| Emphysema is a complex pathology characterized by the progressive enlargement of airspaces and the destruction of alveolar walls. Multiple environmental and genetic risk factors influence the initiation and progression of this disease. Cigarette smoke has been known for a long time to be the major contributor to the development of emphysema. However, a possible impact of hypercholesterolemia on the destruction of alveoli has not been investigated. The work presented in this thesis identifies the role of hypercholesterolemia in the development of emphysema. It also elucidates new molecular mechanisms leading to the proteolytic destruction of lung tissue, secondary to cigarette smoke exposure or to a high-fat diet.;The study reported in chapter two explores the effect of cigarette smoke on the pulmonary inflammation and proteolytic response leading to the development of emphysema in guinea pigs. For the first time, we demonstrated that smoke-induced expression of Cathepsin K in the lungs contributes to the degradation of the extracellular matrix, ultimately resulting in emphysema. Studies in chapters three and four show that hypercholesterolemia is an important risk factor for pulmonary emphysema. These studies discuss the role of MAP kinases, Toll-like signaling, ceramide signaling and proteolytic enzymes in the pathogenesis of emphysema resulting from chronic smoke exposure or from an atherogenic diet. Data obtained with a rabbit model of emphysema further demonstrate that matrix metalloproteinase-1 (MMP-1) likely plays a key role in the pathological degradation of the lung extracellular matrix.;Together, the studies presented in this thesis indicate that, in addition to cigarette smoking, hypercholesterolemia may be an important risk factor in the development of human emphysema and provide novel insights into the molecular mechanisms leading to pulmonary inflammation and alveolar destruction. In addition, our work further illustrates the crucial role of proteases in the development of emphysema and offer novel therapeutic targets for the treatment of this disease. |
