Cellular, Molecular, and Anatomical Abnormalities

In an in-depth study, Bolton and colleagues performed a comparative evaluation of markers of inflammation and tissue destruction, BMI, fat-free mass, and fat mass with bone mineral density in patients with and without COPD. The fat-free mass, fat mass, and bone mineral density were evaluated using dexa scanning, as might be done to determine osteoporosis in postmenopausal women. The authors were able to identify individuals with COPD who had low fat-free mass or fat mass (often with a normal BMI), who had bone mineral density in the osteoporotic or osteopenic range. These subjects were significantly more likely to be present in the COPD group than in the control group. Although there were some differences in inflammatory and tissue destruction markers, the best predictors for osteopenia/osteoporosis were low fat-free or fat mass index. This study strengthens the argument that individuals with COPD, especially those with more severe loss of lung function, are at risk for development of osteoporosis/osteopenia. With more widespread use of inhaled steroids in this population, closer observation of patients with COPD for these comorbid processes is indicated.

Fabbri and coworkers 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.

To assess the role of neutrophilia and neutrophil chemokine and receptor gene expression in severe exacerbations of COPD, Qiu and coworkers did endobronchial biopsies in 15 patients with COPD who were intubated for an acute exacerbation (FEV₁, 36% of predicted), 7 patients with stable COPD (FEV₁, 51% of predicted), and 15 control subjects intubated for a nonrespiratory surgical procedure (FEV₁, 98% of predicted). Compared with the patients with stable COPD, the patients with an acute exacerbation of COPD had a 97-fold increase in neutrophilia; gene expression for epithelial-derived neutrophil attractant–78 (CXCL5) was increased 6-fold, interleukin-8 (CXCL8) was increased 6-fold, CXCR1 was increased 3-fold, and CXCR2 was increased 7-fold. In patients with an exacerbation of COPD, the number of neutrophils was correlated with cells positive for CXCR2 messenger RNA (r = 0.79), but not with cells positive for CXCR1 messenger RNA. Neutrophil number was not correlated with the duration of intubation or viral infection. The authors conclude that a severe exacerbation of COPD causes increased neutrophil recruitment that is associated with upregulation of the neutrophil-selective cytokines, CXCL5 (epithelial-derived neutrophil attractant–78) and CXCL8 (interleukin-8), and CXCR1 and CXCR2, the relevant receptors on which these neutrophil chemoattractant ligands act. An editorial commentary by Saetta and coworkers accompanies this article.

Recent data reveal that both neutrophils and macrophage-derived metalloelastase (MMP-12) are required for the breakdown of connective tissue induced by acute cigarette smoke. Churg and coworkers investigated the link between these mechanisms. Acute cigarette smoke exposure caused rapid increases in whole-lung activation of nuclear factor-B and gene expression of proinflammatory cytokines in both wild-type mice (MMP-12^+/+) and mice lacking metalloelastase (MMP-12^-/-), thus indicating that absence of metalloelastase does not produce a global failure of the upregulation of inflammatory mediators. Only the wild-type mice demonstrated an increase in whole-lung tumor necrosis factor- protein or the release of tumor necrosis factor- from cultured alveolar macrophages exposed to smoke in vitro. Also, only wild-type mice exhibited increases in whole-lung E selectin, a marker of endothelial activation. The authors conclude that macrophage-derived metalloelastase (MMP-12) mediates smoke-induced inflammation by releasing tumor necrosis factor- from macrophages, with subsequent endothelial activation, neutrophil influx, and proteolytic breakdown of the matrix caused by neutrophil-derived proteases, and that release of tumor necrosis factor- may be a general mechanism whereby metalloproteases drive cigarette smoke–induced inflammation. An editorial commentary by Snider accompanies this article.

Little is known about the pathogenesis of the small airway disease (a form of airway remodeling) in cigarette smokers. To better understand the mechanism, Wang and coworkers exposed rat tracheal explants to cigarette smoke and then maintained them in an air–organ culture. At 24 hours after smoke exposure, gene expression of procollagen was increased in a dose-dependent manner and hydroxyproline, a measure of collagen content, was increased. Greater increases in gene expression of procollagen occurred with repeated smoke exposure. The increase in procollagen gene expression was prevented by a selective inhibitor of nuclear factor-B activation (SN50), scavengers of active oxygen species (superoxide dismutase, catalase, and tetramethylthiourea), and an inhibitor of epidermal growth factor receptor signaling (AG1478), but not by inhibitors of mitogen-activated protein kinases (PD98059 and SB203580). The authors conclude that cigarette smoke directly induces airway wall fibrosis, probably through transactivation of the epidermal growth factor receptor (mediated by active oxygen species) and subsequent activation of nuclear factor-B, and that the injury does not require smoke-evoked inflammatory cells.

