabilization of the respiratory control system. The results of this study, however, must be interpreted with caution, because there were no objective measurements of snoring or of tobacco consumption.

Pathophysiology
Cardiovascular mechanisms.
The angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism influences ACE activity, cardiovascular risk, blood pressure (BP), and possibly the risk of developing Alzheimer's dementia. Lin and colleagues (50) studied the association of the insertion/deletion polymorphism with SDB and hypertension in 1,100 subjects of the Wisconsin Sleep Cohort. The polymorphism did not influence BMI or the occurrence of SDB but was dose-dependently associated with BP. Interestingly, SDB and the insertion/deletion polymorphism interacted significantly to modulate BP independently of age, sex, ethnicity, and BMI. Most specifically, the association of the deletion allele with hypertension was most pronounced in subjects with mild to moderate degrees of sleep apnea (5 AHI 30). The authors hypothesized that, in the absence of SDB, the effect of the deletion allele alone may not be sufficient to increase BP. At severe levels of SDB, the effect of sleep apnea on BP overwhelms any association of the deletion allele with hypertension and occurs independently of any ACE gene genotype.

Endothelial function.
To test the hypothesis that OSA is associated with impaired vascular endothelial function, Nieto and colleagues (51) measured brachial artery diameter and flow-mediated dilation (FMD) in 2,798 older subjects (age 68–96 years) in the Sleep Heart Health Study cohort and related it to severity of OSA as quantified by the AHI and hypoxemia index (% time spent below 90% O₂ saturation). After controlling for potential confounding factors, such as age and obesity, they found significant relationships between greater brachial artery diameter and reduced FMD for both AHI and hypoxemia index, but only at relatively severe degrees of OSA (i.e., AHI 30/hour of sleep and hypoxemia 12%). The relationships between indices of vascular dysfunction were stronger for hypoxemia index than for AHI. These findings support previous findings that OSA is associated with a vascular lesion that could predispose to cardiovascular diseases, but extend them to an older age group in a much larger population than has been previously examined.

Impaired endothelium-dependent vascular relaxation is a prognostic marker of cardiovascular disease. Ip and colleagues (52) examined endothelium-dependent FMD and endothelium-independent nitroglycerine-induced dilation of the brachial artery with Doppler ultrasound in 28 men with and 12 men without OSA. Those with OSA had lower FMD than those without OSA. There was no difference in nitroglycerin-induced dilation. Patients with OSA were then randomized to continuous positive airway pressure (CPAP) or no CPAP for 4 weeks, after which FMD increased in the treated group but not in the untreated group. There was no change in nitroglycerin-induced dilation in either group. CPAP was then withdrawn from the treated patients for 1 week, after which FMD decreased. The authors concluded that patients with OSA have impaired FMD that is at least partially reversible with treatment by CPAP.

Upper airway mechanisms.
Humans with OSA show mixed responses to serotonergic therapies. Veasey and coworkers (53) hypothesized that long-term intermittent hypoxia may result in oxidative injury to upper airway motoneurons, thereby diminishing serotonergic motoneuronal excitation. Unilateral serotonin and glutamate agonist and antagonist microinjections into the hypoglossal motor nuclei in adult rats exposed to 3 weeks of intermittent hypoxia reduced hypoglossal nerve responsiveness (logEC50) for serotonin and N-methyl-D-aspartate. However, long-term intermittent hypoxia did not appear to alter hypoglossal response to -amino-3-hydroxy-methylisoxazole-4-propionic acid injections. There was also an increase in isoprostanes in the dorsal medulla. These results suggest that long-term intermittent hypoxia reduces serotonergic and N-methyl-D-aspartate excitatory output of hypoglossal nerves, and that reduced excitatory responsiveness and lipid peroxidation are largely prevented with superoxide dismutase treatment throughout hypoxia/reoxygenation. Similar alterations in neurochemical responsiveness may occur in select persons with OSA.

