1. Academic Validation
  2. Metallothionein 2 activation by pravastatin reinforces epithelial integrity and ameliorates radiation-induced enteropathy

Metallothionein 2 activation by pravastatin reinforces epithelial integrity and ameliorates radiation-induced enteropathy

  • EBioMedicine. 2021 Nov;73:103641. doi: 10.1016/j.ebiom.2021.103641.
Seo Young Kwak 1 Won Il Jang 1 Seungwoo Park 2 Sang Sik Cho 3 Seung Bum Lee 1 Min-Jung Kim 1 Sunhoo Park 1 Sehwan Shim 4 Hyosun Jang 5
Affiliations

Affiliations

  • 1 Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
  • 2 Comprehensive Radiation Irradiation Center, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
  • 3 Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea; Department of Surgery, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
  • 4 Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea. Electronic address: ssh3002@kirams.re.kr.
  • 5 Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea. Electronic address: hsjang@kirams.re.kr.
Abstract

Background: Radiotherapy or accidental exposure to ionizing radiation causes severe damage of healthy intestinal tissues. Intestinal barrier function is highly sensitive to ionizing radiation, and loss of epithelial integrity results in mucosal inflammation, Bacterial translocation, and endotoxemia. Few studies have of epithelial integrity as a therapeutic target to treat radiation toxicity. Here, we examined the effects of pravastatin (PS) and the molecular mechanisms underlying epithelial integrity on radiation-induced enteropathy.

Methods: The radio-mitigative effects of PS were evaluated in a minipig model by quantifying clinical symptoms, and performing histological and serological analyses and mRNA Sequencing in intestinal tissues. To evaluate the role of intercellular junctions on radiation damage, we used tight junction regulator and metallothionein 2 (MT2) as treatments in a mouse model of radiation-induced enteropathy. Caco-2 monolayers were used to examine functional epithelial integrityand intercellular junction expression.

Finding: Using a minipig model of pharmaceutical oral bioavailability, we found that PS mitigated acute radiation-induced enteropathy. PS-treated irradiated minipigs had mild clinical symptoms, lower intestinal inflammation and endotoxin levels, and improved gastrointestinal integrity, compared with control group Animals. The results of mRNA Sequencing analysis indicated that PS treatment markedly influenced intercellular junctions by inhibiting p38 MAPK signaling in the irradiated intestinal epithelium. The PS-regulated gene MT2 improved the epithelial barrier via enhancement of intercellular junctions in radiation-induced enteropathy.

Interpretation: PS regulated epithelial integrity by modulating MT2 in radiation-damaged epithelial cells. These findings suggested that maintenance of epithelial integrity is a novel therapeutic target for treatment of radiation-induced gastrointestinal damage.

Funding: As stated in the Acknowledgments.

Keywords

Epithelial integrity; Metallothionein 2; Minipigs; Pravastatin; Radiation-induced enteropathy.

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