Pirfenidon Prevents Experimental Flow-Associated PAH by Suppression of the NLRP3 Inflammasome

E Mavrogiannis,Q.A Hagdorn,V Bazioti,J.M Douwes,D.E Van Der Feen,S.U Oberdorf-Maass,M Westerterp,R.M Berger

doi:10.1016/j.healun.2022.01.059

E Mavrogiannis, Q.A Hagdorn + Show 6 more

https://doi.org/10.1016/j.healun.2022.01.059

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<h3>Purpose</h3> Pulmonary arterial hypertension (PAH) is a fatal disease with characteristic vascular remodeling, including fibrosis, within an inflammatory milieu in the distal pulmonary vascular bed. Interleukin (IL)-1β and IL-18 levels, two potent proinflammatory cytokines, are elevated in patient serum and animal models of PAH. The release of these cytokines is regulated by the activation of the NLRP3 inlfammasome, hallmarked by caspase-1 cleavage. We hypothesized that pirfenidone (PFD) an antifibrotic and antinflammatory agent delays the progression of PAH by suppressing NLRP3 inflammasome activation. <h3>Methods</h3> We investigated the effect of preventive PFD treatment in the rat model for neointimal PAH induced by monocrotaline and aortocaval shunt. The disease severity was assessed by pulmonary hemodynamics and histology. The NLRP3 inflammasome activation was assessed by immunohistochemisry and immunoblotting on lung homogenate. For proof of concept, the effect of PFD on NLRP3 inflammasome was additionally tested, by qPCR and ELISA, on bone marrow derived macrophages (BMDMs) after LPS/nigericin stimulation. <h3>Results</h3> Inflammasome activation was increased in the model compared to control as assessed by cleavage the ratio of caspase-1 (145%, p=0.023), IL-1β (142%, p=0.002) and IL-18 (210%, p=0.006). PFD treatment led to reduction of mPAP and occlusion (mPAP:28 ±8 mmHg vs 36 ±4mmHg, p=0.004; occlusion 28 ±4% vs 18 ±10%, p=0.008). So did the level of IL-1β and IL-18 activation when compared to the PAH untreated group (35%, p=0.027; 68%, p=0.005). The perivascular collagen content correlated with mPAP (p=0.025) and occlusion (p<0.001) regarding fibrosis. On BMDMs, both the inflammasome related gene expression relative to control and the IL-1β excretion were reduced by PFD (NLRP3: 40% p<0.001; IL-1β: 61% p<0.001; IL-18: 50% p<0.001 & IL-1β in medium: 44% p<0.001). <h3>Conclusion</h3> Inflammasome is activated in experimental flow-associated PAH, based on the cleavage of caspase-1 and its products IL-1β and IL-18. Its activation correlates with pulmonary hemodynamics and vascular remodeling. PFD suppresses NLRP3 inflammasome activation and ameliorates PAH, assessed by pulmonary hemodynamics and vascular remodeling.

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