Title: Modification of hemodynamic and immune responses to exposure with a weak antigen by the expression of a hypomorphic BMPR2 gene.
Authors: Park, Sung-Hyun; Chen, Wen-Chi; Hoffman, Carol; Marsh, Leigh M; West, James; Grunig, Gabriele
Published In PLoS One, (2013)
Abstract: 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.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.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.
PubMed ID: 23383100
MeSH Terms: Animals; Antigens/administration & dosage; Antigens/immunology*; Blood Pressure/physiology*; Body Weight/physiology; Bone Morphogenetic Protein Receptors, Type II/genetics; Bone Morphogenetic Protein Receptors, Type II/metabolism*; Bronchoalveolar Lavage; DNA Primers/genetics; Heart Ventricles/pathology; Hemodynamics; Hypertension, Pulmonary/etiology; Hypertension, Pulmonary/immunology*; Hypertension, Pulmonary/metabolism*; Intercellular Signaling Peptides and Proteins/metabolism; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukins/metabolism; Mice; Mice, Transgenic; Organ Size/physiology; Ovalbumin/administration & dosage; Ovalbumin/immunology; Receptors, Interleukin/metabolism; Th2 Cells/immunology*; Transgenes/genetics