eritoran and Reperfusion-Injury

Toll-like receptors (TLRs) are a family of pattern recognition receptors involved in cardiovascular diseases. Notably, numerous studies have demonstrated that TLR4 activates the expression of several of pro-inflammatory cytokine genes that play pivotal roles in myocardial inflammation, particularly myocarditis, myocardial infarction, ischemia-reperfusion injury, and heart failure. In addition, TLR4 is an emerging target for anti-inflammatory therapies. Given the significance of TLR4, it would be useful to summarize the current literature on the molecular mechanisms and roles of TLR4 in myocardial inflammation. Thus, in this review, we first introduce the basic knowledge of the TLR4 gene and describe the activation and signaling pathways of TLR4 in myocardial inflammation. Moreover, we highlight the recent progress of research on the involvement of TLR4 in myocardial inflammation. The information reviewed here may be useful to further experimental research and to increase the potential of TLR4 as a therapeutic target.

Topics: Animals; Cardiotonic Agents; Clinical Trials as Topic; Disaccharides; Follistatin; Gene Expression Regulation; Heart Failure; Humans; Metformin; Myeloid Differentiation Factor 88; Myocardial Infarction; Myocarditis; Myocardium; NF-kappa B; Reperfusion Injury; Signal Transduction; Sugar Phosphates; Toll-Like Receptor 4

Toll-like receptor 4 (TLR4) is ubiquitously expressed on parenchymal and immune cells of the liver and is the most studied TLR responsible for the activation of proinflammatory signaling cascades in liver ischemia and reperfusion (I/R). Since pharmacological inhibition of TLR4 during the sterile inflammatory response of I/R has not been studied, we sought to determine whether eritoran, a TLR4 antagonist trialed in sepsis, could block hepatic TLR4-mediated inflammation and end organ damage. When C57BL/6 mice were pretreated with eritoran and subjected to warm liver I/R, there was significantly less hepatocellular injury compared to control counterparts. Additionally, we found that eritoran is protective in liver I/R through inhibition of high-mobility group box protein B1 (HMGB1)-mediated inflammatory signaling. When eritoran was administered in conjunction with recombinant HMGB1 during liver I/R, there was significantly less injury, suggesting that eritoran blocks the HMGB1-TLR4 interaction. Not only does eritoran attenuate TLR4-dependent HMGB1 release in vivo, but this TLR4 antagonist also dampened HMGB1's release from hypoxic hepatocytes in vitro and thereby weakened HMGB1's activation of innate immune cells. HMGB1 signaling through TLR4 makes an important contribution to the inflammatory response seen after liver I/R. This study demonstrates that novel blockade of HMGB1 by the TLR4 antagonist eritoran leads to the amelioration of liver injury.

Topics: Animals; Cell Line; Cells, Cultured; Disaccharides; Hepatocytes; HMGB1 Protein; Interleukin-6; Lipopolysaccharides; Liver; Liver Diseases; Male; Mice, Inbred C57BL; Reperfusion Injury; Signal Transduction; Sugar Phosphates; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Ischemia-reperfusion injury (I/R) has a negative effect on renal allograft survival. Using a rat model of kidney IR injury, we demonstrated inhibition of Toll-like receptor (TLR) 4 with erotoran may shed new light on I/R therapy.. All 44 Fisher rats were anesthetized with ethrane. Animals were randomly divided into the S group (sham, n = 11) that received only right kidney nephrectomy or the I/R group of right kidney nephrectomy and ichemia for 40 minutes by clamping of left renal artery (n = 11). In addition, the E group (Eritoran, n = 11) and the V group (vehicle, n = 11) received eritoran (5 mg x kg(-1)) and vehicle pretreatment, respectively. Analysis of renal histology, function, cytokine/chemokine production, as well as animal mortality was performed in parallel groups by ribonuclease protection assay (RPA).. At 24 hours, the creatinine value 1.49 +/- 0.2 mg/dL in the eritoran group was significantly lower than untreated controls (2.17 +/- 0.4 mg/dL). Histological findings showed tubular loss and morphological stutus as well as animal survival post-I/R injury compared to vehicle-treated rats; the difference between the S versus E groups was significant. Eritoran administration significantly attenuated monocyte infiltration into the kidney. RPA assays showed the following fold increase over sham normalized to that of GAPDH mRNA expression of tumor necrosis factor-alpha (4.67 +/- 1.52 vs 1.37 +/- 0.05), interleukin (IL)-1beta (5.11 +/- 1.17 vs 1.92 +/- 0.27), IL-6 (4.20 +/- 0.29 vs 1.21 +/- 0.37) and monocyte chemoattractant protein-1 (8.77 +/- 1.24 vs 2.57 +/- 1.59). GAPDH was markedly reduced by eritoran treatment (eritoran vs vehicle group).. These data demonstrated that inhibition of TLR4 with eritoran reduced I/R-related inflammatory responses and improved the course of kidney I/R injury.

Topics: Animals; Chemokines; Creatinine; Cytokines; Disaccharides; Disease Models, Animal; Kidney; Kidney Function Tests; Male; Rats; Rats, Inbred F344; Renal Artery; Renal Circulation; Reperfusion Injury; RNA, Messenger; Sugar Phosphates; Toll-Like Receptor 4