ArticleAmerican journal of physiology. Lung cellular and molecular physiology2015
α-1-antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease.
Article in American journal of physiology. Lung cellular and molecular physiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 62 citations in OpenAlex.
- The elastin peptide VGVAPG increases CD4Respiratory research · 2021Trial
- Clinical phenotypes in αERJ open research · 2026Article
- The Role of Alpha-1 Antitrypsin in the Pathophysiology and Treatment of Inflammatory Lung Diseases.Journal of inflammation research · 2026Review
- Alpha-1 antitrypsin deficiency: genetics, clinical manifestations, AI prognostics, and advanced imaging in liver disease.Annals of medicine and surgery (2012) · 2025Review
- Genetic and Environmental Contributions to Serological Biomarkers of Extracellular Matrix Remodeling in Asthma: A Twin Study.Clinical and translational allergy · 2025Article
- Alpha-1 antitrypsin deficiency-associated liver disease: From understudied disorder to the poster child of genetic medicine.Hepatology communications · 2025Review
- Article
- Safety and Reactogenicity of COVID-19 Vaccination in Severe Alpha-1 Antitrypsin Deficiency.Chronic obstructive pulmonary diseases (Miami, Fla.) · 2024Article
- A novelFrontiers in pharmacology · 2024Article
- Genotypic Frequencies of Mutations Associated with Alpha-1 Antitrypsin Deficiency in Unrelated Bone Marrow Donors from the Murcia Region Donor Registry in the Southeast of Spain.Diagnostics (Basel, Switzerland) · 2023Article
- Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin.International journal of molecular sciences · 2023Article
- NAFLD and AATD Are Two Diseases with Unbalanced Lipid Metabolism: Similarities and Differences.Biomedicines · 2023Review
- A Bibliometric Analysis of Comorbidity of COPD and Lung Cancer: Research Status and Future Directions.International journal of chronic obstructive pulmonary disease · 2023Article
- Alpha-1 antitrypsin deficiency and risk of lung cancer in never-smokers: a multicentre case-control study.BMC cancer · 2022Article
- Alpha-1-antitrypsin: A possible host protective factor against Covid-19.Reviews in medical virology · 2021Review
- Origin and Expansion of the Serine Protease Repertoire in the Myelomonocyte Lineage.International journal of molecular sciences · 2021Review
- Protease-Specific Biomarkers to Analyse Protease Inhibitors for Emphysema Associated with Alpha 1-Antitrypsin Deficiency. An Overview of Current Approaches.International journal of molecular sciences · 2021Review
- Alpha-1 antitrypsin deficiency and risk of lung cancer: A systematic review.Translational oncology · 2021Article
- Therapeutic SERPINs: Improving on Nature.Frontiers in cardiovascular medicine · 2021Review
- Clarifying the Risk of Lung Disease in SZ Alpha-1 Antitrypsin Deficiency.American journal of respiratory and critical care medicine · 2020Observational
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Authors and funding
6 authors at 3 institutions in 1 country.
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Abstract
The excessive activities of the serine proteinases neutrophil elastase and proteinase 3 are associated with tissue damage in chronic obstructive pulmonary disease. Reduced concentrations and/or inhibitory efficiency of the main circulating serine proteinase inhibitor α-1-antitrypsin result from point mutations in its gene. In addition, α-2-macroglobulin competes with α-1-antitrypsin for proteinases, and the α-2-macroglobulin-sequestered enzyme can retain its catalytic activity. We have studied how serine proteinases partition between these inhibitors and the effects of α-1-antitrypsin mutations on this partitioning. Subsequently, we have developed a three-dimensional reaction-diffusion model to describe events occurring in the lung interstitium when serine proteinases diffuse from the neutrophil azurophil granule following degranulation and subsequently bind to either α-1-antitrypsin or α-2-macroglobulin. We found that the proteinases remained uninhibited on the order of 0.1 s after release and diffused on the order of 10 μm into the tissue before becoming sequestered. We have shown that proteinases sequestered to α-2-macroglobulin retain their proteolytic activity and that neutrophil elastase complexes with α-2-macroglobulin are able to degrade elastin. Although neutrophil elastase is implicated in the pathophysiology of emphysema, our results highlight a potentially important role for proteinase 3 because of its greater concentration in azurophil granules, its reduced association rate constant with all α-1-antitrypsin variants studied here, its greater diffusion distance, time spent uninhibited following degranulation, and its greater propensity to partition to α-2-macroglobulin where it retains proteolytic activity.
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