A selective kinin B1 receptor antagonist called BI113823 reversed pulmonary arterial hypertension (PAH) in left pneumonectomized male Wistar rats, according to a study published in the journal Respiratory Research.
“This regimen offers a unique novel approach for anti-inflammatory and remodeling therapy in progressed pulmonary hypertension,” the authors said.
After 3 weeks of treatment with BI113823, rats presented with normalized values of mean pulmonary arterial pressure (mPAP).
Treatment with BI113823 reversed pulmonary arterial neointimal formation, pulmonary vascular remodeling, and heart and lung fibrosis. Moreover, it reduced right ventricular pressure and right heart hypertrophy, and improved cardiac output. Ultimately, BI113823 treatment prevented right heart failure and death in PAH-induced rats.
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BI113823 decreased the levels of interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) in bronchoalveolar lavage and plasma. It reduced macrophage and neutrophil infiltration in bronchoalveolar lavage by 48% and 80%, respectively. Also, it reduced the recruitment of cluster of differentiation 68 (CD-68) positive macrophages and the expression of proliferating cell nuclear antigen (PCNA) in the perivascular areas.
Mechanistically, BI113823 downregulated the expression of key signaling mediators and pathways. For instance, it reduced the expression of inducible nitric oxide synthase (iNOS), kinin B1 receptors, and matrix metalloproteinases (MMP-2 and MMP-9).
BI113823 also downregulated the expression of the phosphorylated forms of extracellular signal-regulated kinase 1/2 (ERK1/2) and the serine/threonine kinase AKT in the lungs. ERK and PI3K/AKT pathways mediate cell proliferation, survival, extracellular remodeling, and fibrosis.
In previous studies, the authors showed that early treatment with BI113823 reduced lung inflammation and prevented the development of PAH. With the present study, they added that BI113823 is also effective when PAH is already established, which is of utmost importance since the disease is often diagnosed in advanced stages.
Rampa DR, Murugesan P, Chao H, et al. Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade. Respir Res. 2021;22(1):281. doi:10.1186/s12931-021-01875-w