Title:Alpha 1 Anti-Trypsin: One Protein, Many Functions
Volume: 12
Issue: 7
Author(s): J. M. Hunt and R. Tuder
Affiliation:
Keywords:
Alpha-1 antitrypsin, alpha-1 antitrypsin deficiency, apoptosis, COPD, emphysema, inflammation,
proteinase inhibitor, serpin, protease inhibitor, phenotypes, mutations, isoelectric gradient, polymerization, anti-neutrophil cytoplasmic antibody, dyspnea
Abstract: α-1 anti-trypsin (AAT) is the most abundant circulating serine protease inhibitor (serpin) and an
acute phase reactant. Systemic deficiency in AAT (AATD) due to genetic mutations can result in liver failure
and chronic lung disease such as emphysema. Considered the prototypic serpin, the emphysema observed in
patients with AATD, consisting of progressive destruction of the alveoli and small airway structures, formed the
basis of the protease/anti-protease imbalance theory of chronic obstructive pulmonary disease (COPD). Over
the past decade, however, investigations of AATD have described multiple functions of AAT beyond those
generally attributed to its antiprotease activity. Evidence now suggests that AAT plays an important role in
modulating immunity, inflammation, proteostasis, apoptosis, and possibly cellular senescence programs. When
integrated in vivo, these processes contribute to the lung maintenance program which preserves the lung
despite a constant bombardment by damage associated molecular patterns (DAMPs) and/or pathogenassociated
molecular patterns (PAMPs) initiated by cigarette smoke, pollutants, or infections. In this review, we
discuss the clinical aspects of AATD as they pertain to emphysema; including similarities and differences to
cigarette smoke-induced emphysema. Examining the lung maintenance program, we next consider the
multiple mechanisms of airspace destruction and explore the role AATD contributes. Finally, we consider the
data regarding treatment of AATD, including AAT supplementation and its current limitations, and suggest
further avenues of research informed by the multiple functions of AAT.
