Abstract
BackgroundHypomorphic 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.Methodology/Principal FindingsMice 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/SignificanceOur 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.
Highlights
Pulmonary arterial hypertension (PAH) is characterized by increased right ventricular systolic pressures and severe thickening of arteries due to smooth muscle cell hypertrophy and impaired ability to terminate repair responses [1,2]
Conclusions/Significance: Our study suggests that exposure with a mild T helper 2 (Th2) antigen can trigger pulmonary hypertension on the background of the expression of a hypomorphic BMPR2 gene and that the expression of the hypomorphic BMPR2 gene can alter the immune response to a mild, inhaled antigen
The expression of the BMPR2R899X transgene was detected from the first day of birth and persisted at similar levels through the life of the animals (Fig. 1A)
Summary
Pulmonary arterial hypertension (PAH) is characterized by increased right ventricular systolic pressures and severe thickening of arteries due to smooth muscle cell hypertrophy and impaired ability to terminate repair responses [1,2]. Our group has reported that severe pulmonary arterial remodeling can be caused by a T helper 2 (Th2) immune response to inhaled antigen [3]. Increased TGFb signaling induces smooth muscle cell proliferation [9]. Hypomorphic mutations in the bone morphogenic protein receptor (BMPR2) confer a much greater risk for developing pulmonary arterial hypertension (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
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