Authors: Ane Johannessen; Sverre Lehmann; Ernst Omenaas; Geir Egil Eide; Per Bakke; Amund Gulsvik

Authors: Stephen G. Spiro; Sam Janes

Authors: Stephen H. Loring; J. Woodrow Weiss

Author: Gerard A. Silvestri

Authors: Benoit Nemery; Jerrold L. Abraham

Authors: Francis X. McCormack; Joel Moss

Authors: Josep M. Montserrat; Francisco Garcia-Rio; Ferran Barbe

Epidemiological and observational studies suggest that sleep-disordered breathing is associated with the subsequent development of hypertension and ultimately with cardiovascular consequences. It may therefore be assumed that continuous positive airway pressure (CPAP) not only avoids sleep-related symptoms but could also mitigate cardiovascular consequences. Short-term studies have revealed a drop in blood pressure, especially in more severe, symptomatic cases of obstructive sleep apnea. Two recent studies have reported that nonsleepy obstructive sleep apnea is associated with an absence of reduced blood pressure after CPAP treatment. This suggests that this group of patients is less susceptible to the consequences of apneas, even those with mild–moderate hypertension or other cardiovascular disorders. However, in patients with severe cardiovascular disease or a higher number of obstructive events, CPAP treatment should be seriously considered.

Authors: Jeanette P. Brown; Christian Taube; Nobuaki Miyahara; Toshiyuki Koya; Roberta Pelanda; Erwin W. Gelfand; Raul M. Torres

Rationale: Arhgef1 is an intracellular protein, expressed by hematopoietic cells, that regulates signaling by both G protein–coupled receptors and RhoA, and, consequently, is required for appropriate migration and adhesion of diverse leukocyte populations.

Objectives: To evaluate a possible contribution for Arhgef1 in the development of airway inflammation and airway hyperreactivity.

Methods: Arhgef1-deficient (Arhgef1^−/−) and wild-type (WT) mice were sensitized and airway challenged, followed by measurement of airway responsiveness to inhaled methacholine. Inflammation was assessed by several parameters that included flow cytometric analysis and histology. Arhgef1-deficient recipients were reconstituted with WT T lymphocytes before sensitization and challenge, and again measured for airway responsiveness and inflammation. Cytokine production in response to specific antigen was measured in cultures of isolated leukocytes from lung and spleen and compared with the levels generated in lung and spleen explant cultures.

Measurements and Main Results: Arhgef1^−/− mice display significantly reduced airway hyperreactivity, Th2 cytokine production, and lung inflammation, despite intact systemic immunity. After airway challenge of Arhgef1^−/− mice, antigen-specific T cells were present in mutant lungs, but were found to interact with CD11c⁺ cells at a significantly reduced frequency. Adoptive transfer of WT T cells into Arhgef1^−/− mice restored airway hyperreactivity and inflammation.

Conclusions: These data demonstrate that T cells depend on Arhgef1 to promote lung inflammation. Moreover, a deficiency in Arhgef1 results in reduced T cell–CD11c⁺ antigen-presenting cell interaction, and likely underscores the inability of Arhgef1^−/− mice to mount an adaptive immune response to airway challenge.

Authors: Susan Chinn; Joachim Heinrich; Josep M. Antó; Christer Janson; Dan Norbäck; Mario Olivieri; Cecilie Svanes; Jordi Sunyer; Giuseppe Verlato; Matthias Wjst; Jan-Paul Zock; Peter G. Burney; Deborah L. Jarvis

Rationale: The association of asthma with sensitization and allergen exposure is known to be complex. There have been few studies of bronchial responsiveness in relation to both risk factors in adults.

Objectives: To determine the relation of bronchial responsiveness to allergen exposure and IgE sensitization in a community study taking into account the major determinants of bronchial responsiveness in adulthood.

Methods: Cross-sectional data were drawn from 1,884 participants in 20 centers in the European Community Respiratory Health Survey follow-up, which included measurement of house dust mite and cat allergen in mattress dust samples, and IgE sensitization to four allergens. Bronchial responsiveness to methacholine was expressed as a continuous variable, and analyzed by multiple regression.

