| First Author | Krotova K | Year | 2017 |
| Journal | Am J Respir Cell Mol Biol | Volume | 57 |
| Issue | 2 | Pages | 238-247 |
| PubMed ID | 28362108 | Mgi Jnum | J:264482 |
| Mgi Id | MGI:6193016 | Doi | 10.1165/rcmb.2016-0366OC |
| Citation | Krotova K, et al. (2017) Alpha-1 Antitrypsin-Deficient Macrophages Have Increased Matriptase-Mediated Proteolytic Activity. Am J Respir Cell Mol Biol 57(2):238-247 |
| abstractText | Alpha-1 antitrypsin (AAT) deficiency-associated emphysema is largely attributed to insufficient inhibition of neutrophil elastase released from neutrophils. Correcting AAT levels using augmentation therapy only slows disease progression, and that suggests a more complex process of lung destruction. Because alveolar macrophages (M) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation) compromises M function and contributes to emphysema development. Extracellular matrix (ECM) degradation is a hallmark of emphysema pathology. In this study, M from individuals with Z-AAT (Z-M) have greater proteolytic activity on ECM than do normal M. This abnormal Z-M activity is not abrogated by supplementation with exogenous AAT and is likely the result of cellular dysfunction induced by intracellular accumulation of Z-AAT. Using pharmacologic inhibitors, we show that several classes of proteases are involved in matrix degradation by Z-M. Importantly, compared with normal M, the membrane-bound serine protease, matriptase, is present in Z-M at higher levels and contributes to their proteolytic activity on ECM. In addition, we identified matrix metalloproteinase (MMP)-14, a membrane-anchored metalloproteinase, as a novel substrate for matriptase, and showed that matriptase regulates the levels of MMP-14 on the cell surface. Thus, high levels of matriptase may contribute to increased ECM degradation by Z-M, both directly and through MMP-14 activation. In summary, the expression of Z-AAT in M confers increased proteolytic activity on ECM. This proteolytic activity is not rescued by exogenous AAT supplementation and could thus contribute to augmentation resistance in AAT deficiency-associated emphysema. |
