Chinese researchers have discovered that selective inhibition of the NLPR3 inflammasome contributes to the attenuation of lipopolysaccharide (LPS)-induced right ventricular failure (RVF) in rats with pulmonary arterial hypertension (PAH), according to a study published in the Journal of Inflammation Research.
“RVF is the most important prognostic factor for both morbidity and mortality in patients with PAH,” Guo et al wrote.
Medical literature reports an association between NLPR3 activation and cardiovascular disease, and a recent study demonstrated that LPS can induce cardiac dysfunction through the NLPR3 inflammasome pathway. The researchers thus decided to investigate whether the NLPR3 inflammasome promotes RVF through the disturbance of the ventricular immune microenvironment.
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To achieve this, they planned to activate the NLPR3 inflammasome pathway by injecting LPS into rats with PAH, inhibit the NLPR3 pathway in some rats using MCC950 (an NLPR3 inflammasome inhibitor), and then record any differences in clinical outcomes.
Researchers used intravenous monocrotaline to induce PAH in rats. They conducted 2 experiments simultaneously:
- Randomly assigned PAH rats with either saline injection or low-dose LPS (1 mg/kg)
- Injected all PAH rats with LPS, with some receiving MCC950 (10 mg/kg) an hour prior, while others received intravenous saline.
The results demonstrated that PAH rats injected with LPS exhibited right ventricular dysfunction and significantly increased right ventricular tissue inflammation (with an elevated proportion of M1 macrophages). The proportion of M1 macrophages managed to decrease in the group of PAH rats that received MCC950.
The Chinese research team discovered that the inhibition of the NLPR3 inflammasome via MCC950 alleviated LPS-induced changes in the immune microenvironment in the right heart.
“Selective inhibition of NLRP3 pathway interfered the interaction between hypertrophic cardiomyocytes and macrophages in the initial stage of inflammation and maintained the immune microenvironment balance, eventually contributing to attenuation of LPS-induced acute heart failure in PAH rats,” they concluded.
Guo L, Qin G, Cao Y, et al. Regulation of the immune microenvironment by an NLRP3 inhibitor contributes to attenuation of acute right ventricular failure in rats with pulmonary arterial hypertension. J Inflamm Res. Published online November 2, 2021. doi:10.2147/JIR.S336964