Using a custom intraoral surface electrode to record pharyngeal dilator muscle activity (the genioglossus [EMGgg] normalized to the wakeful baseline), Katz and White (54) performed overnight polysomnograms in three groups of children: patients with OSA syndrome (OSAS) without CPAP (n = 13), patients with OSAS with CPAP (n = 5), and control subjects without CPAP (n = 13). In control subjects, the EMGgg in Stage 2 sleep fell to 65 ± 6% (mean ± SD) of baseline, and during REM sleep fell further to 51 ± 9% of baseline (p < 0.05). In patients with OSAS, the EMGgg for apneic breaths during REM (37 ± 9% of baseline) was lower than during stable breathing in REM (83 ± 17% of baseline, p < 0.05) and wakefulness (p < 0.05). CPAP lowered the EMGgg in patients with OSAS during all sleep states. These data indicate that EMGgg compensatory mechanisms remain active during sleep in patients with severe OSAS, that EMGgg reductions are temporally associated with sleep apneas, and that REM sleep is associated with the lowest and most variable EMGgg. These findings are similar to those reported in adults with OSAS, suggesting similar pathophysiology. In addition, these findings demonstrate that CPAP works by passively dilating the upper airway, not by activating upper airway dilating muscles, in children.

Boyd and associates (55) performed morphometric analysis on surgically excised upper airway tissue from nonsnoring control subjects (n = 7) and patients with OSA (n = 11) following palatal surgery. As compared with control subjects, inflammatory cells were increased in the muscular layer of patients with OSA, with CD4+ and activated CD25+ T cells (both increased approximately threefold compared with control subjects) predominating. Inflammation was also present in upper airway mucosa, but with a different pattern consisting of CD8+ (2.8-fold increase) and activated CD25+ (3.2-fold increase) T-cell predominance. As ascertained by immunoreactivity for the panneuronal marker PGP9.5, there was a 5.7-fold increase in intramuscular nerve fibers in patients with OSA compared with control subjects, as well as direct evidence of denervation based on positive immunostaining of the muscle fiber sarcolemmal membrane for the neural cell adhesion molecule in patients with OSA. These data suggest that inflammatory cell infiltration and denervation changes affect not only the mucosa but also the upper airway muscle of patients with OSA. This finding may have important implications for increased susceptibility to upper airway collapse during sleep and impaired ability to generate adequate muscular dilating forces to overcome upper airway obstruction during apneas.

It has been previously reported that OSA is associated with inflammation of the tissues of the soft palate and uvula. Sériès and colleagues (56) investigated the influence of weight and OSA status on inflammatory and histologic features of the uvula. Tissue samples resected during uvulopalatopharyngoplasty in 11 snorers without OSA, 11 subjects with OSA and of similar BMI and age, and 8 additional obese subjects with OSA were examined by immunohistochemistry and histologic staining techniques. The frequency and distribution of immune cells, the amount of collagen, and the integrity of the elastin fiber network were evaluated in uvular sections. T-cell (CD4⁺, CD8⁺) and macrophage counts were higher in the more obese subjects with apnea than in the other two groups. In all patients, T-cell counts correlated with BMI, but there was no relationship with the AHI. A positive correlation was found between elastin fiber network disorganization score and AHI. The authors concluded that the amount of inflammatory markers in the uvula is linked to obesity rather than to OSA, and that OSA is associated with structural alterations of the extracellular matrix of upper airway tissue.

