Pirfenidone and the Inflammasome: Getting to the Heart of Cardiac Remodeling

Fibrosis is the progressive accumulation of interstitial matrix, resulting in impaired organ function and increased patient morbidity and mortality. The underlying mechanisms are often poorly understood even when the clinical progression of the disease is familiar. Effective treatments for fibrosis remain elusive due in part to the involvement of pleiotropic pathways that are challenging to target therapeutically, although hope remains for a ‘magic bullet' capable of attenuating fibrosis regardless of the tissue. In this issue of Cardiology, Wang et al. [1] demonstrate that the anti-inflammatory small-molecule drug pirfenidone, currently used for idiopathic pulmonary fibrosis (IPF), may be efficacious for the treatment of cardiac fibrosis.Cardiac remodeling and fibrosis follow acute or chronic insults, such as myocardial infarction or hypertension-induced pressure overload, respectively. Cardiac failure eventually ensues, with medical intervention typically focused on improving cardiac work capacity or reducing workload. Amelioration of the underlying fibrosis, if it occurs at all, is generally minimal and secondary to improved cardiac function.At first blush, IPF appears starkly different from cardiac fibrosis: an age-related chronic disease of the lung interstitium with a potentially important genetic component and average survival limited to only 3 years [2]. Yet key commonalities in pathophysiology exist between IPF and cardiac fibrosis, including the development of fibrotic foci, fibroblast-to-myofibroblast conversion, and the presence of a chronic inflammatory state. By targeting these commonalities, pirfenidone may be effective in both diseases.Pirfenidone was initially reported to reduce fibrosis and improve lung function in a hamster model of bleomycin-induced lung injury [3,4]. Now marketed as Esbriet® in Europe and Canada, it is undergoing phase III trials in the US for treatment of mild/moderate IPF. By ameliorating lung function decline, pirfenidone appears to slow disease progression although additional data are needed regarding its efficacy in improving patient quality of life [5,6,7,8].Recent studies reported beneficial effects of pirfenidone in various animal models of cardiac dysfunction, including diabetes, pacing-induced heart failure, Duchenne muscular dystrophy, doxorubicin cardiotoxicity, DOCA salt hypertension, and myocardial infarction [9,10,11,12,13,14]. However, the means by which pirfenidone exerted these salutary effects is unclear, and improved cardiac function was usually but not always accompanied by reduced fibrosis, suggesting several modes of action. Clearly, more data are required to determine both the mechanism of action of pirfenidone and, more broadly, its applicability. In vitro studies demonstrate that pirfenidone decreases fibroblast proliferation, reduces the production of fibrotic proteins and cytokines, attenuates the biosynthesis and accumulation of extracellular matrix proteins, and inhibits the synthesis of profibrotic TGF-β and proinflammatory TNF-α, but its molecular target remains unknown [15,16,17].In the present study, Wang et al. [1] provide important new data suggesting that pirfenidone may be an effective therapy for the treatment of pressure overload-induced myocardial fibrosis. Using a thoracic aortic constriction (TAC) mouse model, they report that pirfenidone initiated 10 days after surgery reduced left ventricular remodeling and subsequent fibrosis. Treated animals exhibited improved cardiac parameters following TAC including left ventricular diameter, ejection fraction, and fractional shortening compared to untreated mice. Several measures of fibrosis were also reduced in the myocardium, including fibroblast proliferation, type I fibrillar collagen production, and synthesis of TGF-β. Importantly, these positive effects translated into increased survival.While the paper does not reveal the mechanism of the effects of pirfenidone, it provides interesting insights in this regard including several lines of evidence of reduced myocardial inflammation following treatment. Inflammatory cell infiltration, production of reactive oxygen species and inflammatory mediators c-Jun, NLRP3, and IL-1β were significantly elevated after TAC, but attenuated by pirfenidone. In primary adult rat cardiac myofibroblasts, treatment with pirfenidone similarly prevented H2O2- and hyaluronan-induced increases in reactive oxygen species, NLRP3, and IL-1β.The upregulation of NLRP3 suggests a role for inflammasome formation in post-TAC remodeling. Mitochondrial production of reactive oxygen species activates the NLRP3 inflammasome, a multimolecular complex which induces synthesis and secretion of cytokines IL-1β and IL-18 which in turn leads to increased expression of profibrotic factors such as TGF-β1 and PDGF [18,19,20]. Gene deletion of the inflammasome adaptor protein ASC protected mice from bleomycin-induced pulmonary fibrosis and inflammation [21]. Coupled with the results reported here, a growing case can be made for the involvement of NLRP3 inflammasome formation in myofibroblasts as a central component of fibrotic remodeling in the TAC model. Pirfenidone may thus exert its antifibrotic effect by blocking inflammasome formation.While this is an intriguing model, important questions remain. The authors have demonstrated that pirfenidone reduces evidence of NLRP3 inflammasome formation in vivo and in vitro concomitant with reduced evidence of myocardial fibrosis after TAC, but it remains to be seen whether this is a primary or secondary effect of the drug since the precise molecular target remains unknown. Additional evidence is required to definitively identify inflammasome formation as a driver of cardiac fibrotic remodeling. Additional studies exploiting mice deficient in ASC (or other critical inflammasome components) in conjunction with TAC or other models of cardiac dysfunction may address precisely this question. If pirfenidone targets the inflammasome, loss of its beneficial effects in these animals would be an expected secondary result. Attenuation of cardiac fibrosis in these mice would thus be a key step in placing the inflammasome at the heart of cardiac remodeling.This study was supported by the Canadian Institutes for Health Research (Open Operating Grant MOP-106671 to M.P.C.).

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