NADPH oxidase 1 mediates caerulein-induced pancreatic fibrosis in chronic pancreatitis

Abstract

Inflammatory disorders of the pancreas are divided into acute (AP) and chronic (CP) forms. Both states of pancreatitis are a result of pro-inflammatory mediators, including reactive oxygen species (ROS). One of the sources of ROS is NADPH oxidase (Nox). The rodent genome encodes Nox1-4, Duox1 and Duox2. Our purpose was to assess the extent to which Nox enzymes contribute to the pathogenesis of both AP and CP using Nox-deficient mice. Using RT-PCR, Nox1 was found in both isolated mouse pancreatic acini and pancreatic stellate cells (PaSCs). Subsequently, mice with genetically deleted Nox1 were further studied and showed that the histo-morphologic characteristics of caerulein-induced CP, but not caerulein-induced AP, was ameliorated in Nox1 KO mice. We also found that the lack of Nox1 impaired caerulein-induced ROS generation in PaSCs. Using Western blotting, we found that AKT mediates the fibrotic effect of Nox1 in a mouse model of CP. We also found a decrease in phospho-ERK and p38MAPK levels in Nox1 KO mice with CP, but not with AP. Both CP-induced TGF-β up-regulation and NF-ĸB activation were impaired in pancreas from Nox1 KO mice. Western blotting indicated increases in proteins involved in fibrosis and acinar-to-ductal metaplasia in WT mice with CP. No change in those proteins were observed in Nox1 KO mice. The lack of Nox1 lowered mRNA levels of CP-induced matrix metalloproteinase MMP-9 and E-cadherin repressor Twist in PaSCs. Conclusion: Nox1-derived ROS in PaSCs mediate the fibrotic process of CP by activating the downstream redox-sensitive signaling pathways AKT and NF-ĸB, up-regulating MMP-9 and Twist, and producing α-smooth muscle actin and collagen I and III.

ROS and TGFβ: from pancreatic tumour growth to metastasis

“…As previously discussed, TGFβ can regulate ROS level while NOX-derived ROS associates with fibrosis in pancreas [ 70 ]. ROS mediates PSC activation via AP-1 and MAPK signalling, and the fibrotic process by activating AKT and NF-ĸB signalling pathways, up-regulating MMP-9 and Twist, and producing α-SMA and collagen I and III [ 70 , 71 ]. Increased ROS level links to TGFβ activation and production, suggesting the interplay in the fibrosis process.…”

NOX Inhibitors: From Bench to Naxibs to Bedside

“…1). NOX1 is predominantly expressed in colon epithelium (Szanto et al 2005) and also in the uterus (Banfi et al 2000;Suh et al 1999), placenta (Cui et al 2006), prostate (Banfi et al 2000;Suh et al 1999), pancreas (Xia et al 2019), retina (Manea et al 2005), keratinocytes (Chamulitrat et al 2003), endothelium (Gray et al 2013), and vascular smooth muscle cells (Lassegue et al 2001). NOX2 is expressed in phagocytes which are present in numerous tissues and is often called "the phagocyte NADPH oxidase" (Bedard and Krause 2007); however, it can also be detected in other cell types including cardiomyocytes (Krijnen et al 2003), skeletal muscle (Henriquez-Olguin et al 2019, endothelial cells (Gorlach et al 2000), hepatocytes (Reinehr et al 2005), and neurons (Fan et al 2019).…”

Immune cells and immune cell-targeted therapy in chronic pancreatitis

“…Under sufficient stimulation, neutrophils release excessive ROS, which can induce cellular and tissue damage ( 96 ). In CP, ROS can activate downstream redox-sensitive signaling pathways AKT and NF-ĸB in PSC, upregulate MMP-9 and Twist, produce α-SMA and collagen I and III, leading to the fibrosis process of CP ( 97 ). Recent studies have shown that antioxidants reduce islet fibrosis in animal models of type 2 diabetes in vitro and in vivo ( 98 ).…”