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The Role of Interleukin-33 in the Progression of Pulmonary Arterial Hypertension Through an ST2/MyD88 Pathway


Pulmonary arterial hypertension (PAH) is a multifactorial disorder characterized by elevated right ventricle pressures (RVP) and pulmonary vascular resistance (PVR) thought to result from pulmonary vascular remodeling. Currently, there is no cure for PAH, but inflammatory mechanisms have been implicated in playing a role. Previously, members of our group measured elevated levels of interleukin-33 (IL-33) in Group 1 PAH patient serum. This alarmin, “danger” signal, is expressed by endothelial cells and its signaling can either repair the endothelial layer or, if the danger signals persist, contribute to uncontrolled proliferation. Thus, we hypothesized that pulmonary vascular remodeling in PAH is regulated by an IL-33-dependent pathway. To test this hypothesis, PAH was induced in adult C57BL/6J (wild-type, WT) mice, IL-33 receptor gene-ablated mice (ST2 -/-), in mice with a gene deletion of the upstream adaptor, MyD88 (MyD88 -/-), and in a strain with a conditional, endothelial-specific IL-33 gene-targeted inactivation using IL33 floxed and Tek-Cre transgenes [Tek-Cre (+/-)::IL33fl/fl]. Body weight, RVP, pulmonary vascular remodeling and endothelial cell proliferation were evaluated. PAH was induced using 10% hypoxia and weekly injections of the VEGF receptor antagonist, SU5416 (20 mg/kg) for three weeks (SuHx). The control condition was vehicle and room air, (DMSO/RA). RVP were measured by right heart catheterization in anesthetized mice. Pulmonary vascular wall thickness was morphometrically analyzed from paraffin-embedded H&E sections. Endothelial cell proliferation was analyzed by flow cytometry. Following SuHx conditions: all mice lost weight, except for MyD88 -/- mice, and RVP were increased in WT and Tek-Cre::IL33fl/fl mice, but attenuated in ST2 -/-, and MyD88 -/- mice. Pulmonary vascular wall thickening increased in WT-SuHx males and Tek-Cre::IL-33fl/fl males, but not in SuHx-female mice for any strain. SuHx-WT male mice demonstrated increased endothelial cell proliferation compared to WT-Control mice. These data suggest that the IL-33-receptor, ST2, and MyD88 signaling may play a role in the PAH vascular remodeling and disease progression. Further understanding of IL-33-mediated signaling that regulates endothelial cell proliferation, remodeling and cytokine activation may provide a better understanding of the disease and its advancement and allow the design of new treatment strategies for PAH.

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