The Science

Pathogenesis of COPD

Chronic obstructive pulmonary disease (COPD) is characterized by two pathologic changes in the lungs: 1) Airway inflammation and mucus hypersecretion (Bronchitis) and 2) Alveolar wall destruction (Emphysema). Each of these pathologic changes lead to worsening airway restriction and hypoventilation. In the developed world, COPD is most often caused by exposure to cigarette smoke. Host genetics clearly influences susceptibility because only 15-20% of smokers develop COPD.

The mechanisms by which cigarette smoke causes these pathologic changes remain to be determined. At least three potential pathologic mechanisms have been identified (Figure 1):COPD.jpg

1) Cigarette smoke increases oxidative stress and can directly damage pulmonary tissues

2) Epithelial cell injury and death induced by cigarette smoke leads to the release of endogenous danger signals that activate inflammatory signaling pathways in surviving cells including epithelial, monocytic, and dendritic cells. Cigarette smoke can also directly activate innate immune signaling pathways and induce inflammatory responses.

3) Cigarette smoke also induces airway dehydration by decreasing expression of the Cystic Fibrosis Trans-membrane conductance Regulator (CFTR). Airway dehydration reduces mucus and pathogen clearance, leading to pulmonary inflammation and airway destruction.

Murine models of COPD

1) Exposing several in-bred mouse strains, including C57BL6/J, A/J, and SJ/L, to cigarette smoke leads to mild destruction of alveolar architecture resulting in an emphysematous phenotype. However, these mice are limited surrogates for the human disease, because smoke inhalation causes predominantly emphysema without chronic bronchitis and airway inflammation and remodeling seen in human COPD.

2) Mall, O’Neal, Boucher and colleagues recently generated transgenic mice that overexpress Scnn1b, the gene which codes for the epithelial Na+ channel subunit, βENaC, in the epithelial cells of the airways. Scnn1b overexpression increases Na+ absorption and results in volume depletion and dehydration of the airway surface liquid. This mucus dehydration results pathology consistent with chronic bronchitis in smokers with COPD. These mice also develop an emphysematous component to their disease. However, these mice are missing all other effects of cigarette smoke, which are likely numerous, due to the 3000+ components of cigarette smoke.

Our lab is focused on studying how airway liquid dehydration (using the Scnn1b-tg mouse) and cigarette smoke alter the pathophysiologic immune responses in the lungs to cause.