Lung Inflammation

The pathogenesis of cigarette smoke–induced emphysema is an area of intense investigation. To investigate the role of TNF- ${alpha}$ in the development of emphysema and inflammatory cell recruitment, Churg and coworkers exposed wild-type and TNF- ${alpha}$ receptor knock-out mice (TNFRKO) to cigarette smoke for 6 months. TNFRKO mice exhibited approximately 70% protection against the development of emphysema and had 65% fewer neutrophils than wild-type mice. The levels of metalloproteases (MMP-2, MMP-9, MMP-12, MMP-13, and MT1-MMP) were markedly increased by cigarette smoking in wild-type mice, but some increased MMP activity was present even in TNFRKO mice. The authors concluded that, at least in the mouse, emphysema has two components: the majority of matrix breakdown and emphysema is mediated via TNF- ${alpha}$ and neutrophils, with neutrophil elastase as the presumed major effector, and MMPs (at least MMP-12 and possibly other MMPs) serving to release active TNF- ${alpha}$ . The residual matrix breakdown has a different pathogenesis that may be related to other types of proteases and/or direct MMP destruction of matrix.

Lapperre and coworkers sought to objectively examine the heterogeneity of COPD by categorizing the various functional and inflammatory features of COPD into separate, complementary domains without a priori assumptions. The factor analysis performed on physiologic and inflammatory data from 114 patients with moderate to severe COPD, not treated with inhaled steroids, resulted in a four-factor structure explaining 63.6% of the total variance. The four factors included the following: FEV₁, FEV₁/inspired vital capacity, and hyperinflation (Factor 1); ß2 response, total serum IgE, airway hyperresponsivenes, and Kco (Factor 2); exhaled NO (Factor 3); and percentage of sputum eosinophils and neutrophils (Factor 4). These four factors indicate that airflow limitation, a feature commonly associated with asthma and airway inflammation, is a separate, largely independent dimension that characterizes patients with COPD.

CT scans can be used to "phenotype" patients with COPD. Patel and colleagues suggested that those patients with COPD with evidence for bronchiectasis, usually in the lower lobes, were at risk for greater levels of bacterial colonization, higher sputum IL-8 levels, and a more prolonged course once an exacerbation occurred. However, there was no relationship between frequency of exacerbations and CT phenotype. Larger scale studies are needed to determine whether more aggressive clearance therapy in these patients could improve their level of colonization and risk for more severe exacerbations.

To determine whether the magnitude of bacterial colonization and airway inflammation influences decline in lung function, Wilkinson and coworkers studied 30 patients with COPD (FEV₁, 0.95 liter) over a period of 12 months. FEV₁ declined by 57.6 ml over the 12 months. All sputum samples grew significant numbers of bacteria; quantitative bacteriology revealed an almost 3-fold increase in bacterial count over the period. Decline in FEV₁ was correlated with bacterial load (r = 0.59). Decline in FEV₁ was greater in patients who experienced a change in the type of colonizing bacteria than in patients who were colonized with a single bacterial species over the period: 102 versus 3.6 ml per year. Decline in FEV₁ was greater in patients with high levels of interleukin-8 in sputum. The authors conclude that bacterial colonization is an important factor in the decline of lung function in patients with COPD, and that rising airway bacterial load and a change in bacterial species are associated with greater airway inflammation and accelerated decline in function.

In a mouse model of elastase-induced emphysema, Inoue and coworkers investigated the mechanism for increased susceptibility to bacterial infection. Intratracheal infection with Streptococcus pneumoniae (10³–10⁷ cfu per mouse) increased mortality in a dose-dependent manner in emphysematous mice, but did not kill control mice. Compared with control mice, the emphysematous mice had lower levels of total cells, neutrophils, tumor necrosis factor- ${alpha}$ , and macrophage inflammatory protein-2 in bronchoalveolar lavage. Histology revealed alveoli filled with inflammatory cells and exudates in the control mice, but not in the emphysematous mice. At 72 hours, the emphysematous mice had higher levels of serum cytokines, and significant numbers of S. pneumoniae in both lung tissue and blood. The authors conclude the experimental emphysema impairs the intra-alveolar, but not the systemic, immune response to bacterial infection.

Citations 1-5 of 5 total displayed.

Tumor Necrosis Factor- ${alpha}$ Drives 70% of Cigarette Smoke–induced Emphysema in the Mouse

Andrew Churg, Rong D. Wang, Hsin Tai, Xiaoshan Wang, Changshi Xie, and Joanne L. Wright
Am. J. Respir. Crit. Care Med. 170: 492 -498. First published online as doi:10.1164/rccm.200404-511OC [Abstract] [Full text]

Dissociation of Lung Function and Airway Inflammation in Chronic Obstructive Pulmonary Disease

Thérèse S. Lapperre, Jiska B. Snoeck-Stroband, Margot M.E. Gosman, Jan Stolk, Jaap K. Sont, Désirée F. Jansen, Huib A.M. Kerstjens, Dirkje S. Postma, and Peter J. Sterk
Am. J. Respir. Crit. Care Med. 170: 499 -504. First published online as doi:10.1164/rccm.200401-112OC [Abstract] [Full text]

Bronchiectasis, Exacerbation Indices, and Inflammation in Chronic Obstructive Pulmonary Disease

Irem S. Patel, Ioannis Vlahos, Tom M. A. Wilkinson, Simon J. Lloyd-Owen, Gavin C. Donaldson, Mark Wilks, Rodney H. Reznek, and Jadwiga A. Wedzicha
Am. J. Respir. Crit. Care Med. 170: 400 -407. First published online as doi:10.1164/rccm.200305-648OC [Abstract] [Full text]

Airway Bacterial Load and FEV₁ Decline in Patients with Chronic Obstructive Pulmonary Disease

Tom M. A. Wilkinson, Irem S. Patel, Mark Wilks, Gavin C. Donaldson, and Jadwiga A. Wedzicha
Am. J. Respir. Crit. Care Med. 167: 1090 -1095. First published online as doi:10.1164/rccm.200210-1179OC [Abstract] [Full text]

Impaired Pulmonary Inflammatory Responses Are a Prominent Feature of Streptococcal Pneumonia in Mice with Experimental Emphysema

Sumito Inoue, Hidenori Nakamura, Kazuhisa Otake, Hiroshi Saito, Kyoko Terashita, Jun Sato, Hiroaki Takeda, and Hitonobu Tomoike
Am. J. Respir. Crit. Care Med. 167: 764-770. [Abstract] [Full text]

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