Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice

Abstract

Radiation gastrointestinal (GI) syndrome is a major lethal toxicity that may occur after a radiation/nuclear incident. Currently, there are no prophylactic countermeasures against radiation GI syndrome lethality for first responders, military personnel, or remediation workers entering a contaminated area. The pathophysiology of this syndrome requires depletion of stem cell clonogens (SCCs) within the crypts of Lieberkühn, which are a subset of cells necessary for postinjury regeneration of gut epithelium. Recent evidence indicates that SCC depletion is not exclusively a result of DNA damage but is critically coupled to ceramide-induced endothelial cell apoptosis within the mucosal microvascular network. Here we show that ceramide generated on the surface of endothelium coalesces to form ceramide-rich platforms that transmit an apoptotic signal. Moreover, we report the generation of 2A2, an anti-ceramide monoclonal antibody that binds to ceramide to prevent platform formation on the surface of irradiated endothelial cells of the murine GI tract. Consequently, we found that 2A2 protected against endothelial apoptosis in the small intestinal lamina propria and facilitated recovery of crypt SCCs, preventing the death of mice from radiation GI syndrome after high radiation doses. As such, we suggest that 2A2 represents a prototype of a new class of anti-ceramide therapeutics and an effective countermeasure against radiation GI syndrome mortality.

Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

“…Pertinent to this, ceramides were linked to the pathogenesis of NAFLD through insulin resistance, oxidative stress, and inflammation (65,66). Numerous reports have indicated that ceramide levels were positively associated with the degree of hepatic triglyceride content accumulation (67,68). However, the precise mechanism by which intestinal FXR regulates ceramide synthesis metabolism remains unclear and warrants further investigation.…”

Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure

“…Accumulation of DAGs and ceramides is associated with cellular and tissue dysfunction including defective insulin signaling (23), increased apoptosis (24), and activation of protein kinases (25). To test whether the lipid abnormalities observed in severe human heart failure were due to changes in DGAT1 expression, we deleted Dgat1 in cardiomyocytes; these mice are denoted hDgat1 Ϫ/Ϫ .…”

Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis

“…Previously, it was shown in an in vitro model for tissue fixed macrophages that exposure of cultured THP-1 cells to endotoxin resulted in PKCζ mediated activation of SMPD1, ceramide generation as well as assembly of TLR4 receptors within lipid rafts which was attenuated by functional inhibition with imipramine (16,53). A clearly protective role of inhibition of macrodomain formation was recently shown in irradiation-induced mortality (54). Otherwise, non-lysosomal sphingomyelinase can protect against cytotoxic agents (55).…”