1. Academic Validation
  2. The LipoxinA4 receptor agonist BML-111 ameliorates intestinal disruption following acute pancreatitis through the Nrf2-regulated antioxidant pathway

The LipoxinA4 receptor agonist BML-111 ameliorates intestinal disruption following acute pancreatitis through the Nrf2-regulated antioxidant pathway

  • Free Radic Biol Med. 2021 Feb 1;163:379-391. doi: 10.1016/j.freeradbiomed.2020.12.232.
Zhehao Shi 1 Yi Wang 2 Wen Ye 1 Zixia Lin 1 Tuo Deng 1 Tan Zhang 1 Jungang Zhao 1 Yifan Tong 1 Yunfeng Shan 3 Gang Chen 4
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China; Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China.
  • 2 Department of of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.
  • 3 Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China; Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China. Electronic address: shanyf@yahoo.com.
  • 4 Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China; Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China. Electronic address: chen.gang@wmu.edu.cn.
Abstract

Acute pancreatitis (AP) is characterized by excessive release of pro-inflammatory cytokines and provokes multiorgan dysfunction. Disruption of the intestinal epithelium often occurs during and following acute pancreatitis and may aggravate systemic organ injuries. Although it has been widely investigated, to date, there is no satisfactory clinical therapy to restore the inflammatory damage. BML-111 is an endogenous lipid mediator that is analogous to LipoxinA4. It has been shown that BML-111 has a stable and potent anti-inflammatory ability. However, it is unclear whether BML-111 is involved in the process of relieving acute pancreatitis and its induced intestinal barrier damage, and the underlying mechanism of this effect. Here, we demonstrated that BML-111 could enhance the expression of E-cadherin, alleviate Apoptosis, and mitigate the accumulation of Reactive Oxygen Species in intestinal epithelial cells, thereby contributing to the anti-inflammatory efficacy in vitro and in vivo. Mechanistically, BML-111 upregulates the expression of Nrf2, which is a key regulator of the antioxidant response, and activates its downstream HO-1/NQO-1 pathway to protect against oxidative stress-induced cell death and tissue injury, consequently ameliorating pancreatitis and intestinal epithelium injury. In Nrf2-deficient cell and Nrf2-knockout mouse models, the depletion of Nrf2 blocked BML-111-induced antioxidant effects and thus was unable to exert protective effects in tissue. Taken together, BML-111 attenuated AP-related intestinal injury via an Nrf2-dependent antioxidant mechanism. Targeting this pathway is a potential therapeutic approach for AP-related intestinal injury.

Keywords

Acute pancreatitis; BML-111; Intestinal injury; Nrf2 pathway; Oxidative stress.

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