Measurements and Main Results: The trend toward greater bronchial responsiveness with increasing exposure to cat allergen was greater in those sensitized to any of the four allergens than those not sensitized (p = 0.001); there was no significant interaction between cat sensitization and Fel d 1 exposure. No trend was found with house dust mite allergen exposure. The difference in bronchial responsiveness between those exposed to the highest levels compared with the lowest was approximately −2.02 doubling doses of PD20 (95% confidence interval, −3.06 to −0.97), and nearly as great in those exposed to more moderate levels.

Conclusions: Cat allergen exposure at moderate levels may be harmful to all atopic adults. The clinical implication is that it is insufficient to test patients with asthma for cat sensitization; all atopic individuals may benefit from reduced cat exposure.

Authors: Shigeki Katoh; Naoki Ishii; Atsuya Nobumoto; Keisuke Takeshita; Shu-Yan Dai; Rika Shinonaga; Toshiro Niki; Nozomu Nishi; Akira Tominaga; Akira Yamauchi; Mitsuomi Hirashima

Rationale: Galectin-9 (Gal-9) belongs to the galectin family, which exhibits affinity for β-galactosides. Gal-9 has a variety of biological activities; however, its role in allergic inflammation is unknown.

Objectives: We evaluated the effect of a stable form of the human protein on allergic airway inflammation in a mite allergen–induced asthma model.

Methods: Human stable Gal-9 was given by intravenous injection to mice during antigen challenge. The effect of Gal-9 on airway inflammation and airway hyperresponsiveness (AHR) was then evaluated.

Measurements and Main Results: Gal-9 reduced AHR as well as Th2-associated airway inflammation. Furthermore, administration of Gal-9 as well as anti-CD44 monoclonal antibody inhibited the infiltration of peripheral blood Th2 cells into the airway. Interestingly, Gal-9 directly bound the CD44 adhesion molecule and inhibited interactions with hyaluronan (HA). Consistent with the concept that CD44–HA interactions mediate the migration of T cells into the lung, Gal-9 blocked CD44-dependent adhesion of BW5147 mouse T cells to HA.

Conclusions: We conclude that Gal-9 inhibits allergic inflammation of the airway and AHR by modulating CD44-dependent leukocyte recognition of the extracellular matrix.

Authors: Ralf Eberhardt; Devanand Anantham; Armin Ernst; David Feller-Kopman; Felix Herth

Rationale: Endobronchial ultrasound (EBUS) and electromagnetic navigation bronchoscopy (ENB) have increased the diagnostic yield of bronchoscopic diagnosis of peripheral lung lesions. However, the role of combining these modalities to overcome each individual technique's limitations and, consequently, to further increase the diagnostic yield remains untested.

Objectives: A prospective randomized controlled trial involving three diagnostic arms: EBUS only, ENB only, and a combined procedure.

Methods: All procedures were performed via flexible bronchoscopy and transbronchial forceps biopsies were obtained without fluoroscopic guidance. In the combined group, after electromagnetic navigation, the ultrasound probe was passed through an extended working channel to visualize the lesion. Biopsies were taken if ultrasound visualization showed that the extended working channel was within the target. Primary outcome was diagnostic yield. The reference “gold standard” was a surgical biopsy if bronchoscopic biopsy did not reveal a definite histological diagnosis compatible with the clinical presentation. Secondary outcomes were yields by size, lobar distribution, and lesion pathology. Complication rates were also documented.

Measurements and Main Results: Of the 120 patients recruited, 118 had a definitive histological diagnosis and were included in the final analysis. The diagnostic yield of the combined procedure (88%) was greater than EBUS (69%) or ENB alone (59%; p = 0.02). The combined procedure's yield was independent of lesion size or lobar distribution. The pneumothorax rates ranged from 5 to 8%, with no significant differences between the groups.

Conclusions: Combined EBUS and ENB improves the diagnostic yield of flexible bronchoscopy in peripheral lung lesions without compromising safety.

Authors: Dawn L. DeMeo; Craig P. Hersh; Eric A. Hoffman; Augusto A. Litonjua; Ross Lazarus; David Sparrow; Joshua O. Benditt; Gerard Criner; Barry Make; Fernando J. Martinez; Paul D. Scanlon; Frank C. Sciurba; James P. Utz; John J. Reilly; Edwin K. Silverman

Rationale: Computed tomography (CT) scanning of the lung may reduce phenotypic heterogeneity in defining subjects with chronic obstructive pulmonary disease (COPD), and allow identification of genetic determinants of emphysema severity and distribution.

