Bilirubin prevents acute DSS-induced colitis by inhibiting leukocyte infiltration and suppressing upregulation of inducible nitric oxide synthase

Abstract

Bilirubin is thought to exert anti-inflammatory effects by inhibiting vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration and by suppressing the expression of inducible nitric oxide synthase (iNOS). As VCAM-1 and iNOS are important mediators of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. Male C57BL/6 mice were administered 2.5% DSS in the drinking water for 7 days, while simultaneously receiving intraperitoneal injections of bilirubin (30 mg/kg) or potassium phosphate vehicle. Disease activity was monitored, peripheral blood counts and serum nitrate levels were determined, and intestinal specimens were analyzed for histological injury, leukocyte infiltration, and iNOS expression. The effect of bilirubin on IL-5 production by HSB-2 cells and on Jurkat cell transendothelial migration also was determined. DSS-treated mice that simultaneously received bilirubin lost less body weight, had lower serum nitrate levels, and exhibited reduced disease severity than vehicle-treated animals. Concordantly, histopathological analyses revealed that bilirubin-treated mice manifested significantly less colonic injury, including reduced infiltration of eosinophils, lymphocytes, and monocytes, and diminished iNOS expression. Bilirubin administration also was associated with decreased eosinophil and monocyte infiltration into the small intestine, with a corresponding increase in peripheral blood eosinophilia. Bilirubin prevented Jurkat migration but did not alter IL-5 production. In conclusion, bilirubin prevents DSS-induced colitis by inhibiting the migration of leukocytes across the vascular endothelium and by suppressing iNOS expression.

Bilirubin Prevents Atherosclerotic Lesion Formation in Low‐Density Lipoprotein Receptor‐Deficient Mice by Inhibiting Endothelial VCAM‐1 and ICAM‐1 Signaling

“…Binding of leukocyte integrins to VCAM‐1 or ICAM‐1 has been shown to trigger signaling cascades that lead to production of superoxide and hydrogen peroxide within the endothelial cell . These ROS induce downstream alterations in the endothelial junctional structure that facilitate the transmigration of leukocytes . Given that bilirubin is a potent, chain‐breaking antioxidant, we postulated that it would disrupt the endothelial response to adhesion molecule activation by scavenging superoxide and hydrogen peroxide signaling intermediaries (Figure ).…”

“…Bilirubin is a potent chain‐breaking antioxidant that uniquely undergoes intracellular redox cycling, facilitating the efficient consumption of ROS. Our group has shown that bilirubin inhibits the transendothelial migration of murine lymphocytes in vitro and also attenuates tissue injury in mouse models of VCAM‐1‐dependent inflammation . Based on these findings, we postulate that bilirubin's cardioprotective effect is derived from its ability to disrupt VCAM‐1‐mediated leukocyte migration by scavenging Nox‐derived ROS …”

Bilirubin suppresses Th17 immunity in colitis by upregulating CD39

“…However, physiological concentrations of this metabolite have immunomodulatory effects on antigen-presenting cells (2,3) and effector cells (2,4), ultimately favoring the expansion of FOXP3 + Tregs (5,6). UCB immunomodulatory properties have been confirmed by in vivo experimental studies, as in the setting of islet cell transplantation (6,7), experimental autoimmune encephalomyelitis (2), and in acute colitis induced by dextran sodium sulfate (DSS) (8).…”

Hemin reduces postoperative ileus in a heme oxygenase 1‐dependent manner while dimethyl fumarate does without heme oxygenase 1‐induction

“…This also included gut inflammatory models such as I/R injury, indomethacin‐induced injury of the small intestine and colitis . Hemin might also be efficient in POI as inhalation of CO or administration of the CO‐releasing molecule CORM‐3 improved the delay in transit and reduced intestinal inflammation upon IM in mice; and biliverdin/bilirubin is effective in intestinal inflammatory models …”

“…Exogenous administration of CO was investigated to protect the gastrointestinal tract upon diabetic gastroparesis, inflammatory bowel disease, and organ transplantation . Also, bilirubin and biliverdin demonstrated a cytoprotective effect in experimental models of ischemia/reperfusion (I/R) injury, sepsis, and colitis …”