Abstract

Inflammation plays a major role in the pathogenesis of pulmonary hypertension (PH). We sought to investigate the effects of a cell-based immunomodulation in a dysimmune model of PH. PH was induced in athymic nude rats using semaxinib (Su group, n=6). Tolerogenic macrophages (toM) were generated from monocyte isolation and then injected either the day before semaxinib injection (Prevention group, n=6) or 3 weeks after (Reversion group, n=6). Six athymic nude rats were used as controls. In vivo trafficking of toM was investigated with bioluminescence imaging showing that toM were mainly located into the lungs until 48 hours after injection. Right ventricular end-systolic pressure (RVESP) and right ventricular systolic function were assessed at 4 weeks using echocardiography. Morphometric analysis and RNA sequencing of the lungs were realized at 4 weeks. Rats treated with toM (Prevention and Reversion groups) had a significantly lower RVESP at 4 weeks (respectively 25±8 and 30±6 vs. 67±9 mmHg, P<0.001), while right ventricular systolic dysfunction was observed in Su and Reversion groups... Mean medial wall thickness of small arterioles was lower in Prevention and Reversion groups compared to the Su group (respectively 10.9±0.8% and 16.4±1.3% vs. 28.2±2.1%, P<0.001). Similarly, cardiomyocyte area was decreased in rats treated with toM (150±18 and 160±86 vs. 279±50 m, P<0.001). A trend towards upregulation of genes involved in PAH pathobiology was found in Su rats, while KCNK3 was significantly downregulated (Fold-change=9.8, P<0.001). Injection of toM was associated with a less severe phenotype of PH in rats exposed to angioproliferative stress. Preserved expression of KCNK3 may explain the protective effect of toM.

View details for DOI 10.1089/scd.2021.0007

View details for PubMedID 33726521