In:
American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
1040-0605
,
1522-1504
DOI:
10.1152/ajplung.00023.2023
Sprache:
Englisch
Verlag:
American Physiological Society
Publikationsdatum:
2023
ZDB Id:
1477300-4
SSG:
12
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