Rationale: Milk fat globule epidermal growth factor 8 (MFG-E8) is a potent opsonin for the clearance of apoptotic cells and is produced by mononuclear cells of immune competent organs including the spleen and lungs. It attenuates chronic and acute inflammation such as autoimmune glomerulonephritis and bacterial sepsis by enhancing apoptotic cell clearance. Ischemia-reperfusion (I/R) injury of the gut results in severe inflammation, apoptosis, and remote organ damage, including acute lung injury (ALI). Objectives: To determine whether MFG-E8 attenuates intestinal and pulmonary inflammation after gut I/R. Methods: Wild-type (WT) and MFG-E8 2/2 mice underwent superior mesenteric artery occlusion for 90 minutes, followed by reperfusion for 4 hours. A group of WT mice was treated with 0.4 mg/20 g recombinant murine MFG-E8 (rmMFG-E8) at the beginning of reperfusion. Four hours after reperfusion, MFG-E8, cytokines, myeloperoxidase activity, apoptosis, and histopathology were assessed. A 24-hour survival study was conducted in rmMFG-E8-and vehicletreated WT mice. Measurements and Main Results: Mesenteric I/R caused severe widespread injury and inflammation of the small intestines and remote organs, including the lungs. MFG-E8 levels decreased in the spleen and lungs by 50 to 60%, suggesting impaired apoptotic cell clearance. Treatment with rmMFG-E8 significantly suppressed inflammation (TNF-a, IL-6, IL-1b, and myeloperoxidase) and injury of the lungs, liver, and kidneys. MFG-E8-deficient mice suffered from greatly increased inflammation and potentiated ALI, whereas treatment with rmMFG-E8 significantly improved the survival in WT mice. Conclusions: MFG-E8 attenuates inflammation and ALI after gut I/R and may represent a novel therapeutic agent.
Objective-We have recently shown that ghrelin, a novel orexigenic hormone, is reduced in sepsis. Ghrelin treatment, mediated through ghrelin receptors in the brain, attenuates sepsis-induced inflammation and mortality. Gut barrier dysfunction is common in sepsis. High mobility group B1 (HMGB1) increases gut permeability both in vitro and in vivo. However, it remains unknown whether ghrelin has any effects on HMGB1 and gut barrier function in sepsis. We hypothesized that ghrelin decreases HMGB1 release and attenuates sepsis-induced gut barrier dysfunction through central ghrelin receptors.Design-Prospective, controlled, and randomized animal study. Setting-A research institute laboratory. Subjects-Male Sprague-Dawley rats (275-325g).Measurements and Main Results-Male adult rats were subjected to sepsis by cecal ligation and puncture (CLP). Five hours after CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via an osmotic mini-pump for 15h. Twenty hours after CLP, brain ghrelin levels, serum HMGB1 levels, ileal mucosal permeability to fluorescein-isothiocyanate dextran (FD4), bacterial counts in the mesenteric lymph nodes complex, and gut water content were determined. In additional groups of animals, bilateral trunk vagotomy was performed at 5h after CLP before ghrelin injection. Moreover, to confirm the role of central ghrelin receptors in ghrelin's effect, ghrelin (1 nmol) was administered through intracerebroventricular injection at 5h after CLP. Our results showed that brain levels of ghrelin decreased by 34% at 20 h after CLP. Intravenous administration of ghrelin completely restored brain levels of ghrelin, significantly reduced the elevated HMGB1 levels, and attenuated gut barrier dysfunction. Vagotomy eliminated ghrelin's inhibition on HMGB1 and attenuation on gut barrier dysfunction. Intracerebroventricular injection of ghrelin decreased serum HMGB1 levels and ameliorated gut barrier dysfunction.Conclusion-Ghrelin reduces serum HMGB1 levels and ameliorates gut barrier dysfunction in sepsis by vagus nerve activation via central ghrelin receptors. Ghrelin can be further developed as a novel agent to protect gut barrier function in sepsis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.