Control of breathing.
Ventilatory instability may play an important role in the pathogenesis of OSA. Wellman and colleagues (57) hypothesized that the influence of ventilatory instability in this disorder would vary depending on the underlying collapsibility of the upper airway. To test this hypothesis, they correlated loop gain with AHI during supine, non-REM sleep in three groups of patients with OSA based on pharyngeal closing pressure: negative pressure group (pharyngeal closing pressure < –1 cm H₂O), atmospheric pressure group (between –1 and +1 cm H₂O), and positive pressure group (> +1 cm H₂O). In an attempt to induce respiratory control system instability by increasing loop gain, the tidal volume amplification factor of proportional assist ventilation was increased until periodic breathing developed, which occurred in 24 of 25 subjects. A significant correlation was found between loop gain and AHI in the atmospheric group only (r = 0.88, p = 0.0016). The authors concluded that loop gain has a substantial impact on apnea severity in certain patients with OSA, particularly those with a pharyngeal closing pressure near atmospheric.

Younes (58) tested the hypothesis that arousal from sleep is not needed to cause opening of the upper airway at the termination of obstructive apneas and hypopneas in patients with OSA. He studied 82 patients with OSA who were on CPAP. During an overnight sleep study, he dialed down their CPAP to 1 cm H₂O and examined the timing of arousals from sleep in relation to termination of obstructive events. He found that only 83% of events were associated with arousals, and that the frequency of airway opening without or before a discernible arousal was greater with hypopneas than apneas, and for events that occurred during delta-wave sleep than in other sleep stages. Furthermore, he found greater airflow undershoot (i.e., a more pronounced reduction in airflow) after the ventilatory period after airway opening when arousals occurred than if they did not occur. He concluded that, contrary to previous thinking, arousals are not necessary for opening of the upper airway at termination of obstructive apneas and hypopneas and that arousals, rather than being a defense mechanism to terminate apneas, may actually predispose to worsening OSA by causing ventilatory instability characterized by ventilatory overshoot at termination of apneas and ventilatory undershoot following the ventilatory period. These conclusions must be interpreted with caution, however, because of difficulties in defining arousals, and because it remains possible that arousals do act as a defense mechanism to terminate apneas in spontaneously occurring OSA in untreated individuals.

Molecular mechanisms.
Matrix metalloproteinases (MMPs) play a role in adverse vascular remodeling in coronary artery disease, and their production is stimulated by hypoxia and inflammatory mediators. Elevated MMP-9 is a poor prognostic marker in patients with atherosclerotic diseases. MMP-9 causes degradation of fibrous plaques and can therefore contribute to plaque rupture. Tazaki and colleagues (59) measured MMP-9 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), in 48 men with OSA and in 18 snoring control subjects matched for age and weight. They found that, compared with control subjects, patients with OSA had higher serum levels of MMP-9 (p < 0.05), but not TIMP-1, and that MMP-9 levels were directly proportional to the frequency of apneas and hypopneas. In a subset of 24 patients with OSA who received CPAP for 1 month, serum MMP-9 decreased significantly (p < 0.01), but had no effect on TIMP-1 levels. These findings suggest that OSA may increase the risk of atherosclerosis through its effects on MMP-9.

Clinical Aspects
In children.
Gozal and colleagues (60) determined cross-sectional area of the pharynx in awake, seated children before and after application of topical anesthesia designed to reduce upper airway reflexes that maintain pharyngeal patency. The authors found that, in snoring children, those with OSA had a greater reduction in pharyngeal cross-sectional area after topical upper airway anesthesia than in children without OSA. In addition, in those in whom upper airway obstruction was related to adenotonsillar hypertrophy, the reduction in pharyngeal cross-sectional area after topical anesthesia was less pronounced than it was before surgery. They concluded that increased pharyngeal collapsibility in response to topical upper airway anesthesia is a sensitive and specific means of identifying snoring children with OSA while they are awake. However, the authors did not report weights or BMIs in children with and without OSA, so that it remains uncertain as to whether differences in dynamic pharyngeal properties were specific to OSA or were related to differences in body habitus between the two groups.

