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

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 proinflammatory 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 NSAIDinduced 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.

NSAID-Associated Small Intestinal Injury: An Overview From Animal Model Development to Pathogenesis, Treatment, and Prevention

“…The application of antibiotics may be an effective preventive measure. Treatment with the bactericidal antibiotic polymyxin B, ampicillin, ciprofloxacin significantly inhibited NSAID-induced ulcers ( Konaka et al, 1999 ; Park et al, 2020 ; Zhong et al, 2016 ). We can also use probiotics to improve intestinal inflammation.…”

“…Mice with different genotypes had different intestinal microbial compositions. After the administration of the same NSAID, different degrees of small intestinal injury could be seen ( Park et al, 2020 ). Besides, no ulcers were observed in germ-free rats treated with NSAIDs (Robert and Asano, 1977; Uejima et al, 1996 ), which indicates bacterial flora may play an important role in developing NSAID-associated enteropathy.…”

“…Following the administration of indomethacin, researchers found that F4/80+ macrophages were increased in the ulcerated lesions. Clodronate functionally inhibited macrophages, thereby alleviating small intestinal mucosal injury in indomethacin-administered mice ( Park et al, 2020 ). HO-1 exerted a protective effect against NSAID-induced enteritis, HO-1-immunopositive cells accumulated in the small intestine were confirmed to be mainly F4/80 positive macrophages ( Harusato et al, 2011 ).…”

“…Neutrophil-mediated inflammation has been implicated in NSAID-induced small bowel injury ( Stadnyk et al, 2002 ). Ly6G + neutrophils were detected in the ulcers of indomethacin-treated mice rather than the control WT mice ( Park et al, 2020 ). MPO activity represents the degree of neutrophil infiltration in the intestinal mucosa.…”

Gastroprotection against Rat Ulcers by Nephthea Sterol Derivative

“…Galectin-3 (Gal3) is a biomarker highly represented by activating macrophages and several cell types constitutively, such as gastrointestinal epithelial cells [7][8][9]. In patients with gastric cancer, serum levels of galectin-3 are significantly increased, in contrast with both patients with benign disease and healthy control subjects.…”