In:
American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society
Abstract:
Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by non-resolving inflammation fueled by breach in the endothelial barrier and leukocyte recruitment into the airspaces. Among the ligand-receptor axes that control leukocyte recruitment, the full-length fractalkine ligand (CX3CL1)-receptor (CX3CR1) ensures homeostatic endothelial-leukocyte interactions. Cigarette smoke (CS) exposure and respiratory pathogens increase expression of endothelial sheddases, such as a-disintegrin-and-metalloproteinase-domain 17 (ADAM17, TACE), inhibited by the anti-protease alpha-1 antitrypsin (AAT). In the systemic endothelium, TACE cleaves CX3CL1 to release soluble CX3CL1 (sCX3CL1). During CS-exposure it is not known whether AAT inhibits sCX3CL1shedding and CX3CR1 + leukocyte trans-endothelial migration across lung microvasculature. Objectives: We investigated the mechanism of sCX3CL1 shedding, its role in endothelial-monocyte interactions, and AAT effect on these interactions during acute inflammation. Methods: We used two, CS and lipopolysaccharide (LPS) models of acute inflammation in transgenic CX3CR1 gfp/gfp mice and primary human endothelial cells and monocytes to study sCX3CL1-mediated CX3CR1 + monocyte adhesion and migration. We measured sCX3CL1 levels in plasma and bronchoalveolar lavage (BALF) of COPD individuals. Results: Both sCX3CL1 shedding and CX3CR1 + monocytes trans-endothelial migration were triggered by LPS- and CS-exposure in mice, and were significantly attenuated by AAT. The inhibition of monocyte-endothelial adhesion and migration by AAT was TACE-dependent. Compared to healthy controls, sCX3CL1 levels were increased in plasma and BALF of COPD individuals, and were associated with clinical parameters of emphysema. Conclusion: Our results indicate that inhibition of sCX3CL1 as well as AAT augmentation may be effective approaches to decrease excessive monocyte lung recruitment during acute and chronic inflammatory states.
Type of Medium:
Online Resource
ISSN:
1040-0605
,
1522-1504
DOI:
10.1152/ajplung.00023.2023
Language:
English
Publisher:
American Physiological Society
Publication Date:
2023
detail.hit.zdb_id:
1477300-4
SSG:
12
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