Amin and colleagues (61) performed polysomnography and 24-hour ambulatory BP monitoring in 60 children, divided into those without OSA who had an AHI of lower than 1 per hour of sleep, those with an AHI of 1 to 5 per hour of sleep, and those with an AHI of greater than 5 per hour. The authors found that nocturnal systolic and diastolic BP and daytime systolic BP did not differ among the groups, but that daytime diastolic BP was actually lower in the group with an AHI greater than 5 than in the other groups. In addition, the variability of BP, assessed by the standard deviation of BP calculated from BP measurements taken every 15 minutes, was higher in the subjects with an AHI of greater than 5 per hour than in the other groups, and varied according to the frequency of O₂ desaturations and arousals and by BMI. They concluded that because increased BP variability is abnormal, OSA in children is associated with dysregulation of BP, but not with hypertension. However, the lower daytime diastolic BP that they observed in subjects with an AHI of greater than 5 per hour is not consistent with higher diastolic BP that has been described in association with OSA both in children and adults in previous studies, making these results difficult to interpret.

Neuropsychologic function.
Patients with SDB often have daytime sleepiness and impaired quality of life but may be unaware of nocturnal events or of social problems associated with impaired alertness and inattention, which may be apparent to their bed partner. However, it is not known whether there are differences in quality of life ratings as reported by the patient and by the bed partner on the patient's behalf. Quality of life in 122 patients with SDB was assessed by the patients themselves and their bed partners using the Short-Form 36. Breugelmans and colleagues (62) found that patients with SDB generally rate their quality of life higher than their respective bed partners. Moreover, male patients reported a higher functional status compared with female patients relative to their respective bed partners. In contrast, no differences were noted between self and bed partner quality of life in normal subjects (n = 15) without SDB recruited from the general community. This study suggests that systematic differences exist between patient- and bed partner–assessed quality of life in SDB. Bed partner ratings provide supplemental information on quality of life impairment in SDB. Reasons for differences in perceived quality of life between men and women related to SDB is of interest but remain to be determined.

Diagnostic Techniques
Critical closing pressure (Pcrit) is related to the collapsibility of the upper airway in patients with OSA. However, previous techniques to determine Pcrit were invasive and required technical expertise in its determination. Patil and colleagues (63) described a new, simplified, relatively noninvasive approach to determining Pcrit. The authors studied 44 subjects with OSA during which subjects wore a nasal mask and pressure transducer. During sleep, CPAP was applied at a holding pressure sufficient to maintain upper airway patency, after which a graded reduction in pressures was applied until the upper airway collapsed. They determined that the slope of the pressure–flow relationship at various pressures when flow limitation was present, and by regression analysis, was able to extrapolate the Pcrit. Using this technique, they could therefore determine Pcrit without actually inducing complete occlusion of the upper airway. They concluded that this new technique for determining Pcrit is valid and simpler than previous techniques, and therefore is more widely applicable.

The American Thoracic Society (64) published a report that examined the high demand for in-laboratory polysomnography, combined with long waiting lists and the high cost of this service, and evaluated other more accessible and less expensive means of diagnosing SDB.

Treatment
Airway pressure and flow.
There is growing evidence that OSA is a causal factor for glucose intolerance and insulin resistance. Harsch and colleagues (65) tested the hypothesis that treatment of OSA by CPAP would increase insulin sensitivity. They performed an uncontrolled clinical trial of CPAP in 40 patients with OSA who were nondiabetic. At baseline, an assessment of insulin resistance using the hyperinsulinemic euglycemic clamp technique was performed, followed by repeated assessments after 2 days and 3 months of CPAP therapy. They found that insulin sensitivity increased after just 2 days of CPAP therapy and remained elevated after 3 months of CPAP. Moreover, the increased insulin sensitivity that accompanied CPAP therapy was more pronounced in less obese than in more obese subjects. The authors concluded that OSA is an independent contributor to insulin resistance, and that treatment of OSA by CPAP increases insulin sensitivity. However, one must remain cautious in interpreting these results, because they did not include a control group of untreated patients with OSA with which to compare results in patients treated with CPAP.

