Therapeutic use of pirfenidone against septic shock



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Texas Tech University


Tumor necrosis factor (TNF) is an extremely potent cytokine which is involved in the pathogenesis of a number of diseases. Interruption of its synthesis can result in a reduction of inflammation and subsequent pathology. A new experimental drug, pirfenidone, (5-methyl-l-phenyl-2-(lH)-pyridone, trade name: Deskar) has been reported to have beneficial effects for the treatment of certain fibrotic diseases. The present study describes the use of pirfenidone, which inhibits both the release of TNF in vitro as well as circulating TNF in vivo. Isolated thioglycollate-induced murine peritoneal macrophages (Mo) were exposed to either hpopolysaccharide (LPS) or another TNF inducer then incubated with 0.1 to 0.9 mg/ml of pirfenidone. This substance inhibited the production of TNF in a dose-dependent manner. The induction of circulating TNF following a single i.v. injection of LPS was also inhibited by an i.p. injection of 1(X) to 2(X) mg/kg pirfenidone. Endotoxin shock was induced in mice using injections of galactosamine and LPS. The higher dose of pirfenidone (200 mg/kg), completely inhibited shock and subsequent mortality. Lower doses of pirfenidone or administration either prior to or post challenge only partially inhibited symptoms. These results indicate that pirfenidone is able to inhibit both TNF induction and subsequent endotoxin shock. Additional studies are warranted to establish this drug as a potential treatment for diseases where TNF plays a major role.