Objectives: We sought to identify genes associated with CT scan distribution of emphysema in individuals without α1-antitrypsin deficiency but with severe COPD.

Methods: We evaluated baseline CT densitometry phenotypes in 282 individuals with emphysema enrolled in the Genetics Ancillary Study of the National Emphysema Treatment Trial, and used regression models to identify genetic variants associated with emphysema distribution.

Measurements and Main Results: Emphysema distribution was assessed by two methods—assessment by radiologists and by computerized density mask quantitation, using a threshold of −950 Hounsfield units. A total of 77 polymorphisms in 20 candidate genes were analyzed for association with distribution of emphysema. GSTP1, EPHX1, and MMP1 polymorphisms were associated with the densitometric, apical-predominant distribution of emphysema (p value range = 0.001–0.050). When an apical-predominant phenotype was defined by the radiologist scoring method, GSTP1 and EPHX1 single-nucleotide polymorphisms were found to be significantly associated. In a case–control analysis of COPD susceptibility limited to cases with densitometric upper-lobe–predominant cases, the EPHX1 His139Arg single-nucleotide polymorphism was associated with COPD (p = 0.005).

Conclusions: Apical and basal emphysematous destruction appears to be influenced by different genes. Polymorphisms in the xenobiotic enzymes, GSTP1 and EPHX1, are associated with apical-predominant emphysema. Altered detoxification of cigarette smoke metabolites may contribute to emphysema distribution, and these findings may lead to further insight into genetic determinants of emphysema.

Authors: Tomoaki Hoshino; Seiya Kato; Naoki Oka; Haruki Imaoka; Takashi Kinoshita; Satoko Takei; Yasuhiko Kitasato; Tomotaka Kawayama; Tsutomu Imaizumi; Kentaro Yamada; Howard A. Young; Hisamichi Aizawa

Rationale: Chronic obstructive pulmonary disease (COPD) is believed to be an inflammatory cytokine–driven disease, but a causal basis that can be associated with a specific cytokine has not been directly demonstrated. We have previously reported that proinflammatory cytokine IL-18 expression is important in the pathogenesis of pulmonary inflammation and lung injury in mice. Our results demonstrate that IL-18 overproduction in the lungs can induce lung diseases, such as pulmonary inflammation, lung fibrosis, and COPD.

Objectives: We analyzed the role of IL-18 in the pathogenesis of COPD.

Methods: Using the human surfactant protein C promoter to drive expression of mature mouse IL-18 cDNA, we developed two different lines of transgenic (Tg) mice that overproduced mouse mature IL-18 in the lungs either constitutively or in response to doxycycline.

Measurements and Main Results: Constitutive overproduction of IL-18 in the lungs resulted in the increased production of IFN-γ, IL-5, and IL-13, and chronic pulmonary lung inflammation with the appearance of CD8⁺ T cells, macrophages, neutrophils, and eosinophils. Increased lung volume, severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension were observed in (more than 15-wk-old) Tg mice. Interestingly, disruption of the IL-13 gene, but not the IFN-γ gene, prevented emphysema and pulmonary inflammation in Tg mice. Moreover, when IL-18 production was induced in lung tissues for 4 weeks through the use of a doxycycline-dependent surfactant protein C promoter, interstitial inflammation was induced.

Conclusions: Our results indicate that IL-18 and IL-13 may have an important role in the pathogenesis of COPD.

Authors: J. Jane Pillow; Noah Hillman; Timothy J. M. Moss; Graeme Polglase; Geoff Bold; Chris Beaumont; Machiko Ikegami; Alan H. Jobe

Rationale: The technique used to provide continuous positive airway pressure (CPAP) to the newborn may influence lung function and breathing efficiency.

Objectives: To compare differences in gas exchange physiology and lung injury resulting from treatment of respiratory distress with either bubble or constant pressure CPAP and to determine if the applied flow influences short-term outcomes.

Methods: Lambs (133 d gestation; term is 150 d) born via cesarean section were weighed, intubated, and treated with CPAP for 3 hours. Two groups were treated with 8 L/minute applied flow using the bubble (n = 12) or the constant pressure (n = 12) technique. A third group (n = 10) received the bubble method with 12 L/minute bias flow. Measurements at study completion included arterial blood gases, oxygraphy, capnography, tidal flow, multiple breath washout, lung mechanics, static pressure–volume curves, and bronchoalveolar lavage fluid protein.

