
Jamila H Siamwala, PhD
Brown University and VA Providence
830 Chalkstone Avenue
Providence 02908
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Pulmonary arterial hypertension (PAH) is a devastating syndrome associated with vasoconstriction and pulmonary vascular remodeling, resulting in increased right ventricular (RV) afterload and RV hypertrophy. Therapies such as prostacyclins, calcium channel blockers, endothelin receptor blockers, phosphodiesterase inhibitors and guanylate cyclase stimulators for vascular management of PAH exists however none exists for the failing RV. Cardiac fibroblasts (CF’s) are the predominant cell type contributing to increased interstitial, perivascular fibrosis and abnormal accumulation of fibrillary collagen in the heart. However, little is known about the mechanisms of CF’s proliferation and consequent RV fibrosis and failure. Pro-inflammatory cytokines secreted by the macrophages specifically, IL-1 β are associated with adverse RV modelling and mortality in animal and humans with PAH. Our preliminary data suggests that conditioned media from the primary macrophages increases primary CF proliferation. Moreover, the IL-1β levels in the RV from pulmonary artery banded animals (PAB) is higher compared to sham surgery mice. The goal of this pilot study is to investigate the inflammatory processes of RV fibrosis to develop immune based therapy for improving RV systolic and diastolic function in PAH. We will employ unique macrophage specific IL-1β knockout and periostin (myofibroblast specific) IL-1R knockout pulmonary artery banded mice model of PAH to evaluate if IL-1β inhibition will prevent RV fibrosis and RV dysfunction. The hypothesis is that RV pressure overload in PAH leads to macrophage IL-1β-dependent fibrosis through cardiac fibroblast IL-1R signaling with consequent fibroblast proliferation and collagen deposition. The macrophage cell specific inducible IL-1β knockout mice model subjected to pulmonary artery banding (PAB) will be used to demonstrate the dependence of RV fibrosis on macrophage IL-1β expression. A second unique periostin specific IL-1R knockout mice subjected to PAB will be used to demonstrate the dependence of RV fibrosis on cardiac fibroblast IL-1R signaling. Finally, an FDA approved IL-1β blocker Anakinra will be employed to validate IL-1 receptor antagonist therapy as a viable clinical strategy for preventing RV failure in a rat model of PAH.
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Alan Morrison, MD, PhD
Assistant Professor of Medicine at the Warren Alpert Medical School of Brown University
Gaurav Choudhary, MD
Associate Professor of Medicine, Brown University
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Ocean State Research Institute
Providence VA Medical Center
Building 35
830 Chalkstone Avenue
Providence RI 02908
T: 401-273-7100
Research Funded by
Research reported in this website was supported by the National Institute of General Medical Science of the National Institutes of Health under grant number P20GM103652.