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

Di Xia, Bithika Halder, Catalina Godoy, Ananya Chakraborty, Bhupesh Singla, Eyana Thomas, Jasim B. Shuja, Hisham Kashif, Laurence Miller, Gabor Csanyi, Maria E. Sabbatini

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)139-149
Number of pages11
JournalFree Radical Biology and Medicine
Volume147
DOIs
StatePublished - Feb 1 2020

Keywords

  • Chronic pancreatitis
  • MMP-9
  • NADPH oxidase 1
  • NF-ĸB
  • Twist

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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