Low Molecular Weight Heparin Relieves Experimental Colitis in Mice by Downregulating IL-1β and Inhibiting Syndecan-1 Shedding in the Intestinal Mucosa

Abstract

Low molecular weight heparin (LMWH) exhibits anti-inflammatory properties, but its effect on inflammation in colitis remains unclear. This study aimed to evaluate the therapeutic effects of LMWH on dextran sulfate sodium (DSS)-induced colitis in mice, in which acute colitis progresses to chronic colitis, and to explore the potential mechanism involved in this process. C57BL/6 mice were randomly divided into control, DSS, and DSS plus LMWH groups (n = 18). Disease activity was scored by a disease activity index (DAI). Histological changes were evaluated by hematoxylin and eosin (HE) staining. The mRNA levels of syndecan-1, interleukin (IL)-1β, and IL-10 were determined by quantitative reverse transcription polymerase chain reaction. Protein expression of syndecan-1 was detected by immunohistochemistry. The serum syndecan-1 level was examined by a dot immunobinding assay. LMWH ameliorated the disease activity of colitis induced by DSS administration in mice. Colon destruction with the appearance of crypt damage, goblet cell loss, and a larger ulcer was found on day 12 after DSS administration, which was greatly relieved by the treatment of LMWH. LMWH upregulated syndecan-1 expression in the intestinal mucosa and reduced the serum syndecan-1 level on days 12 and 20 after DSS administration (P<0.05 vs. DSS group). In addition, LMWH significantly decreased the expression of both IL-1β and IL-10 mRNA on days 12 and 20 (P<0.05 vs. DSS group). LMWH has therapeutic effects on colitis by downregulating inflammatory cytokines and inhibiting syndecan-1 shedding in the intestinal mucosa.

Syndecan-1 deficiency promotes tumor growth in a murine model of colitis-induced colon carcinoma

“…Repeated oral administration of DSS-supplemented water to mice is a reliable model of chronic bowel inflammation (particularly, ulcerative colitis), recapitulating characteristic changes in the colon observed in human disease [38]. Single administration of DSS causes an acute inflammation in the colon [39], and we and others have previously shown that expression of Sdc1 is decreased in the DSS model and that Sdc1 deficiency results in an exacerbated acute inflammatory response [20,25,26,27]. When 2–3 cycles of DSS administration are applied, acute inflammation is followed by chronic colitis [39,40,41].…”

“…Additionally, loss of Sdc1 expression is a characteristic feature of IBD both in experimental [20,25,26] and clinical [22,23,24] settings.…”

“…Indeed, Sdc1 deficiency was shown to cause protein leakage and to make the intestine more susceptible to proinflammatory cytokines and pressure [19]. Importantly, reduced levels of Sdc1 were found in the colon of patients with chronic inflammatory bowel disease (IBD) [22,23,24] and in a murine model of IBD [20,25,26]. Of note, Sdc1 deficient ( Sdc1-KO ) mice exhibit an enhanced inflammatory phenotype in a model of chemically induced acute colitis as evidenced by enhanced leukocyte infiltration, increased levels of inflammatory cytokines and adhesion molecules, and increased mortality [27]; however the effect of Sdc1 deficiency on chronic colitis was not investigated until recently.…”

Postexposure aerosolized heparin reduces lung injury in chlorine-exposed mice

“…In addition, binding of chemokines to heparins decreases their ability to activate their receptors, thus decreasing their proinflammatory effects (29). Finally, heparin downregulates IL-1b and inhibits syndecan-1 shedding in the intestinal mucosa in an experimental model of colitis in mice (53). Interestingly, early heparin treatment or late urokinase treatment prevents lung fibrosis in response to bleomycin (18).…”

“…Moreover, pulmonary inflammation can cause local disturbances in fibrin turnover whereas increased intra-alveolar fibrin deposition with decreased breakdown may induce inflammation (44). Given this tight cross talk between coagulation and inflammation, the administration of an agent (such as heparin) that has both anti-coagulant as well as anti-inflammatory properties (53) may reduce the disturbance in pulmonary coagulopathy and inflammation, thereby ameliorating the clinical course of ALI. Aerosolized heparin has been shown to be effective in patients with ALI, making this agent a candidate for clinical use in patients with Cl 2 -induced lung injury (11,19,20,49).…”