P2X7 blockade attenuates mouse liver fibrosis

Abstract

P2X7 is important in inflammation and tissue injury. The aim of the present study was to investigate the effect of P2X7 inhibition, using a specific inhibitor (A438079) to prevent the development of liver injury and fibrosis in a mouse model of liver fibrosis. The mouse liver fibrosis model was induced by carbon tetrachloride (CCl4). Mice received subcutaneous administration of vehicle (saline/olive oil), CCl4 or subcutaneous CCl4 and A438079. The pro‑inflammatory and pro‑fibrotic factors were determined by western blot analysis. The biochemistry, histopathology, collagen deposition and nuclear factor‑κB (NF‑κB) activity were also analyzed. Chronic CCl4 treatment resulted in liver injury and collagen accumulation. The expression levels of P2X7, pro‑inflammatory and pro‑fibrotic mediators, and the activity of NF‑κB were markedly increased. Treatment with A438079 significantly inhibited CCl4‑induced P2X7 expression, and attenuated CCl4‑induced liver injury and the inflammatory response. P2X7 blockade also significantly reduced the formation of collagen in the liver and the expression of α-smooth muscle actin and transforming growth factor‑β1. This study demonstrated that P2X7 inhibition attenuated liver injury and fibrosis in a mouse model. Thus, P2X7 is a potential novel therapeutic target for liver injury and fibrosis.

The role of P2X7 receptors in tissue fibrosis: a brief review

“…P2X 7 R promotes macrophage infiltration and collagen deposition contributing to the inflammation and fibrosis of unilateral ureteral obstruction in mice [62]. In accordance, results suggested that P2X 7 R activity was present in animal models of liver injury and fibrosis, and contributed to fibrogenesis [71,72]. Finally, it has been demonstrated that P2X 7 R may be a potential target for the treatment of pancreatic [79,80] and cardiac fibrosis [86,87].…”

“…Studies using models of hepatic fibrosis in transgenic mice have revealed IL-1β and TGF-β1 as key players mediating liver fibrogenesis [69,70]. Huang and colleagues [71] investigated the role of P2X 7 R in a mouse model of liver fibrosis induced by carbon tetrachloride (CCl 4 ), reporting that P2X 7 R inhibition with a competitive antagonist (A438079) prevented collagen deposition and also significantly reduced the expression of alpha-smooth muscle actin (α-SMA) and TGF-β1. Finally, in rats affected by common bile duct-ligated (CBDL)-induced liver cirrhosis, Brilliant blue G (BBG), the most potent P2X 7 R antagonist in rats, significantly reduces hepatic proinflammatory cytokines IL-6, TNF-α, platelet-derived growth factor (PDGF), and IL-1β expression.…”

Involvement of P2X7 receptor in neuronal degeneration triggered by traumatic injury

“…In particular, the specific P2X7 receptor antagonism used in this study, A437089, has been satisfactory used in different preclinical models of inflammation in the periphery3334353637. A438079 has been found to be CNS permeable, and its treatment reduced seizure severity during status epilepticus, as well as dopamine depletion in a model of Parkinson’s disease6970.…”

“…In particular, A438079 is a selective competitive antagonist for the human and rodent P2X7 receptor with good bioavailability and CNS penetration widely used in preclinical animal models of disease3132. A438079 reduces inflammation in models of colitis, ischemic acute kidney injury, contact dermatitis, and liver injury and fibrosis3334353637.…”

Evodiamine Attenuates P2X7‐Mediated Inflammatory Injury of Human Umbilical Vein Endothelial Cells Exposed to High Free Fatty Acids

“…P2X 7 , a subtype of P2X receptors, plays an important role in inflammatory and immune responses. Uncontrolled Ca 2+ influx may be induced due to the overstimulation of P2X 7 receptor by extracellular ATP [11, 12]. ATP in the extracellular space can be increased after endothelial cells are damaged upon inflammation [13].…”