Mansfield and coworkers (66) performed a randomized controlled clinical trial of CPAP to treat OSA (AHI > 5/hour of sleep) in 55 patients with congestive heart failure and a left ventricular ejection fraction of less than 55% over 3 months. Forty subjects completed the trial, whereas 15 dropped out. A per protocol analysis, rather than an intention to treat analysis, was performed on the 40 subjects who completed the trial. Among the 21 subjects randomized to CPAP, there was a significant increase in left ventricular ejection fraction, and decreases in overnight urinary norepinephrine concentration and Epworth Sleepiness Scale in association with abolition of OSA. The control group did not experience any such improvements. The authors concluded that treatment of OSA in patients with congestive heart failure can improve cardiovascular function, confirming the findings of a previous study by another group. However, these results need to be interpreted with some caution because two subjects in the CPAP-treated group, but none in the control group, died during the course of the study, and because a very high cutoff left ventricular ejection fraction of less than 55% was used to define left ventricular systolic dysfunction.

Standard practice for CPAP treatment in sleep apnea and hypopnea syndrome requires pressure titration during attended laboratory polysomnography. However, polysomnographic titration is expensive and time-consuming. To ascertain whether CPAP titration performed by an unattended domiciliary autoadjusted CPAP device or with a predicted formula was as effective as CPAP titration performed by full polysomnography, Masa and coworkers (67) performed a multicenter study of 360 patients with sleep apnea and hypopnea syndrome requiring CPAP treatment. The main outcomes were the AHI and subjective daytime sleepiness. Patients were randomly allocated into three groups: standard, autoadjusted, and predicted formula titration with domiciliary adjustment. The follow-up period was 12 weeks. With CPAP treatment, the improvement in subjective sleepiness and AHI was very similar in the three groups. There were no differences in the objective compliance of CPAP treatment and in the drop-out rate of the three groups at the end of the follow-up. The authors concluded that autoadjusted titration at home and predicted formula titration with domiciliary adjustment can replace standard titration, leading to considerable savings in cost and to significant reductions in the waiting list.

Pharmacotherapy.
Ogasa and colleagues (68) examined the effects of (±)-2,5-dimethoxy-4-iodoaminophentamine, a serotonin(2A/2C) receptor agonist, on pharyngeal airflow mechanics in Zucker rats. The pharyngeal pressure associated with flow limitation, maximum inspiratory flow, oronasal resistance, and genioglossus muscle activity was measured before and after the intravenous administration of the agonist. Robust activation of the genioglossus muscle in all rats was associated with decreased upper airway collapsibility (p < 0.05), unchanged maximum flow, and increased oronasal resistance (p < 0.05). There was a smaller decrease (p < 0.05) in upper airway collapsibility that was also associated with increased upstream resistance when the drug was administered after bilateral hypoglossal nerve transection. The authors concluded that systemic administration of a serotonin(2A/2C) receptor agonist improves upper airway collapsibility predominantly, but not exclusively, via stimulation of the hypoglossal nerves, and also increases upstream resistance, at least in part, through activation of nonhypoglossal motoneuronal pools innervating the upper airway muscles. These findings indicate that serotonin agonists have complex effects on upper airway mechanics such that pharyngeal dilating forces are to some extent counteracted by increases in upstream resistance. This may help to explain inconsistent results of serotonin agonists on OSA in humans.

