title: Modification of hemodynamic and immune responses to exposure with a weak antigen by the expression of a hypomorphic BMPR2 gene.
abstract: BACKGROUND
  Hypomorphic mutations in the bone morphogenic protein receptor (BMPR2) confer a much greater risk for developing pulmonary arterial hypertension (PAH). However, not all carriers of a mutation in the BMPR2 gene suffer from PAH. We have previously shown that prolonged T helper 2 (Th2) responses in the lungs to a mild antigen delivered via the airways induce severe pulmonary arterial remodeling, but no pulmonary hypertension. The current studies were designed to test the idea that Th2 responses to a mild antigen together with the expression of a hypomorphic BMPR2 gene would trigger pulmonary hypertension.
  
  
  RESULTS
  Mice that expressed a hypomorphic BMPR2 transgene (transgene-positive) and transgene-negative mice were either exposed to saline, or primed and exposed to a mild antigen (Ovalbumin) over a prolonged period of time. Only transgene-positive but not transgene-negative mice exposed to antigen developed significantly increased right ventricular systolic pressures, while both groups showed pulmonary artery remodeling with severe muscularization and airway inflammation to a similar degree. Antigen exposure resulted in a smaller increase in the percentage of Interleukin (IL)-13 positive T cells in the lymph nodes, and in a smaller increase in resistin-like-molecule (RELM)α expression and a decreased ratio of expression of IL-33 relative to its receptor (IL-1-receptor-like 1, IL1RL1-ST2) in the right ventricles of transgene-positive mice compared to transgene-negative animals. Furthermore, only antigen-challenged transgene-positive mice showed a significant increase in Interferon (IFN)γ positive T cells over saline-exposed controls.
  
  
  CONCLUSIONS
  Our study suggests that exposure with a mild Th2 antigen can trigger pulmonary hypertension on the background of the expression of a hypomorphic BMPR2 gene and that conversely, the expression of the hypomorphic BMPR2 gene can alter the immune response to a mild, inhaled antigen.
authors: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America.
authors: Sung-Hyun
authors: SH
authors: Park
authors: Wen-Chi
authors: WC
authors: Chen
authors: Carol
authors: C
authors: Hoffman
authors: Leigh M
authors: LM
authors: Marsh
authors: James
authors: J
authors: West
authors: Gabriele
authors: G
authors: Grunig
mesh_terms: D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D001794:Blood Pressure / Q000502:physiology*; D001835:Body Weight / Q000502:physiology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D018893:Bronchoalveolar Lavage; D017931:DNA Primers / Q000235:genetics; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000276:immunology* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size / Q000502:physiology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D018123:Receptors, Interleukin / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*; D019076:Transgenes / Q000235:genetics
chemical_list: D000941:Antigens; D017931:DNA Primers; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin; C413576:Retnla protein, mouse; D010047:Ovalbumin; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II
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