Mechanism of alpha-1 antitrypsin endocytosis by lung endothelium.

The integrity of lung alveoli is maintained by proper circulating levels of alpha-1 antitrypsin (A1AT). Next to cigarette smoking, A1AT deficiency is a major risk factor for lung emphysema development. We recently reported that in addition to neutralizing neutrophil elastases in the extracellular compartment, A1AT is internalized by lung endothelial cells and inhibits apoptosis. We hypothesized that the intracellular uptake of A1AT by endothelial cells may be required for its protective function; therefore, we studied the mechanisms of A1AT internalization by primary rat lung microvascular endothelial cells and the effect of cigarette smoke on this process both in vitro and in vivo (in mice). Purified A1AT was taken up intracellularly by endothelial cells in a time-dependent, dose-dependent, and conformer-specific manner and was detected in the cytoplasm of endothelial cells of nondiseased human lung sections. Despite a critical role for caveoli in endothelial cell endocytosis in general, specific inhibition of clathrin-mediated, but not caveoli-mediated, endocytosis profoundly decreased A1AT internalization and reversed the A1AT's antiapoptotic action. Further more, A1AT associated with clathrin heavy chains, but not with caveolin-1 in the plasma membrane fraction of endothelial cells. Interestingly, cigarette smoke exposure significantly inhibited A1AT uptake both in endothelial cells and in the mouse lung and altered the intracellular distribution of clathrin heavy chains. Our results suggest that clathrin-mediated endocytosis regulates A1AT intracellular function in the lung endothelium and may be an important determinant of the serpin's protection against developing cigarette smoke-induced emphysema.

Management of central airway obstruction.

The efficacy of interventional pulmonology for palliation of patients with central airway obstruction has been established, and its curative potential for early cancer has raised great interest in current screening programs. The success of endoscopic strategies for palliation and treatment with curative intent strongly depends on the diligent identification of the various factors in lung cancer management, including full comprehension of the limits and potential of each particular technique. In the palliative setting of alleviating central airway obstruction, laser resection, electrocautery, argon plasma coagulation, and stenting are techniques that can provide immediate relief, in contrast with cryotherapy, brachytherapy, and photodynamic therapy, which have delayed effects. With curative intent, intraluminal techniques that easily coagulate early-stage cancer lesions will increase the implementation of interventional pulmonology for benign and relatively benign diseases, as well as early cancer lesions and its precursors at their earliest stage of disease.