Disturbed sleep is common in asthma. Melatonin has sleep-inducing activity and reportedly affects smooth muscle tone and inflammation. Campos and colleagues (69) evaluated the effect of melatonin on subjective sleep quality in patients with mild and moderate asthma. Twenty-two women with asthma were randomized to receive melatonin 3 mg (n = 12) or placebo (n = 10) before bedtime for 4 weeks. Subjective sleep quality and daytime somnolence were assessed by the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. Pulmonary function was assessed by spirometry. Use of relief medication, asthma symptoms, and morning and evening peak expiratory flow rate were recorded daily. Melatonin treatment significantly improved subjective sleep quality, as compared with placebo (p = 0.04). No significant difference in asthma symptoms, use of relief medication, and daily peak expiratory flow rate was found between groups. The authors concluded that melatonin can improve subjective sleep quality in patients with asthma. However, because subjects did not undergo polysomnography, the authors could not be certain that there was any objective improvement in sleep. Moreover, as they did not include a nonasthmatic control group, it is not clear that the improvement in subjective sleep quality was specific to subjects with asthma. Further studies are needed before melatonin can be recommended in patients with asthma.

Mandibular devices.
Barnes and colleagues (70) performed a randomized controlled crossover trial of 3 months of treatment with nasal CPAP, a mandibular advancement splint (MAS), or a placebo tablet in 114 patients with mild to moderate OSA (AHI 5–30). Both CPAP and MAS reduced the AHI and frequency of arousals and improved nocturnal O₂ saturation, but CPAP had a greater effect. The quality of life, symptoms, and subjective but not objective sleepiness improved to a similar degree with both treatments; however, many of the changes seen in neuropsychologic function and mood were not better than during the placebo period. This study demonstrated that both CPAP and MAS treated OSA and sleepiness effectively, and improved some, but not all, aspects of neurobehavioral function. The relatively small beneficial effects of CPAP and MAS on neuropsychologic function may be from the splint having a lesser effect on OSA than CPAP, and from CPAP being used less in this patient group. Nevertheless, patients preferred CPAP to both MAS and placebo at the end of the trial, suggesting that the better objective improvement in AHI was associated with improved outcomes and greater patient preference.

Anterior mandibular positioners (AMPs) are an alternative to CPAP for the treatment of OSA. However, AMP use is limited by an efficacy rate of 50 to 80% and an inability to predict which patients will respond to therapy. Tsai and coworkers (71) evaluated 23 patients with OSA (respiratory disturbance index 15/hour) with a remotely controlled mandibular positioner, a temporary oral appliance that can advance or retract the mandible. The authors tested the hypothesis that elimination of respiratory events during a remotely controlled mandibular positioner overnight study would predict AMP efficacy, as defined by an absolute reduction in respiratory disturbance index to less than 15 per hour, a relative reduction in respiratory disturbance index of more than 30% from baseline, and a subjective improvement in symptoms. AMP compliance was 82%, and therapeutic efficacy was 53%. Among compliant patients, the positive and negative predictive value of a remotely controlled mandibular positioner study in predicting AMP treatment success was 90 and 89%, respectively. The authors concluded that an overnight remotely controlled mandibular positioner study is highly predictive of a clinical AMP response.

	FOOTNOTES

 
Conflict of Interest Statement: T.D.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; Y.E.M. was site principal investigator for multicenter trials sponsored by Xillix, Inc. ($39,000) in 2003, Peceptronix ($87,000) in 2004, and SomaLogic ($60,000) in 2004; F.J.M. was on an Advisory Board for Intermune Pharmaceuticals in 2003 and was a speaker at conferences sponsored by Intermune Pharmaceuticals in 2003–2004 and received a grant from Actelion Pharmaceuticals for participating in a multicenter clinical trial; D.C.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; W.M. has been reimbursed for travel by GSK, Zambon, AZ, Boehringer Ingelheim, Pfizer, and Micromet and has received honoraria from GSK, AZ, Zambon, and Pfizer for participating as a speaker at scientific meetings. He serves on Advisory Boards for GSK, Pfizer, Aimirall, Amgen, Bayer, and Micromet. He serves as a consultant for Pfizer and SMB Pharmaceuticals and has received research grants to support work carried out in W.M.'s laboratory from SMB, Pfizer, Ceremedix, GSK, Chugi, and Novartis; E.A. has been a consultant for Eli Lilly in 2002 and 2003 and also received clinical research contracts from Eli Lilly.

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