ArticleAmerican journal of respiratory cell and molecular biology2017
Alpha-1 Antitrypsin-Deficient Macrophages Have Increased Matriptase-Mediated Proteolytic Activity.
Article in American journal of respiratory cell and molecular biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Bioinformatic analysis of serpina1 expression in papillary thyroid carcinoma and its potential association with Hashimoto's thyroiditis.Discover oncology · 2025Article
- Advances on the Role of Lung Macrophages in the Pathogenesis of Chronic Obstructive Pulmonary Disease in the Era of Single-Cell Genomics.International journal of medical sciences · 2025Review
- Lung microhaemorrhage drives oxidative/inflammatory damage in αERJ open research · 2023Article
- Comparison of cell subsets in chronic obstructive pulmonary disease and controls based on single-cell transcriptome sequencing.Technology and health care : official journal of the European Society for Engineering and Medicine · 2023Article
- Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency.Respiratory research · 2022Article
- Modulating macrophage function to reinforce host innate resistance againstFrontiers in immunology · 2022Review
- Changes in inflammation and oxidative stress signalling pathways in coarcted aorta triggered by bicuspid aortic valve and growth in young children.Experimental and therapeutic medicine · 2020Article
- Neutrophil elastase promotes macrophage cell adhesion and cytokine production through the integrin-Src kinases pathway.Scientific reports · 2020Article
- Monocytes and Macrophages in Alpha-1 Antitrypsin Deficiency.International journal of chronic obstructive pulmonary disease · 2020Review
- Alpha 1 Antitrypsin-Deficient Macrophages Have Impaired Efferocytosis of Apoptotic Neutrophils.Frontiers in immunology · 2020Article
- An Engineered AAV6-Based Vaccine Induces High Cytolytic Anti-Tumor Activity by Directly Targeting DCs and Improves Ag Presentation.Molecular therapy oncolytics · 2019Article
- A cellular census of human lungs identifies novel cell states in health and in asthma.Nature medicine · 2019Article
- Sex-specific differences in emphysema using a murine antisense oligonucleotide model of α-1 antitrypsin deficiency.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- Heme scavenging reduces pulmonary endoplasmic reticulum stress, fibrosis, and emphysema.JCI insight · 2018Observational
- An oxidation-resistant, recombinant alpha-1 antitrypsin produced in Nicotiana benthamiana.Free radical biology & medicine · 2018Article
- Dysregulated Functions of Lung Macrophage Populations in COPD.Journal of immunology research · 2018Review
- A checkpoint on innate myeloid cells in pulmonary arterial hypertension.Pulmonary circulationArticle
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
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.
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