Measurements and Main Results: Birth weight and arterial gas variables at 15 minutes were comparable. Flow (8 or 12 L/min) did not influence the 3-hour outcomes in the bubble group. Bubble technique was associated with a higher pH, PaO2, oxygen uptake, and area under the flow–volume curve, and a decreased alveolar protein, respiratory quotient, PaCO2, and ventilation inhomogeneity compared with the constant pressure group.

Conclusions: Compared with constant pressure technique, bubble CPAP promotes enhanced airway patency during treatment of acute postnatal respiratory disease in preterm lambs and may offer protection against lung injury.

Authors: Hiroshi Moriyama; Masayoshi Kobayashi; Toshinori Takada; Takashi Shimizu; Masaki Terada; Jun-Ichi Narita; Michio Maruyama; Kouichi Watanabe; Eiichi Suzuki; Fumitake Gejyo

Rationale: Hard metal lung disease is caused by exposure to hard metal, a synthetic compound that combines tungsten carbide with cobalt as well as a number of other metals. Interstitial lung disease caused by hard metal is uniquely characterized by giant cell interstitial pneumonia. The pathogenesis of hard metal lung disease is unclear.

Objectives: To elucidate the distribution of inhaled hard metal and reactive inflammatory cells in biopsy lung tissue from patients with hard metal lung disease.

Methods: Seventeen patients with interstitial lung disease in which tungsten was detected and five control subjects were studied. Detection and mapping of elements were performed with an electron probe microanalyzer equipped with a wavelength dispersive spectrometer. We immunohistochemically stained mononuclear cells, in tissue samples available from five patients, with anti-human CD4, CD8, CD20, CD68, and CD163 antibodies, and compared the distribution of positive cells with hard metal elements.

Measurements and Main Results: Thirteen of 17 patients were pathologically diagnosed as having giant cell interstitial pneumonia. Tungsten and cobalt were accumulated in the centrilobular fibrotic lesions, but were never found in the control lungs. CD8⁺ lymphocytes and CD163⁺ monocyte-macrophages were distributed predominantly in centrilobular fibrotic lesions around the hard metal elements. CD163⁺ colocalized with tungsten. Small numbers of CD8⁺ and CD163⁺ cells were also immunohistochemically shown in peribronchiolar areas and alveolar walls.

Conclusions: Macrophages may phagocytose inhaled tungsten via CD163 and play an important role in forming the fibrotic lesion of hard metal lung disease with cytotoxic T lymphocytes.

Authors: Christopher P. Baran; Judy M. Opalek; Sara McMaken; Christie A. Newland; James M. O'Brien; Melissa G. Hunter; Benjamin D. Bringardner; Martha M. Monick; David R. Brigstock; Paul C. Stromberg; Gary W. Hunninghake; Clay B. Marsh

Rationale: An increase in the number of mononuclear phagocytes in lung biopsies from patients with idiopathic pulmonary fibrosis (IPF) worsens prognosis. Chemokines that recruit mononuclear phagocytes, such as CC chemokine ligand 2 (CCL2), are elevated in bronchoalveolar lavage (BAL) fluid (BALF) from patients with IPF. However, little attention is given to the role of the mononuclear phagocyte survival and recruitment factor, macrophage colony-stimulating factor (M-CSF), in pulmonary fibrosis.

Objectives: To investigate the role of mononuclear phagocytes and M-CSF in pulmonary fibrosis.

Methods: Wild-type, M-CSF^−/−, or CCL2^−/− mice received intraperitoneal bleomycin. Lung inflammation and fibrosis were measured by immunohistochemistry, ELISA, collagen assay, BAL differentials, real-time polymerase chain reaction, and Western blot analysis. Human and mouse macrophages were stimulated with M-CSF for CCL2 expression. BALF from patients with IPF was examined for M-CSF and CCL2.

