Chymotrypsin-like Elastase-1 Mediates Progressive Emphysema in Alpha-1 Antitrypsin Deficiency.

Autor:	Devine AJ; Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States., Smith NJ; University of Cincinnati School of Medicine, Cincinnati, Ohio, United States., Joshi R; Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States., Fan Q; Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States., Borchers MT; Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States.; Division of Pulmonary and Critical Care Medicine, University of Cincinnati, Cincinnati, Ohio, United States., Clair GC; Pacific Northwest National Laboratory, Richland, Washington, United States., Adkins JN; Pacific Northwest National Laboratory, Richland, Washington, United States., Varisco BM; Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States.; University of Cincinnati School of Medicine, Cincinnati, Ohio, United States.; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States.; Arkansas Children's Research Institute, Little Rock, Arkansas, United States.
Jazyk:	angličtina
Zdroj:	Chronic obstructive pulmonary diseases (Miami, Fla.) [Chronic Obstr Pulm Dis] 2023 Oct 26; Vol. 10 (4), pp. 380-391.
DOI:	10.15326/jcopdf.2023.0416
Abstrakt:	Chymotrypsin-like elastase 1 (CELA1) is a serine protease that is neutralized by alpha-1antitrypsin (AAT) and prevents emphysema in a murine antisense oligonucleotide model of AAT-deficient emphysema. Mice with genetic ablation of AAT do not have emphysema at baseline but develop emphysema with injury and aging. We tested the role of the CELA1 gene in emphysema development in this genetic model of AAT -deficiency following tracheal lipopolysaccharide (LPS), 10 months of cigarette smoke exposure, aging, and a low-dose tracheal porcine pancreatic elastase (LD-PPE) model we developed. In this last model, we performed proteomic analysis to understand differences in lung protein composition. We were unable to show that AAT -deficient mice developed more emphysema than wild type with escalating doses of LPS. In the LD-PPE model, AAT- deficient mice developed significant and progressive emphysema from which Cela1 -/- & AAT -deficient mice were protected. Cela1 -/- & AAT- deficient lungs had more matrix-associated proteins than AAT- deficientlungs but also had more leukocyte-associated proteases. With cigarette smoke exposure, Cela1 -/- &AAT -deficient mice had more emphysema than AAT- deficient mice but had less myeloperoxidase activity. Cela1 -/- &AAT -deficient mice had less age-related airspace simplification than AAT-deficient and were comparable to wild type. While CELA1 promotes inflammation-independent emphysema progression and its absence preserves the lung matrix in multiple models of AAT-deficient emphysema, for unclear reasons Cela1 deficiency is associated with increased emphysema with cigarette smoke. While anti-CELA1 therapies could potentially be used to prevent emphysema progression in AAT deficiency after smoking cessation, an understanding of why and how cigarette smoke exacerbates emphysema in Cela1 deficiency and whether AAT replacement therapy mitigates this effect is needed first. (JCOPDF © 2023.)
Databáze:	MEDLINE
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