Molecular multitasking in the airspace: alpha1-antitrypsin takes on thrombin and plasmin.

For the past 40 years, research focused on α1-antitrypsin (A1AT) deficiency greatly enhanced the understanding of the pathobiology of chronic obstructive pulmonary diseases (COPD). The discovery that A1AT-deficient patients are at increased risk of developing COPD (1) led to the protease/antiprotease hypothesis of emphysema development (2), postulated to ultimately cause its hallmark irreversible alveolar destruction (3). Elegant investigations into pathological lung matrix proteolysis converged on implicating excessive alveolar inflammation as the potential source of extracellular proteolytic enzymes (proteases) (2). More recently, excessive alveolar cell apoptosis has also been linked to emphysema pathogenesis (4). These processes, rather than operating in isolation, manifest complex interactions with each other and may therefore create feed-forward mechanisms that overwhelm the lung's repair capability (5, 6). For example, alterations in alveolar maintenance and excessive apoptosis may further enhance inflammation and exacerbate the protease/antiprotease imbalance (7). However, viable therapeutic options for the millions of patients with COPD have not yet emerged from these discoveries, signaling that substantial missing links in the pathogenesis of this disease still exist. As in the past, studies centered on A1AT function continue to provide fascinating and important novel knowledge into the pathogenesis of COPD. The findings of Churg and coworkers that A1AT blocks cigarette smoke and thrombin-dependent activation of TNF-α and MMP-12 in alveolar macrophages expand our understanding of biological functions of A1AT (49). Furthermore, their work has the potential to unveil both novel investigative leads connecting blood coagulation events to the pathogenesis of COPD and common targets between lung and cardiovascular diseases caused by cigarette smoke.