title: Alpha-1 Antitrypsin-Deficient Macrophages Have Increased Matriptase-Mediated Proteolytic Activity.
abstract: 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 (Mɸ) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation) compromises Mɸ function and contributes to emphysema development. Extracellular matrix (ECM) degradation is a hallmark of emphysema pathology. In this study, Mɸ from individuals with Z-AAT (Z-Mɸ) have greater proteolytic activity on ECM than do normal Mɸ. This abnormal Z-Mɸ 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-Mɸ. Importantly, compared with normal Mɸ, the membrane-bound serine protease, matriptase, is present in Z-Mɸ 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-Mɸ, both directly and through MMP-14 activation. In summary, the expression of Z-AAT in Mɸ 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.
authors.affiliation: 1 Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and.
authors.forename: Karina
authors.initials: K
authors.lastname: Krotova
authors.affiliation: 1 Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and.
authors.forename: George W
authors.initials: GW
authors.lastname: Marek
authors.affiliation: 1 Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and.
authors.forename: Rejean L
authors.initials: RL
authors.lastname: Wang
authors.affiliation: 2 Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: George
authors.initials: G
authors.lastname: Aslanidi
authors.affiliation: 2 Department of Pediatrics, University of Florida, Gainesville, Florida.
authors.forename: Brad E
authors.initials: BE
authors.lastname: Hoffman
authors.affiliation: 1 Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and.
authors.forename: Nazli
authors.initials: N
authors.lastname: Khodayari
authors.affiliation: 1 Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and.
authors.forename: Farshid N
authors.initials: FN
authors.lastname: Rouhani
authors.affiliation: 1 Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D004790:Enzyme Induction; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D016676:Macrophages, Alveolar / Q000201:enzymology*; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000473:pathology; D009154:Mutation; D011656:Pulmonary Emphysema / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D019896:alpha 1-Antitrypsin Deficiency / Q000097:blood / Q000150:complications / Q000235:genetics / Q000503:physiopathology*
chemical_list: D016326:Extracellular Matrix Proteins; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D012697:Serine Endopeptidases; C485596:ST14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: alpha-1 antitrypsin deficiency; extracellular matrix degradation; macrophages; matriptase; matrix metalloproteinase-14