Extracellular matrix metalloproteinase inducer (EMMPRIN) is present in the lung during development but expression in the healthy adult lung is minimal. To determine whether EMMPRIN might be associated with smoking-induced injury, Betsuyaku and coworkers did bronchoalveolar lavages in 7 never-smokers, 16 former smokers, and 58 current smokers (7 of the former smokers and 32 of the current smokers had emphysema on computed tomography). Levels of EMMPRIN were higher in current smokers (315 pg per ml) and former smokers (175 pg per ml) than in never smokers (31 pg per ml); the levels did not discriminate between the presence or absence of emphysema among the smokers. Immunochemistry of smokers' lung tissue revealed EMMPRIN in bronchiolar epithelium and alveolar macrophages; messenger RNA for EMMPRIN in alveolar macrophages did not differ between current and never-smokers. Matrix metalloproteinase-1 was detected in bronchoalveolar fluid of some smokers, but not in the never-smokers. The authors conclude that smoking is associated with increases in extracellular matrix metalloproteinase inducer (EMMPRIN) in bronchoalveolar fluid and that the increase persists for a long time after smoking cessation.

Because glucocorticoids can affect matrix metalloproteinases, Choe and coworkers studied the effect of methylprednisolone on lung structure in adult rats. Daily methylprednisolone (2 mg per kg) for 1, 2, or 4 weeks produced an increase in mean linear intercept and a decrease in the surface–volume ratio. Animals also exhibited increased activity of matrix metalloproteinase-9. Rats treated with a broad-spectrum matrix metalloproteinase inhibitor (GM6001) did not develop emphysema. The authors conclude that methylprednisolone increases the activity of matrix metalloproteinases in rat lung and causes emphysema.

In a state of the art review article, Ryu and colleagues discuss bronchiolar disorders.

In a report from an international workshop, Jeffery and colleagues 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.

In a state of the art review article, Kinnula and Crapo discuss superoxide dismutase in lung disease.

In a pulmonary perspective, Turino and Cantor discuss the role of hyaluronan in respiratory injury and repair.

In a summary report from a National Heart, Blood, and Lung Institute Workshop, Croxton and colleagues discuss needs for opportunities for research on COPD.

Citations 1-15 of 15 total displayed.

Associated Loss of Fat-free Mass and Bone Mineral Density in Chronic Obstructive Pulmonary Disease

Charlotte E. Bolton, Alina A. Ionescu, Kathleen M. Shiels, Rebecca J. Pettit, Peter H. Edwards, Michael D. Stone, Lisette S. Nixon, William D. Evans, Timothy L. Griffiths, and Dennis J. Shale
Am. J. Respir. Crit. Care Med. 170: 1286 -1293. First published online as doi:10.1164/rccm.200406-754OC [Abstract] [Full text]  

Elevated Plasma Ghrelin Level in Underweight Patients with Chronic Obstructive Pulmonary Disease

Takefumi Itoh, Noritoshi Nagaya, Masanori Yoshikawa, Atsuhiko Fukuoka, Hideaki Takenaka, Yoshito Shimizu, Yoshinori Haruta, Hideo Oya, Masakazu Yamagishi, Hiroshi Hosoda, Kenji Kangawa, and Hiroshi Kimura
Am. J. Respir. Crit. Care Med. 170: 879 -882. First published online as doi:10.1164/rccm.200310-1404OC [Abstract] [Full text]  

Bronchiolar Disorders

Jay H. Ryu, Jeffrey L. Myers, and Stephen J. Swensen
Am. J. Respir. Crit. Care Med. 168: 1277-1292. [Abstract] [Full text]  

Cigarette Smoke Produces Airway Wall Remodeling in Rat Tracheal Explants

Rong D. Wang, Hsin Tai, Changshi Xie, Xiaoshan Wang, Joanne L. Wright, and Andrew Churg
Am. J. Respir. Crit. Care Med. 168: 1232 -1236. First published online as doi:10.1164/rccm.200307-1006OC [Abstract] [Full text]  

Neutrophil Chemokines in Severe Exacerbations of Chronic Obstructive Pulmonary Disease: Fatal Chemo-Attraction?

