title: Lack of CCR7 induces pulmonary hypertension involving perivascular leukocyte infiltration and inflammation.
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 contribute to the pathogenesis of pulmonary hypertension, we utilized mice deficient of the CCR7 receptor. The cardiopulmonary and inflammatory responses of CCR7 depletion were 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 subgroups, possibly via pulmonary infiltration of lymphocytes and secretion of interleukin-12 and CX3CL1.
authors.affiliation: Department of Pulmonary Medicine, Oslo University Hospital Ullevål, Oslo, Norway. karlottl@medisin.uio.no
authors.forename: Karl-Otto
authors.initials: KO
authors.lastname: Larsen
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Else Marit
authors.initials: EM
authors.lastname: Løberg
authors.forename: Ingeborg Løstegaard
authors.initials: IL
authors.lastname: Goverud
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.forename: Jing
authors.initials: J
authors.lastname: Jia
authors.forename: Arne K
authors.initials: AK
authors.lastname: Andreassen
authors.forename: Cathrine
authors.initials: C
authors.lastname: Husberg
authors.forename: Sofia
authors.initials: S
authors.lastname: Jonasson
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Ole Henning
authors.initials: OH
authors.lastname: Skjønsberg
mesh_terms: D000328:Adult; D000818:Animals; D002465:Cell Movement; D054428:Chemokine CX3CL1 / Q000097:blood; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D005786:Gene Expression Regulation; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D018664:Interleukin-12 / Q000097:blood; D016209:Interleukin-8 / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology*; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D011014:Pneumonia / Q000097:blood / Q000150:complications* / Q000473:pathology* / Q000503:physiopathology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054400:Receptors, CCR7 / Q000172:deficiency* / Q000378:metabolism
chemical_list: C515371:Ccr7 protein, mouse; D054428:Chemokine CX3CL1; D016209:Interleukin-8; D012333:RNA, Messenger; D054400:Receptors, CCR7; D018664:Interleukin-12