Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease.

Current understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD), a source of substantial morbidity and mortality in the United States, suggests that chronic inflammation leads to the airways obstruction and parenchymal destruction that characterize this condition. Environmental factors, especially tobacco smoke exposure, are known to accelerate longitudinal decline of lung function, and there is substantial evidence that upregulation of inflammatory pathways plays a vital role in this process. Genetic regulation of both inflammatory responses and anti-inflammatory protective mechanisms likely underlies the heritability of COPD observed in family studies. In alpha-1 protease inhibitor deficiency, the only genetic disorder known to cause COPD, lack of inhibition of elastase activity, results in the parenchymal destruction of emphysema. Other genetic polymorphisms have been hypothesized to alter the risk of COPD but have not been established as causes of this condition. It is likely that multiple genetic factors interacting with each other and with a number of environmental agents will be found to result in the development of COPD

Cellularity of the alveolar walls in smokers and its relation to alveolar destruction. Functional implications.

Abstract Inflammatory cells are believed to play an important role in the pathogenesis of emphysema; however, a relationship between presence of cells in the lung parenchyma and its destruction has never been shown. The aim of this study was to quantitate alveolar septal cellularity in smokers' lungs and to investigate its relationship with parenchymal destruction and lung function. The lungs of 23 smokers (SS) undergoing thoracotomy for localized pulmonary lesions were compared with those of eight nonsmokers (NS) and five smokers (AS) who died suddenly of nonrespiratory causes. Pulmonary function tests were performed within 1 wk of surgery in SS. For each subject, we quantitated alveolar wall cells (CELLS), an index of alveolar wall destruction (DI), and the mean linear intercept (Lm). As no significant differences were found between S and AS with regard to these indices, we combined them (Group S) for comparison with NS. Although Lm was not significantly different between S and NS, (0.331 +/- 0.072 versus 0.288 +/- 0.038), CELLS and DI were higher in S than in NS (48 +/- 8 versus 25 +/- 2 cells/mm, p less than 0.001; 47 +/- 20 versus 17 +/- 5, p less than 0.001, respectively). Further, CELLS and DI were significantly correlated (r = 0.799, p less than 0.001). The number of polymorphonuclear cells (PMN) in S can exceed that in NS by as much as 5-fold; however, PMN were inversely correlated with parenchymal destruction (DI) (r = 0.598, p less than 0.01). Thus, smokers' lungs have alveolar septal hypercellularity, possibly inflammatory, and closely related to destruction involving cells other than the PMN