Modification of Hemodynamic and Immune Responses to Exposure with a Weak Antigen by the Expression of a Hypomorphic BMPR2 Gene

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.

Interleukin 13– and Interleukin 17A–Induced Pulmonary Hypertension Phenotype Due to Inhalation of Antigen and Fine Particles from Air Pollution

“…[66][67][68][69][70] These key molecules are BMPR2, vascular endothelial growth factor a (VEGFa), and the potassium channel Kcnk3/TASK-1. 40,[71][72][73][74] Here we show significantly decreased expression of all three molecules in the lungs of animals exposed to antigen and PM (Fig. 7A-7C), constituting a molecular risk profile for pulmonary arterial remodeling.…”

“…40 To understand the biological significance, we examined right ventricles for signs of molecular change because right ventricular remodeling and ultimately failure are the cause of …”

“…2B, 2C ) Functional evaluation and tissue collection RVSP was measured after inserting a catheter via the jugular vein in anaesthetized, spontaneously breathing mice. 40,44 Right ventricular hypertrophy was determined as right ventricular weight relative to the weight of the left ventricle and septum. 44 Bronchoalveolar lavage (BAL) and tissue harvest were performed after right heart catheterization and euthanasia of animals.…”

“…All cell analysis was performed without prior knowledge of the group designation of the samples. BAL samples were analyzed as described elsewhere 40,41 for the presence of eosin- The cell populations were analyzed using monoclonal antibodies tagged with Pacific Blue, AlexaFluor, fluorescein isothiocyanate, phycoerythrin, peridinin-chlorophyll, allophycocyanin, or cyanine tandem dyes that were purchased from BD Biosciences (San Jose, CA), Ebioscience (San Diego, CA), or Biolegend (San Diego, CA).…”

Inflammation and Immunity in the Pathogenesis of Pulmonary Arterial Hypertension

“…IL-1 can induce fibroblast growth factor (FGF)-2 13 and both FGF-2 and IL-6 and play an integral role in mediating the proliferative response in the smooth muscle like cells and fibroblasts of the pulmonary vasculature in PAH 14-19 . Mutations in BMPR2 seen in heritable PAH 20,21 and dysfunction of the BMPR2 signaling pathway seen in all forms of PAH 22 can lead to inappropriate expression of growth factors and pro-inflammatory responses in vascular cells as described both in experimental and human PAH 23-26 . For example, in PA endothelial cells, loss of BMPR2 causes repression of apelin 19 and this reduces a microRNA that normally represses FGF-2 15 .…”