Attenuation of leukocyte recruitment via inhibition of CXCR1/2 inhibition stops the progression of PAH in mice with genetic ablation of endothelial BMPR-II.
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Burton, Victoria, Holmes, Alan, Ciuclan, Loredana, Robinson, Alexander, Roger, Jan, Jarai, Gabor, 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 |