A Novel Antiapoptotic Role for α₁-Antitrypsin in the Prevention of Pulmonary Emphysema

Abstract

Our findings suggest that inhibition of structural alveolar cell apoptosis by alpha1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of alpha1-antitrypsin.

Molecular Multitasking in the Airspace

“…What are the sources of A1AT that may regulate its effect on alveolar macrophages? We have recently shown that A1AT is taken up by primary lung endothelial cells, where it interacts with intracellular activated caspase-3, inhibiting its function, as also seen in the murine lung in vivo (16,17). These findings supported the existence of expanded noncanonical functions of A1AT.…”

“…Furthermore, abnormal variants of A1AT may themselves have pathogenic effects in the lung, as oxidatively modified or polymerized A1AT activate monocytes or attract neutrophils, respectively (14,15). Another noncanonical function of A1AT is that of apoptosis inhibition, exerted in lung microvascular endothelial cells (16,17) or pancreatic B cells (18). The work of Churg and colleagues expanded the knowledge of the mechanisms by which A1AT may exert other activities beyond neutrophil elastase inhibition (49).…”

“…Bridging molecules, SP-A and -D are also decreased in the lungs of smokers (16), also potentially contributing to the defect. Of note, statins (17) and macrolides (18) were recently reported to enhance phagocytosis.…”

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

“…Last, protease inhibition revealed preventing effects in animal models of emphysema [75,76]. These different trials are summarized in Table 2.…”

Anti‐inflammaging effects of human alpha‐1 antitrypsin

“…Human AAT has serine proteinase inhibitor activity, which can inhibit neutrophil elastase, proteinase 3, and cathepsin G. Human AAT can be chemically modified by nitric oxide (NO) and exhibits antibacterial and cysteine protease inhibitor activities (Miyamoto et al ., 2000). We and others have shown that hAAT directly inhibits caspase‐3 and prevents apoptosis (Petrache et al ., 2006; Zhang et al ., 2007). Increasing evidence indicates that hAAT is a multifunctional protein and may play an important role in modulating the immune system.…”