Marina Saetta, Simonetta Baraldo, and Renzo Zuin
Am. J. Respir. Crit. Care Med. 168: 911-913. [Full text]  

Biopsy Neutrophilia, Neutrophil Chemokine and Receptor Gene Expression in Severe Exacerbations of Chronic Obstructive Pulmonary Disease

Yusheng Qiu, Jie Zhu, Venkata Bandi, Robert L. Atmar, Keith Hattotuwa, Kay K. Guntupalli, and Peter K. Jeffery
Am. J. Respir. Crit. Care Med. 168: 968 -975. First published online as doi:10.1164/rccm.200208-794OC [Abstract] [Full text]  

Methods for the Assessment of Endobronchial Biopsies in Clinical Research: Application to Studies of Pathogenesis and the Effects of Treatment

Peter Jeffery, Stephen Holgate, and Sally Wenzel
Am. J. Respir. Crit. Care Med. 168: S1-17S. [Full text]  

Extracellular Matrix Metalloproteinase Inducer Is Increased in Smokers' Bronchoalveolar Lavage Fluid

Tomoko Betsuyaku, Mishie Tanino, Katsura Nagai, Yasuyuki Nasuhara, Masaharu Nishimura, and Robert M. Senior
Am. J. Respir. Crit. Care Med. 168: 222 -227. First published online as doi:10.1164/rccm.200301-103OC [Abstract] [Full text]  

Superoxide Dismutases in the Lung and Human Lung Diseases

Vuokko L. Kinnula and James D. Crapo
Am. J. Respir. Crit. Care Med. 167: 1600-1619. [Abstract] [Full text]  

Methylprednisolone Causes Matrix Metalloproteinase–dependent Emphysema in Adult Rats

Kang-Hyeon Choe, Laimute Taraseviciene-Stewart, Robertas Scerbavicius, Lajos Gera, Rubin M. Tuder, and Norbert F. Voelkel
Am. J. Respir. Crit. Care Med. 167: 1516 -1521. First published online as doi:10.1164/rccm.200210-1207OC [Abstract] [Full text]  

Hyaluronan in Respiratory Injury and Repair

Gerard M. Turino and Jerome O. Cantor
Am. J. Respir. Crit. Care Med. 167: 1169-1175. [Full text]  

Understanding Inflammation in Chronic Obstructive Pulmonary Disease: The Process Begins

Gordon L. Snider
Am. J. Respir. Crit. Care Med. 167: 1045-1046. [Full text]  

Macrophage Metalloelastase Mediates Acute Cigarette Smoke–induced Inflammation via Tumor Necrosis Factor- Release

Andrew Churg, Rong D. Wang, Hsin Tai, Xiaoshan Wang, Changshi Xie, Jin Dai, Steven D. Shapiro, and Joanne L. Wright
Am. J. Respir. Crit. Care Med. 167: 1083 -1089. First published online as doi:10.1164/rccm.200212-1396OC [Abstract] [Full text]  

Clinical Research in Chronic Obstructive Pulmonary Disease: Needs and Opportunities

Thomas L. Croxton, Gail G. Weinmann, Robert M. Senior, Robert A. Wise, James D. Crapo, and A. Sonia Buist
Am. J. Respir. Crit. Care Med. 167: 1142-1149. [Abstract] [Full text]  

Differences in Airway Inflammation in Patients with Fixed Airflow Obstruction Due to Asthma or Chronic Obstructive Pulmonary Disease

Leonardo M. Fabbri, Micaela Romagnoli, Lorenzo Corbetta, Gianluca Casoni, Kamelija Busljetic, Graziella Turato, Guido Ligabue, Adalberto Ciaccia, Marina Saetta, and Alberto Papi
Am. J. Respir. Crit. Care Med. 167: 418 -424. First published online as doi:10.1164/rccm.200203-183OC [Abstract] [Full text]