Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling.

RATIONALE Severe pulmonary arterial hypertension (SPH) is a frequently lethal condition characterized by pulmonary vascular remodeling and right heart strain or failure. SPH is also often associated with autoimmune and collagen vascular disorders. OBJECTIVES To study the effects of T cells on the development of experimental SPH. METHODS Athymic nude rats lacking T cells were treated with a single subcutaneous injection of vascular endothelial growth factor (VEGF) receptor blocker SU5416 (20 mg/kg) to induce pulmonary vascular endothelial cell apoptosis. Immunohistochemical analysis and IL-4 levels of the lung tissue were performed. Cell death and proliferation were assessed by Western blot and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS In contrast to SU5416-treated euthymic rats that develop SPH only in combination with chronic hypoxia, athymic nude rats developed SPH and vascular remodeling (similar to clinical SPH) at normoxic conditions as demonstrated by measurements of pulmonary artery pressure and right ventricle hypertrophy. Pulmonary arterioles became occluded with proliferating endothelial cells and were surrounded by mast cells, B cells, and macrophages. IL-4, proliferating cell nuclear antigen, and collagen type I levels were markedly increased in SU5416-treated athymic rat lungs. Antibody deposition was noted along the vascular endothelium in rats with SPH. Finally, protection from SPH was conferred by immune challenge with spleen cells from euthymic nude rats. CONCLUSIONS These studies demonstrate the importance of a complete, intact immune system in protecting against pulmonary angioproliferation in this new model of SPH as well as the importance of intact VEGF receptor signaling for lung endothelial cell homeostasis.

[1]  M. Koss,et al.  Immunopathologic and clinical studies in pulmonary hypertension associated with systemic lupus erythematosus. , 1984, Seminars in arthritis and rheumatism.

[2]  C. Benoist,et al.  Mast Cells: A Cellular Link Between Autoantibodies and Inflammatory Arthritis , 2002, Science.

[3]  J. Loscalzo,et al.  Pulmonary arterial hypertension. , 2004, Annals of medicine.

[4]  J. Alcocer-Varela,et al.  Quantification of regulatory T cells in patients with systemic lupus erythematosus. , 2003, Journal of autoimmunity.

[5]  N. Horiike,et al.  Serum levels of soluble CD4 and CD8 in patients with chronic viral hepatitis. , 1994, Hepato-gastroenterology.

[6]  E. Leroy,et al.  Primary heart disease in systemic sclerosis (scleroderma): advances in clinical and pathologic features, pathogenesis, and new therapeutic approaches. , 1981, American heart journal.

[7]  N. Voelkel,et al.  The protective role of T-lymphocytes in pulmonary vascular remodeling. , 2005, Chest.

[8]  J. Song,et al.  Clinical associations of anti-endothelial cell antibodies in patients with systemic lupus erythematosus , 2000, Rheumatology International.

[9]  D. Badesch,et al.  Pulmonary hypertension associated with connective tissue disease. , 2002, Progress in cardiovascular diseases.

[10]  M. Gershwin,et al.  Regulatory T cells: development, function and role in autoimmunity. , 2005, Autoimmunity reviews.

[11]  R. Grover,et al.  Lung mast cell hyperplasia and pulmonary histamine-forming capacity in hypoxic rats. , 1974, The American journal of physiology.

[12]  I. McMurtry,et al.  Lung mast cell density and distribution in chronically hypoxic animals. , 1977, Journal of applied physiology: respiratory, environmental and exercise physiology.

[13]  J. Williams,et al.  Anti-endothelial cell antibodies from lupus patients bind to apoptotic endothelial cells promoting macrophage phagocytosis but do not induce apoptosis. , 2005, Rheumatology.

[14]  T. Chatila.  Role of regulatory T cells in human diseases. , 2005, The Journal of allergy and clinical immunology.

[15]  G. Berry,et al.  Triptolide attenuates pulmonary arterial hypertension and neointimal formation in rats. , 2000, American journal of respiratory and critical care medicine.

[16]  M. Hoeper,et al.  Pulmonary hypertension in collagen vascular disease , 2002, European Respiratory Journal.

[17]  M. Humbert,et al.  Cellular and molecular pathobiology of pulmonary arterial hypertension. , 2004, Journal of the American College of Cardiology.

[18]  P. Youinou,et al.  Antiendothelial cell antibodies in systemic lupus erythematosus. , 2002, Autoimmunity reviews.

[19]  P. Lehmann,et al.  Indirect IL-4 Pathway in Type 1 Immunity1 , 2002, The Journal of Immunology.

