Mechanisms of cigarette smoke-induced COPD: insights from animal models

Abstract

Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches.

Ascorbate attenuates pulmonary emphysema by inhibiting tobacco smoke and Rtp801-triggered lung protein modification and proteolysis

“…However, our study shows that lung-specific inhibition of iNOS cannot significantly prevent such lung damage in the guinea pig, whose four-lobed lung architecture and physiological responses to CS exposure are more comparable to humans than mouse, which has a two-lobed lung (41,42). Moreover unlike mouse, guinea pigs resemble humans with respect to their response to oxidative stress because they cannot synthesize ascorbate or vitamin C de novo to dynamically attenuate such stress (43).…”

Cigarette Smoke Induces Akt Protein Degradation by the Ubiquitin-Proteasome System

“…Chronic obstructive pulmonary disease (COPD), 2 caused mainly by cigarette smoking, is characterized by emphysema, small airway remodeling, chronic bronchitis, and vascular remodeling (1). Although overwhelming protease activity due to persistent inflammation has long been suggested to play a pivotal role in the development of emphysema (1), recent data suggest that apoptosis, cell cycle arrest, and cellular senescence may contribute to the development of emphysema.…”

“…Although overwhelming protease activity due to persistent inflammation has long been suggested to play a pivotal role in the development of emphysema (1), recent data suggest that apoptosis, cell cycle arrest, and cellular senescence may contribute to the development of emphysema. Cigarette smoke causes apoptotic death in human lung fibroblasts and mouse lungs (2), inhibits cell proliferation, and induces cellular senescence in human lung fibroblasts, with elevation of p53 and p21 (3).…”

Targeted Disruption of Ig-Hepta/Gpr116 Causes Emphysema-like Symptoms That Are Associated with Alveolar Macrophage Activation

“…smoke-exposed mice and gene knock-out mice) to study the pathogenesis of emphysema, none of them accurately reproduce the human disease condition. The reason for this problem is probably due to the differences among species and strains in lung anatomy and in response to lung injury (14,15). Therefore, the use and identification of an appropriate model will be essential to address specific concerns related to the pathogenesis and treatment of emphysema.…”