Measurements and Main Results: M-CSF^−/− and CCL2^−/− mice had less lung fibrosis, mononuclear phagocyte recruitment, collagen deposition, and connective tissue growth factor (CTGF) expression after bleomycin administration than wild-type littermates. Human and mouse macrophages stimulated with M-CSF had increased CCL2 production, and intratracheal administration of M-CSF in mice induced CCL2 production in BALF. Finally, BALF from patients with IPF contained significantly more M-CSF and CCL2 than BALF from normal volunteers. Elevated levels of M-CSF were associated with elevated CCL2 in BALF and the diagnosis of IPF.

Conclusions: These data suggest that M-CSF contributes to the pathogenesis of pulmonary fibrosis in mice and in patients with IPF through the involvement of mononuclear phagocytes and CCL2 production.

Authors: Martha L. Bustos; Sara Frías; Sandra Ramos; Andrea Estrada; José Luis Arreola; Felipe Mendoza; Miguel Gaxiola; Mauricio Salcedo; Annie Pardo; Moisés Selman

Rationale: Hypersensitivity pneumonitis (HP) is a lymphocytic alveolitis provoked by exposure to a variety of antigens. However, the disease occurs in only a subset of exposed individuals, suggesting that additional factors may be involved. Microchimerism has been implicated in the pathogenesis of autoimmune diseases, especially in those showing increased incidence after childbearing age.

Objectives: To evaluate the presence of circulating and local microchimeric cells in female patients with HP.

Methods: Male microchimerism was examined in 103 patients with HP, 30 with idiopathic pulmonary fibrosis (IPF), and 43 healthy women. All of them had given birth to at least one son, with no twin siblings, blood transfusions, or transplants. Microchimerism was examined by dot blot hybridization (peripheral blood), and by fluorescence in situ hybridization in bronchoalveolar lavage cells and lungs.

Measurements and Main Results: Blood microchimerism was found in 33% of the patients with HP in comparison with 10% in those with IPF (p = 0.019) and 16% in healthy women (p = 0.045). Patients with HP with microchimerism showed a significant reduction of diffusing capacity of carbon monoxide (DlCO; 53.5 ± 11.9% vs. 65.2 ± 19.7%; p = 0.02) compared with patients with HP without microchimerism. In bronchoalveolar lavage cells, microchimerism was detected in 9 of 14 patients with HP compared with 2 of 10 patients with IPF (p = 0.047). Cell sorting revealed that microchimeric cells were either macrophages or CD4⁺ or CD8⁺ T cells. Male microchimeric cells were also found in the five HP lungs examined by fluorescence in situ hybridization.

Conclusions: Our findings (1) demonstrate that patients with HP exhibit increased frequency of fetal microchimerism, (2) confirm the multilineage capacity of microchimeric cells, and (3) suggest that microchimeric cells may increase the severity of the disease.

Authors: Mario Schiavina; Valerio Di Scioscio; Paola Contini; Alberto Cavazza; Andrea Fabiani; Marco Barberis; Alessandro Bini; Annalisa Altimari; Robin M. T. Cooke; Walter F. Grigioni; Antonia D'Errico-Grigioni

Rationale: The three previously reported cases of conclusively documented pulmonary lymphangioleiomyomatosis (LAM) in men were associated with definite or probable tuberous sclerosis complex (TSC).

Objectives: To describe an unequivocal case of pulmonary LAM occurring in a man with no clinical or genotypic evidence of TSC.

Methods: At high-resolution computed tomography, a 37-year-old phenotypically and karyotypically normal man with left pneumothorax and massive pulmonary collapse had widespread thin-walled cysts throughout both lungs. Histological diagnosis of LAM was performed on biopsy material, and immunohistochemically confirmed with the HMB-45 monoclonal antibody.

Measurements and Main Results: Remarkably, the HMB-45–positive cells lining the cysts also showed strong reactivity for estrogen and progesterone receptor proteins. TSC was clinically excluded, and TSC1 and TSC2 germline mutations were not detected at DNA analysis.

Conclusions: This article indicates that occurrence of LAM may be possible in a chromosomally normal man unaffected by TSC. On diagnostic grounds, the possibility of LAM should be borne in mind when diffuse cystic lung disease occurs in a man, even in the absence of signs of TSC.

Authors: Jouke T. Annema; Klaus F. Rabe

Authors: V. Marco Ranieri; Luciano Gattinoni; Arthur S. Slutsky

Authors: Martin R. Miller; Irene Steenbruggen; Philip H. Quanjer; Gregg Ruppel; Robert O. Crapo; Ole F. Pedersen