Muscularization of pulmonary arteries induced by an adaptive immune response

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DESCRIPTION (provided by applicant): Muscularization of pulmonary arteries induced by an adaptive immune response Abstract Pulmonary arterial hypertension (PAH) is a devastating condition because of its deleterious impact on quality of life, and life expectancy. Clinical correlation studies have suggested an immune pathogenesis because of the increased incidence of PAH in autoimmune and infectious diseases. Helminth infections can also cause PAH, but direct injury by the migrating parasites to the arteries has been thought to be the major cause of arterial remodeling. Pulmonary arterial remodeling associated with smooth muscle cell hyperplasia is frequently seen in PAH. In preliminary experiments, severe pulmonary arterial muscularization was induced by intermittent antigen challenge for a prolonged period of time via the inhaled route in primed mice. Essential roles for CD4+ T cells, the antigen- specific T helper (Th)2 response, and a pathogenic Th2 cytokine [Interleukin (IL) 13] in inducing severe pulmonary arterial musularization were identified. This indicated that the host's immune response developed to fight helminth infections alone is sufficient to induce severe pulmonary arterial muscularization, even without the presence of parasites. The severity of arterial remodeling was highly significantly correlated with the numbers of cells that bordered pulmonary arteries and expressed resistin-like molecule (RELM)1. RELM1 is known as a smooth muscle cell mitogen, induced by Th2 responses and by chronic hypoxia. But the role of RELM1 in pulmonary arterial remodeling has not been experimentally tested. The preliminary data show that the majority of proliferation marker positive cells within the remodeled pulmonary arteries had the appearance of endothelial cells and neo-intima cells. Few cells with smooth muscle morphology were proliferation marker positive. These data indicate that the origin of the cells within the remodeled pulmonary arteries might not be smooth muscle cells. The long range goal of this proposal is to understand how the Th2 immune response induces pulmonary arterial muscularization. To accomplish this goal, specific aims are proposed to identify the origin of the cells that populate the remodeled pulmonary arteries and to define the role of RELM1. The experimental approach will be to study mice that carry fluorescent tags driven by cell-type specific promoters for endothelial cells, leukocytes, and monocytes / myeloid cells, and RELM1 KO mice. Studies with mice that express receptors that can be used for cell ablation, and in vitro cell culture will be used for mechanistic analysis. The working hypothesis is that precursor cell proliferation followed by differentiation into smooth muscle cells and RELM1 are essential contributors to Th2-response-induced pulmonary arterial remodeling. PUBLIC HEALTH RELEVANCE: Muscularization of pulmonary arteries induced by an adaptive immune response Relevance: Pulmonary arterial hypertension (PAH) is a devastating condition that can accompany chronic parasite infections and auto-immune diseases. Thickening of the walls of pulmonary arteries by layers of smooth muscle cells is one of the typical morphological alterations seen in PAH and this process is a target for the development of new treatment strategies. The proposed studies are aimed at delineating the cellular origin and mediators that cause the accumulation of these smooth muscle cells in a mouse model of severe pulmonary arterial remodeling induced by the adaptive immune response.