Ischemia/Reperfusion Injury Alters Sphingolipid Metabolism in the Gut

Abstract

Background: Intestinal ischemia/reperfusion injury (I/R) is a significant cause of morbidity and mortality in surgical patients. Ceramide is a mediator of apoptosis and has been implicated as increasing bacterial infection susceptibility. The metabolite of ceramide, sphingosine, was recently shown to play an important role in the cell-autonomous, innate immune response of the upper respiratory tract by killing bacterial pathogens. The role of ceramide and/or sphingosine after mesenteric I/R is unknown. We investigated the specific effects of intestinal I/R on tissue ceramide and sphingosine concentration and resulting susceptibility to bacterial invasion. Methods: To simulate intestinal I/R, C57BL/6 mice underwent 30 minutes of vascular clamp-induced occlusion of the superior mesenteric artery followed by variable reperfusion times. Jejunum segments and intraluminal contents were analyzed for ceramide, sphingosine and bacteria using immunohistochemistry. Jejunum samples were also homogenized and cultured to quantify bacterial presence in the proximal intestine. Results: We hypothesized that I/R induces an increase of ceramide in the intestine resulting in increased permeability, while a concomitant decrease of sphingosine may permit bacterial overgrowth. Control mice had no measurable bacteria in their proximal jejunum as measured by tissue culture and immunohistochemistry. After I/R, bacterial counts in the jejunum increased in a time-dependent manner, reaching a peak at 12 hours after reperfusion. Immunohistochemical analysis revealed a marked increase in ceramide in the vasculature of jejunal villi. In contrast, while ceramide concentrations in the epithelial cells decreased after I/R, sphingosine levels appeared to remain unchanged. Surprisingly, bacteria present in the jejunal lumen following I/R contained a ceramide coat. Conclusion: These data indicate that intestinal I/R leads to small intestine bacterial overgrowth as well as ceramide formation in the jejunal vasculature, which may contribute to the gut permeability associated with this injury. Moreover, our novel finding of ceramide in bacterial membranes represents a new opportunity to investigate the dynamic pathogenicity of the gut microbiome. The hypothesis that a decrease of sphingosine after I/R permits bacterial overgrowth in the intestine was not confirmed.

Administration of Curcumin Protects Kidney Tubules Against Renal Ischemia-Reperfusion Injury (RIRI) by Modulating Nitric Oxide (NO) Signaling Pathway

“…In recent years, research hotspots focus on energy metabolism disorder, reactive oxygen, signaling pathways, etc. There into, energy metabolism disorder is considered to be the initiation link of RIRI, while the signaling pathway of NO/cGMP/PKG, all which [NO, cGMP and PKG (cGMP-dependent protein kinase)] play important biological functions in a variety of histocytes, is considered as the key link to induce IRI [29-31]. PKG is an extensively existed serine/threonine kinase in eukaryocytes, while cGMP plays the role as the second messenger through the interaction between intracellular receptor proteins, in which the most key receptor of cGMP in the vascular smooth muscle cells is serine/threonine kinase (i.e., PKG) [32].…”

Current Mechanistic Concepts in Ischemia and Reperfusion Injury

“…Necroptosis is a form of programmed cell death that is controlled by death signals and displays a death pattern like that of necrosis [98]. Local ischemia is caused by obstruction of blood flow to tissue, resulting in a limited supply of oxygen and nutrients, which if prolonged, can impair energy metabolism and cell death [99]. The recovery of blood loss (reperfusion) leads to the reintroduction of oxygen and the production of ROS, leading to cell death associated with inactivation [100, 101].…”

Microarray Analysis of Differentially Expressed Profiles of Circular RNAs in a Mouse Model of Intestinal Ischemia/Reperfusion Injury with and Without Ischemic Postconditioning

“…Recent study has demonstrated that I/R injury altered sphingolipid metabolism in the intestine [40]. Moreover, regulation of cell communication, ROS biosynthesis and multiple signaling pathways such as cGMP-PKG, cAMP, MAPK and PPAR were identified in the iPoC group compared with the I/R group, suggesting that related coding genes may play crucial roles in iPoC-mediated protection against intestinal I/R injury through regulating the above mentioned biological mechanisms and signal transduction pathways.…”