[20]  A. Kojima,et al.  Mast cell chymase in pulmonary hypertension , 1999, Thorax.

[21]  D. Heath.  Pulmonary hypertension in pulmonary parenchymal disease. , 1972, Cardiovascular clinics.

[22]  M. Yacoub,et al.  Lung mast cells in plexogenic pulmonary arteriopathy. , 1991, Journal of clinical pathology.

[23]  V. Negi,et al.  Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. , 1998, The Journal of rheumatology.

[24]  P. Hirth,et al.  Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. , 2000, The Journal of clinical investigation.

[25]  L. Jara,et al.  Accelerated atherosclerosis, immune response and autoimmune rheumatic diseases. , 2006, Autoimmunity reviews.

[26]  M. Sherman.  The role of STAT6 in mast cell IL‐4 production , 2001, Immunological reviews.

[27]  T. Medsger,et al.  Physiologic abnormalities of cardiac function in progressive systemic sclerosis with diffuse scleroderma. , 1984, The New England journal of medicine.

[28]  B. Ryffel,et al.  Constitutive Expression of Interleukin (IL)-4 In Vivo Causes Autoimmune-type Disorders in Mice , 1997, The Journal of experimental medicine.

[29]  Y. Shoenfeld,et al.  HIV and autoimmunity. , 2002, Autoimmunity reviews.

[30]  H. Ohira,et al.  Athymic Nude Rats Develop Severe Pulmonary Hypertension following Monocrotaline Administration , 2000, International Archives of Allergy and Immunology.

[31]  J. Seibold,et al.  Soluble and cellular markers of immune activation in patients with systemic sclerosis. , 1990, Clinical immunology and immunopathology.

[32]  P. Hirth,et al.  Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death‐dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  M. Gershwin,et al.  In vivo analysis of the apoptosis-inducing effect of anti-endothelial cell antibodies in systemic sclerosis by the chorionallantoic membrane assay. , 2003, Arthritis and rheumatism.

[34]  G. Proctor,et al.  Enzyme histochemistry of rat mast cell tryptase , 1998, The Histochemical Journal.

[35]  D. Heath.  Mast cells in the human lung at high altitude , 1992, International journal of biometeorology.

[36]  M. Humbert,et al.  Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension , 2007, European Respiratory Journal.

[37]  D. Badesch,et al.  Autoimmunity and pulmonary hypertension: a perspective , 2005, European Respiratory Journal.

[38]  M. Clerici,et al.  Distinct immune profiles characterize patients with diffuse or limited systemic sclerosis. , 2003, Clinical immunology.

[39]  K. Shroyer,et al.  Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. , 1998, The Journal of clinical investigation.

[40]  B. Groves,et al.  Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. , 1994, The American journal of pathology.

[41]  I. Gál,et al.  Anti-endothelial cell antibodies in mixed connective tissue disease: frequency and association with clinical symptoms. , 2004, Clinical and Experimental Rheumatology.

[42]  L-L Fung,et al.  Decreased CD4+CD25+ T Cells in Peripheral Blood of Patients with Systemic Lupus Erythematosus , 2004, Scandinavian journal of immunology.

[43]  K. Kikuchi,et al.  Severe pulmonary hypertension associated with primary Sjögren's syndrome. , 2003, Internal medicine.

[44]  N. Voelkel,et al.  Initial apoptosis is followed by increased proliferation of apoptosis‐resistant endothelial cells , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[45]  S. Erzurum,et al.  Definitive evidence of fundamental and inherent alteration in the phenotype of primary pulmonary hypertension endothelial cells in angiogenesis. , 2005, Chest.

[46]  M. Corbellino,et al.  Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman's disease. , 1997, The American journal of pathology.

[47]  J. Cairns,et al.  Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. , 1997, The Journal of clinical investigation.

[48]  L. Kemény,et al.  Human herpesvirus 8 in classic Kaposi sarcoma. , 1996, Acta microbiologica et immunologica Hungarica.

[49]  P. Flemming,et al.  Pulmonary Hypertension after Splenectomy? , 1999, Annals of Internal Medicine.

[50]  N. Voelkel,et al.  Severe Angioproliferative Pulmonary Hypertension: The Lung Circulation Between Vasoconstriction and Cancer , 2003 .

[51]  M. Tsai,et al.  Mast cells in the development of adaptive immune responses , 2005, Nature Immunology.

[52]  R. L. Williams,et al.  Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. , 1999, The American journal of pathology.