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Attenuation of leukocyte recruitment via inhibition of CXCR1/2 inhibition stops the progression of PAH in mice with genetic ablation of endothelial BMPR-II.

Burton, Victoria and Holmes, Alan and Ciuclan, Loredana and Robinson, Alexander and Roger, Jan and Jarai, Gabor and Pearce, Andrew and Budd, David (2011) Attenuation of leukocyte recruitment via inhibition of CXCR1/2 inhibition stops the progression of PAH in mice with genetic ablation of endothelial BMPR-II. Blood, 118 (17). pp. 4750-4758. ISSN 0006-4971

Abstract

Previous studies from our group have demonstrated that Bone Morphogenetic Protein Receptor-II (BMPR-II) expressed on pulmonary artery endothelial cells, imparts profound anti-inflammatory effects by regulating the release of pro-inflammatory cytokines and promoting barrier function by suppressing the transmigration of leukocytes into the pulmonary vessel wall. Here we demonstrate that in mice with endothelial-specific loss of BMPR-II expression (L1Cre(+);BMPR2f/f), reduction in barrier function and the resultant pulmonary hypertension observed in vivo is due to reduced leukocyte recruitment through inhibition of CXCR2 signaling. Loss of endothelial expressed BMPR-II leads to elevated plasma levels of a wide range of soluble mediators important in regulating leukocyte migration and extravasation including the CXCR2 ligand, KC. Treatment of L1Cre(+);BMPR2f/f mice with the CXCR2 antagonist, SCH527123 inhibits leukocyte transmigration into lung and subsequently reverses the pulmonary hypertension. Our data has uncovered a previously unrecognized regulatory function of BMPR-II which acts to regulate the expression of CXCR2 on endothelial cells. suggesting that dysregulation of CXCR2 signaling may also be a feature of the human pathology and that CXCR2 pathway antagonists may represent a novel therapeutic approach for treating pulmonary hypertension due to defects in BMPR-II expression.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); On author's personal web site or On departmental web site
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/5473

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