Alpha-1 antitrypsin: therapeutic applications beyond serine protease inhibition.

INTRODUCTION: Alpha-1 antitrypsin (AAT) is an acute-phase glycoprotein belonging to the serine protease inhibitor (SERPIN) superfamily. An advanced understanding of functional and post-translational modifications highlighted a broad range of AAT effects on inflammation, metabolism, and cell survival. AAT's SERPIN activity is important to inhibit overactivation of several endogenous proteases, a crucial function evidenced by the fact that mutant AAT isoforms can promote lung and liver disease. However, recent research highlighted that AAT's physiological and pathophysiological functions extend beyond SERPIN function. AAT isolated from healthy donors' plasma is approved for augmentation therapy and remains the only disease-modifying therapy approved for patients with severe AAT deficiency.

AREA COVERED: We searched PubMed and Google Scholar to review the current literature on AAT function, the pathophysiology of AAT deficiency, and the growing evidence of additional biological effects independent of protease inhibition.

EXPERT OPINION: Preclinical and clinical studies highlighted that AAT is more than a SERPIN. AAT can regulate cell function, inflammation, and response to injury. AAT showed a disease-modifying effect in cellular, animal, and human studies. In addition, novel recombinant isoforms or peptides that mimic some of AAT's properties, are the focus of preclinical and clinical research as an alternative to plasma-derived AAT.