title: Perivascular T-cell infiltration leads to sustained pulmonary artery remodeling after endothelial cell damage.
abstract: Pulmonary hypertension is a vascular proliferative disease characterized by pulmonary artery remodeling because of dysregulated endothelial and smooth muscle cell proliferation. Although the role of inflammation in the development of the disease is not well-defined, plexogenic lesions in human disease are characterized by perivascular inflammation composed, in part, of T cells. We explored the role of T-cell infiltration on pulmonary vascular remodeling after endothelial cell damage. We induced endothelial cell damage using monocrotaline and isolated the role of T cells by using Rag1(tm1Mom) mice and performing adoptive T-cell transfer. We found that monocrotaline causes pulmonary vascular endothelial cell injury followed by a perivascular inflammatory response. The infiltration of inflammatory cells primarily involves CD4(+) T cells and leads to the progressive muscularization of small (<30 μm) arterioles. Pulmonary vascular proliferative changes were accompanied by progressive and persistent elevations in right ventricular pressure and right ventricular hypertrophy. Supporting the central role of CD4(+) T cells in the inflammatory response, Rag1(tm1Mom) (Rag1(-/-)) mice, which are devoid of T and B cells, were protected from the development of vascular injury when exposed to monocrotaline. The introduction of T cells from control mice into Rag1(-/-) mice reproduced the vascular injury phenotype. These data indicate that after endothelial cell damage, CD4(+) T-cell infiltration participates in pulmonary vascular remodeling. This finding suggests that a CD4(+) T-cell immune response may contribute to the pathogenesis of inflammatory vascular lesions seen in some forms of pulmonary hypertension.
authors.affiliation: Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, MSC1454, Building 10-CRC, Room 5 East 3132, Bethesda, MD 20892, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cuttica
authors.forename: Thomas
authors.initials: T
authors.lastname: Langenickel
authors.forename: Audrey
authors.initials: A
authors.lastname: Noguchi
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: Manfred
authors.initials: M
authors.lastname: Boehm
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular; D011651:Pulmonary Artery / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein
references.citation: Chest. 2006 Jul;130(1):182-9
references.pmid: 16840400
references.citation: Microvasc Res. 1989 Jul;38(1):57-80
references.pmid: 2503687
references.citation: J Immunol. 1998 May 1;160(9):4606-14
references.pmid: 9574568
references.citation: Eur Respir J. 2005 Dec;26(6):1110-8
references.pmid: 16319344
references.citation: Toxicol Pathol. 1995 Jan-Feb;23(1):63-71
references.pmid: 7770701
references.citation: J Clin Invest. 2001 Jul;108(2):251-9
references.pmid: 11457878
references.citation: Semin Arthritis Rheum. 2000 Aug;30(1):33-46
references.pmid: 10966211
references.citation: J Clin Invest. 2004 Aug;114(3):419-26
references.pmid: 15286808
references.citation: Ann Rheum Dis. 2003 Nov;62(11):1088-93
references.pmid: 14583573
references.citation: Antioxid Redox Signal. 2002 Oct;4(5):833-43
references.pmid: 12470512
references.citation: Am J Respir Crit Care Med. 2007 Jun 15;175(12):1280-9
references.pmid: 17413127
references.citation: Rheum Dis Clin North Am. 2008 Feb;34(1):41-55; vi
references.pmid: 18329531
references.citation: Rheumatology (Oxford). 2009 Jun;48 Suppl 3:iii54-7
references.pmid: 19487226
references.citation: AIDS. 2008 Sep;22 Suppl 3:S27-33
references.pmid: 18845919
references.citation: Arch Pathol. 1965 Apr;79:409-18
references.pmid: 14254913
references.citation: Respirology. 2006 Mar;11(2):158-63
references.pmid: 16548900
references.citation: Prog Cardiovasc Dis. 2002 Nov-Dec;45(3):225-34
references.pmid: 12525998
references.citation: J Am Coll Cardiol. 2009 Apr 7;53(14):1211-8
references.pmid: 19341863
references.citation: Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3652-6
references.pmid: 8170963
references.citation: Am J Physiol. 1998 Dec;275(6):H1948-56
references.pmid: 9843792
references.citation: Medicine (Baltimore). 2006 Mar;85(2):95-104
references.pmid: 16609348
references.citation: Am J Respir Crit Care Med. 2006 May 1;173(9):1023-30
references.pmid: 16456139
references.citation: Arterioscler Thromb Vasc Biol. 2001 Jun;21(6):1011-6
references.pmid: 11397712
references.citation: J Clin Invest. 2009 May;119(5):1298-311
references.pmid: 19381013
references.citation: Eur Respir J. 1995 Dec;8(12):2129-38
references.pmid: 8666110
references.citation: Chest. 1998 Sep;114(3 Suppl):225S-230S
references.pmid: 9741573
references.citation: Am J Pathol. 1994 Feb;144(2):275-85
references.pmid: 7508683
references.citation: Clin Chest Med. 2001 Sep;22(3):405-18
references.pmid: 11590837
references.citation: Toxicol Pathol. 1997 Nov-Dec;25(6):574-81
references.pmid: 9437801
references.citation: Virchows Arch B Cell Pathol Incl Mol Pathol. 1989;57(3):149-55
references.pmid: 2570481
references.citation: Lab Invest. 1961 Jul-Aug;10:744-50
references.pmid: 13758395
references.citation: Circulation. 2000 Nov 28;102(22):2781-91
references.pmid: 11094047
references.citation: Antioxid Redox Signal. 2002 Aug;4(4):563-8
references.pmid: 12230867
references.citation: Eur Heart J. 2004 Dec;25(24):2243-78
references.pmid: 15589643
references.citation: Am J Physiol Heart Circ Physiol. 2002 Nov;283(5):H2021-8
references.pmid: 12384481
references.citation: J Am Coll Cardiol. 2004 Jun 16;43(12 Suppl S):5S-12S
references.pmid: 15194173
references.citation: Thorax. 2005 Sep;60(9):765-72
references.pmid: 16135682
references.citation: Respiration. 2008;75(3):272-80
references.pmid: 18025812
references.citation: Eur Respir J. 2001 Nov;18(5):838-45
references.pmid: 11757635
references.citation: Eur Respir J. 2006 Oct;28(4):799-807
references.pmid: 16774952
references.citation: Am J Respir Crit Care Med. 1997 Oct;156(4 Pt 1):1114-9
references.pmid: 9351610
references.citation: Curr Opin Rheumatol. 2009 Jan;21(1):29-34
references.pmid: 19077715
references.citation: Circulation. 2000 Dec 12;102(24):2919-22
references.pmid: 11113040
references.citation: Eur Heart J. 2005 Aug;26(16):1618-24
references.pmid: 15800017