Anti-monocyte chemoattractant protein 1 gene therapy attenuates experimental chronic pancreatitis induced by dibutyltin dichloride in rats

Abstract

Background: Monocyte chemoattractant protein 1 (MCP-1) is a member of the C-C chemokine family and exerts strong chemoattractant activity in monocytes, macrophages, and lymphocytes. Rat pancreatic fibrosis induced by dibutyltin dichloride (DBTC) is considered to be an appropriate chronic pancreatitis model histologically and enzymatically, as has demonstrated in a previous study. Aim: We examined the effect of human dominant negative inhibitor of MCP-1 (mutant MCP-1) on progression of chronic pancreatitis induced by DBTC in a rat model. Methods: We used the experimental model of chronic pancreatitis induced by DBTC in rats. Mutant MCP-1 or empty plasmid at a dose of 50 mg/body weight was administrated into rat thigh muscles on days 4, 11, and 18 after administration of DBTC. On days 14 and 28, we evaluated the effect of mutant MCP-1 morphologically and biochemically. Results: The mutant MCP-1 treated group inhibited early pancreatic inflammation and later pancreatic fibrosis histologically, and showed a decrease in serum MCP-1 concentration, intrapancreatic hydroxyproline, a-smooth muscle actin, and an increase in intrapancreatic amylase and protein content compared with the empty plasmid treated group. The mutant MCP-1 group also inhibited intrapancreatic mRNA expression of cytokines and chemokines. Conclusions : Our findings suggest that monocyte/macrophage recruitment and the systemic MCP-1 signal pathway contribute to progression of chronic pancreatitis, and that blockade of MCP-1 may suppress the development of pancreatic fibrosis.

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

“…[51][52][53] As a result of increased recruitment of inflammatory cells, activated mononuclear cells release profibrotic cytokines and chemokines, such as TGF-b, TNF-a and MCP-1, which in turn activate hPSCs and promote fibrosis in CP. 4,52,53 The chemokine MCP-1, one of the major monocyte chemoattractants, is highly expressed in fibroblasts in CP, induces TGF-b upregulation and is associated with the progression of pancreatic fibrosis. 52,54 Blocking of MCP-1 attenuates the degree of fibrosis in experimental CP.…”

“…52,54 Blocking of MCP-1 attenuates the degree of fibrosis in experimental CP. 52 Regarding fractalkine and fibrosis, CX3CR1 was identified to have a genetic and functional importance in higher stages of liver fibrosis in chronic hepatitis C, and was noticeably upregulated in patients with enhanced renal fibrosis. 21,22 In experimental post-ischemic renal fibrosis, fractalkine and CX3CR1 expression levels were associated with enhanced inflammation and fibrosis, which could be diminished by blocking antibodies to CX3CR1 through the reduction of a-SMA and Collagen-1.…”

“…4,52,53 The chemokine MCP-1, one of the major monocyte chemoattractants, is highly expressed in fibroblasts in CP, induces TGF-b upregulation and is associated with the progression of pancreatic fibrosis. 52,54 Blocking of MCP-1 attenuates the degree of fibrosis in experimental CP. 52 Regarding fractalkine and fibrosis, CX3CR1 was identified to have a genetic and functional importance in higher stages of liver fibrosis in chronic hepatitis C, and was noticeably upregulated in patients with enhanced renal fibrosis.…”

Simultaneous characterization of pancreatic stellate cells and other pancreatic components within three-dimensional tissue environment during chronic pancreatitis

“…The experimental model of chronic pancreatitis was induced by a single intravenous administration of dibutyltin dichloride (DBTC), as described elsewhere. 31 Briefly, DBTC (SigmaAldrich, China) was first dissolved in 100% ethanol (two parts) and mixed with glycerol (three parts), then the DBTC solution was injected into the tail vein at a dose of 8 mg∕kg body weight.…”

ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells

“…13 Recent studies have also reported that chemokines other than MCP-1 induce inflammation and fibrosis in other organs, and that multiple chemokines are involved in chronic inflammation.…”