Lung disease associated with alpha1-antitrypsin deficiency

Abstract

α(1)-Antitrypsin (A1AT) is a polyvalent, acute-phase reactant with an extensive range of biological functions that go beyond those usually linked to its antiprotease (serpin) activities. Genetic mutations cause a systemic deficiency of A1AT, leading to liver and pulmonary diseases, including emphysema and chronic bronchitis. The pathogenesis of emphysema, which involves the destruction of small airway structures and alveolar units, is triggered by cigarette smoke and pollutants. The tissue damage caused by these agents is further potentiated by the mutual interactions between apoptosis, oxidative stress, and protease/antiprotease imbalance. These processes lead to the activation of endogenous mediators of tissue destruction, including the lipid ceramide, extracellular matrix proteins, and abnormal inflammatory cell signaling. In this review, we propose that A1AT has a range of actions that are not restricted to protease inhibition but rather extend to mitigate a range of these pathological processes involved in the development of emphysema. We discuss the evidence indicating that A1AT blocks apoptosis by binding and inhibiting active caspase-3 and modulates a broad range of inflammatory responses induced by neutrophils and by lipopolysaccharide and tumor necrosis factor-α signaling.

Figure 1.

Expression of human α₁-antitrypsin (A1AT) in mouse lungs, which were transduced with adenoassociated virus-human A1AT or adenoassociated virus control via muscular route. Human A1AT (green signal) colocalized with the endothelial cell marker CD34 (red signal), type II cell marker prosurfactant protein C (SPC, red signal), and interstitial fibroblasts (smooth muscle cell actin [SMA], red signal). Mice were treated with the vascular endothelial growth factor–receptor blocker SU5416, which promotes apoptosis-dependent emphysema phenotype. Negative controls consisted of a mouse lung section stained with goat serum (upper right panel), and positive control consisted of A1AT liver with the characteristic globular A1AT cellular deposits (lower right panel). Arrows highlight colocalization signals between human A1AT and cell-specific marker (yellow signal). (Reprinted by permission from Reference 48).

Figure 2.

Colocalization of human A1AT labeled with DyLight 547 (green signal) and active caspase 3 (red signal) in cultured mouse lung endothelial cells (panels I and ii). Superimposed fluorescence signals (yellow signal) are highlighted by arrows. EC = endothelial cells. (Reprinted by permission from Reference 49).

Figure 3.

Evidence of receptor mediated internalization of labeled human A1AT by primary cultures of lung endothelial cells. Human A1AT (labeled in red) is internalized in serum-free conditions at 37°C; internalization is abolished at 4°C. The immunofluorescence data are confirmed by Western blot for human A1AT and vinculin (loading control) in cytoplasmic (cyt) and supernatant (SN) protein fractions of cells cultured at 37°C and 4°C culture conditions. (Reprinted by permission from Reference 50).

Figure 4.

Summary of known functions that may affect inflammation of the different forms of A1AT. aa = aminoacid; PMN = neutrophils; PPAR = peroxisome protein activated receptor; RE = endoplasmic reticulum). (Adapted from Reference 4 with permission).