Galectin-3 as a Therapeutic Target for NSAID-Induced Intestinal Ulcers.

Ah-Mee Park,Mitsugu Fujita,Fu-Tong Liu,Daniel K Hsu,Sundar Khadka,Ikuo Tsunoda,Seiichi Omura,Fumitaka Sato

doi:10.3389/fimmu.2020.550366

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) induce ulcers in the gastrointestinal tract, including the stomach and small intestine. NSAID-induced gastric ulcers can be prevented by taking acid-neutralizing/inhibitory drugs and cytoprotective agents. In contrast, there are no medicines to control NSAID-induced small intestinal ulcers, which are accompanied by a mucosal invasion of bacteria and subsequent activation of immune cells. Galectin-3 (Gal3), an endogenous lectin, has anti-microbial and pro-inflammatory functions. In the small intestine, since Gal3 is highly expressed in epithelial cells constitutively and macrophages inducibly, the Gal3 level can affect microbiota composition and macrophage activation. We hypothesized that the modulation of Gal3 expression could be beneficial in NSAID-induced intestinal ulcers. Using Gal3 knockout (Gal3KO) mice, we determined whether Gal3 could be a therapeutic target in NSAID-induced intestinal ulcers. Following the administration of indomethacin, an NSAID, we found that small intestinal ulcers were less severe in Gal3KO mice than in wild-type (WT) mice. We also found that the composition of intestinal microbiota was different between WT and Gal3KO mice and that bactericidal antibiotic polymyxin B treatment significantly suppressed NSAID-induced ulcers. Furthermore, clodronate, a macrophage modulator, attenuated NSAID-induced ulcers. Therefore, Gal3 could be an exacerbating factor in NSAID-induced intestinal ulcers by affecting the intestinal microbiota population and macrophage activity. Inhibition of Gal3 may be a therapeutic strategy in NSAID-induced intestinal ulcers.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT03832946.

Highlights

Non-steroidal anti-inflammatory drug (NSAID) therapy has been used to suppress inflammation and pain, it sometimes induces potentially life-threatening complications related to Non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrointestinal ulcers [1,2,3]
We found that the fecal occult blood (FOB) levels were significantly lower in the Gal3 knockout (Gal3KO)+Indo mice than in the with Indo (WT+Indo) mice, which were associated with the ulcer scores (Figure 3)
We found no significant differences between the two mouse groups (Figure 4), suggesting that the β-glucuronidase levels are irrelevant to the suppression of Indo-induced ulcers in Gal3KO mice

Summary

Introduction

Non-steroidal anti-inflammatory drug (NSAID) therapy has been used to suppress inflammation and pain, it sometimes induces potentially life-threatening complications related to NSAID-induced gastrointestinal ulcers [1,2,3]. NSAID-induced ulcers are occasionally fatal, it can be prevented/treated by taking acid-neutralizing/inhibitory drugs and cytoprotective agents. NSAIDs can induce ulcers, resulting in bleeding. There is no treatment to control NSAID-induced small intestinal ulcers. Galectin-3 (Gal3) is one of the galectin family members, which is highly expressed by activated macrophages as well as various cell types constitutively including gastrointestinal epithelial cells [4, 5]. Gal is considered as a therapeutic target for these diseases [18], in which the development of Gal inhibitors has been attempted

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Discussion

Conclusion