| First Author | Mikosz A | Year | 2023 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 325 |
| Issue | 6 | Pages | L711-L725 |
| PubMed ID | 37814796 | Mgi Jnum | J:342471 |
| Mgi Id | MGI:7545423 | Doi | 10.1152/ajplung.00023.2023 |
| Citation | Mikosz A, et al. (2023) Alpha-1 antitrypsin inhibits fractalkine-mediated monocyte-lung endothelial cell interactions. Am J Physiol Lung Cell Mol Physiol |
| abstractText | 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. |
