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Lack of CCR7 induces pulmonary hypertension involving perivascular leukocyte infiltration and inflammation

Item Type:Article
Title:Lack of CCR7 induces pulmonary hypertension involving perivascular leukocyte infiltration and inflammation
Creators Name:Larsen, K.O. and Yndestad, A. and Sjaastad, I. and Loberg, E.M. and Goverud, I.L. and Halvorsen, B. and Jia, J. and Andreassen, A.K. and Husberg, C. and Jonasson, S. and Lipp, M. and Christensen, G. and Aukrust, P. and Skjonsberg, O.H.
Abstract:The chemokine receptor CCR7 regulates lymphocyte trafficking, and CCR7 deficiency induces infiltration of T-and B-cells adjacent to vessels in mouse lungs. Perivascular infiltration of T-and B-cells has also been found in human pulmonary arterial hypertension, and downregulation of the CCR7 receptor in circulating leukocytes of such patients has been observed. To investigate whether changes in the CCR7 system contributes to the pathogenesis of pulmonary hypertension, we utilized mice deficient of the CCR7 receptor. The cardiopulmonary and inflammatory responses of CCR7 depletion was evaluated in CCR7 deficient and wild-type mice. Measurements of cytokines upregulated in the animal model, were also performed in patients with pulmonary hypertension and controls and in vascular smooth muscle cells. We found that mice lacking CCR7 had increased right ventricular systolic pressure, reduced pulmonary artery acceleration time, increased right ventricular/tibial length ratio, Rho kinase-mediated pulmonary vasoconstriction, and increased muscularization of distal arteries indicating pulmonary hypertension. These mice also showed increased perivascular infiltration of leukocytes consisting mainly of T-and B-cells, and increased mRNA levels of the inflammatory cytokines interleukin-12 and CX3CL1 within pulmonary tissue. Increased serum levels of interleukin-12 and CX3CL1 were also observed in patients with pulmonary hypertension, particularly in those with pulmonary hypertension associated with connective tissue disorder. In smooth muscle cells, interleukin-12 induced secretion of the angiogenic cytokine interleukin-8. We conclude that these results suggest a role for CCR7 in the development of pulmonary arterial hypertension, at least in some sub-groups, possibly via pulmonary infiltration of lymphocytes and secretion of interleukin-12 and CX3CL1.
Keywords:Pulmonary Hypertension, Lymphocytes, Cytokines, Animals, Mice
Source:American Journal of Physiology Lung Cellular and Molecular Physiology
ISSN:1040-0605
Publisher:American Physiological Society (U.S.A.)
Volume:301
Number:1
Page Range:L50-L59
Date:July 2011
Official Publication:https://doi.org/10.1152/ajplung.00048.2010
PubMed:View item in PubMed

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