BackgroundPulmonary hypertension (PH) refers to a spectrum of diseases with elevated pulmonary artery pressure. Pulmonary arterial hypertension (PAH) is a disease category that clinically presents with severe PH and that is histopathologically characterized by the occlusion of pulmonary arterioles, medial muscular hypertrophy, and/or intimal fibrosis. PAH occurs with a secondary as well as a primary onset. Secondary PAH is known to be complicated with immunological disorders. The aim of the present study is to histopathologically and genetically characterize a new animal model of PAH and clarify the role of OX40 ligand in the pathogenesis of PAH.ResultsSpontaneous onset of PAH was stably identified in mice with immune abnormality because of overexpression of the tumor necrosis factor (TNF) family molecule OX40 ligand (OX40L). Histopathological and physical examinations revealed the onset of PAH-like disorders in the C57BL/6 (B6) strain of OX40L transgenic mice (B6.TgL). Comparative analysis performed using different strains of transgenic mice showed that this onset depends on the presence of OX40L in the B6 genetic background. Genetic analyses demonstrated a susceptibility locus of a B6 allele to this onset on chromosome 5. Immunological analyses revealed that the excessive OX40 signals in TgL mice attenuates expansion of regulatory T cells the B6 genetic background, suggesting an impact of the B6 genetic background on the differentiation of regulatory T cells.ConclusionPresent findings suggest a role for the OX40L-derived immune response and epistatic genetic effect in immune-mediated pathogenesis of PAH.
[Background] Ligation of OX40 receptor on T cells provides potent co-stimulatory signals associated with memory T cell generation, Ag-specific T cell migration, and enhanced inflammatory responses. OX40L is expressed on antigen presenting cells and vascular endothelial cells. Previous studies have shown that OX40L transgenic mice (OX40L-Tg) spontaneously developed ulcerative colitis-like disease and undetermined lung disease, which were evident in C57BL/6 (B6) but not BALB/c (BALB) genetic background. [Objective] The aim of this study is histopathological and genetic characterizations of the lung disease in OX40L-Tg. [Methods] We generated 351 OX40L-Tg from (BALB x B6) x B6 OX40L-Tg backcrosses. Severity of pulmonary arterial lesion was evaluated with microscopic examinations (0-1-2 grades). Genome-wide scan and other genetic analyses were carried out based on microsatellite polymorphisms. [Results] Pulmonary arterial lesion characterized by intimal and medial thickening that was observed in B6 but not BALB OX40L-Tg. Pulmonary hypertension (PH) in OX40L-Tg was shown by the elevation of right ventricular systolic pressure. We identified a novel susceptibility locus to the PH with suggestive linkage (P=0.0012, LOD=1.8) on chromosome 5. [Conclusion] Augmented OX40-OX40L interaction predisposes mice to spontaneous onset of PH under the influence of particular genetic background.
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