Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock

2002 ◽  
Vol 283 (1) ◽  
pp. G212-G221 ◽  
Author(s):  
Runkuan Yang ◽  
David J. Gallo ◽  
Jeffrey J. Baust ◽  
Takashi Uchiyama ◽  
Simon K. Watkins ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Colonic Mucosa ◽  
Ethyl Pyruvate ◽  
Parent Compound ◽  
Mucosal Injury ◽  
Nuclear Factor Κb ◽  
Organ Injury ◽  
Mesenteric Lymph Nodes ◽  
Ileal Mucosa ◽  
Mucosal Permeability

Administration of pyruvate, an effective scavenger of reactive oxygen species, has been shown to be salutary in numerous models of redox-mediated tissue or organ injury. Pyruvate, however, is unstable in solution and, hence, is not attractive for development as a therapeutic agent. Herein, ethyl pyruvate, which is thought to be more stable than the parent compound, was formulated in a calcium-containing balanced salt solution [Ringer ethyl pyruvate solution (REPS)] and evaluated in a murine model of hemorrhagic shock and resuscitation (HS/R). Resuscitation with REPS instead of Ringer lactate solution (RLS) significantly improved survival at 24 h and abrogated bacterial translocation to mesenteric lymph nodes and the development of increased ileal mucosal permeability to FITC-labeled dextran (4,000 Da) at 4 h. Mice treated with REPS instead of RLS also had lower circulating levels of alanine aminotransferase at 4 h. Treatment with REPS instead of RLS decreased activation of nuclear factor-κB in liver and colonic mucosa after HS/R and also decreased the expression of inducible nitric oxide synthase, tumor necrosis factor, cyclooxygenase-2, and interleukin-6 mRNA in liver, ileal mucosa, and/or colonic mucosa. These data support the view that resuscitation with REPS modulates the inflammatory response and decreases hepatocellular and gut mucosal injury in mice subjected to HS/R.

Microvascular perfusion deficits are not a prerequisite for mucosal injury in septic rats

1999 ◽  
Vol 276 (4) ◽  
pp. G933-G940 ◽  
Author(s):  
R. R. Nevière ◽  
M. L. Pitt-Hyde ◽  
R. D. Piper ◽  
W. J. Sibbald ◽  
R. F. Potter
Keyword(s):  
Cell Injury ◽  
Mucosal Injury ◽  
Endotoxin Tolerance ◽  
Capillary Density ◽  
Microvascular Perfusion ◽  
Myeloperoxidase Activity ◽  
Capillary Perfusion ◽  
Ileal Mucosa ◽  
Mucosal Permeability ◽  
Perfusion Deficits

Our major objective was to investigate whether injury to the mucosa of the small intestine occurred in a normotensive model of sepsis and whether such injury was associated with microvascular perfusion deficits. Using fluorescence intravital microscopy, we show direct evidence of cell injury within the mucosa (pneumonia 12.4 ± 2.6 cells/field, sham 2.2 ± 0.7 cells/field), whereas use of51Cr-labeled EDTA showed evidence of increased mucosal permeability (pneumonia 1.90 ± 0.67 ml · min−1 · 100 g−1; sham 0.24 ± 0.04 ml · min−1 · 100 g−1), 48 h following induction of pneumonia. Despite such injury the capillary density in the ileal mucosa and submucosa of pneumonic rats (1,027 ± 77 and 1,717 ± 86 mm2) was not significantly different compared with sham (998 ± 63 and 1,812 ± 101 mm2). However, a modest albeit significant decrease in capillary perfusion was measured in the muscularis layer of pneumonia (11.0 ± 1.3 mm) compared with sham (13.9 ± 0.63 mm) and appeared to be associated with leukocyte entrapment. Pretreatment using low doses of endotoxin to induce endotoxin tolerance not only increased muscularis capillary density but reduced the number of leukocytes trapped within the microvasculature, decreased myeloperoxidase activity within the ileum in pneumonic rats, and prevented mucosal injury. In conclusion, we have shown that pneumonia results in remote injury to the mucosa of the ileum and that such injury was not associated with concurrent mucosal perfusion deficits.

IL-6 is essential for development of gut barrier dysfunction after hemorrhagic shock and resuscitation in mice

2003 ◽  
Vol 285 (3) ◽  
pp. G621-G629 ◽  
Author(s):  
Runkuan Yang ◽  
Xiaonan Han ◽  
Takashi Uchiyama ◽  
Simon K. Watkins ◽  
Arino Yaguchi ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Barrier Function ◽  
Mrna Levels ◽  
Barrier Dysfunction ◽  
Mesenteric Lymph Nodes ◽  
Gut Barrier ◽  
Mucosal Permeability ◽  
Average Molecular Mass ◽  
Gut Barrier Function ◽  
Junction Protein

We sought to determine the role of IL-6 as a mediator of the alterations in gut barrier function that occur after hemorrhagic shock and resuscitation (HS/R). C57Bl/6 wild-type (WT) and IL-6 knockout (KO) mice on a C57Bl/6 background were subjected to either a sham procedure or HS/R. Organ and tissue samples were obtained 4 h after resuscitation. In WT mice, HS/R significantly increased ileal mucosal permeability to fluorescein isothiocyanate-labeled dextran (average molecular mass, 4 kDa) and bacterial translocation to mesenteric lymph nodes. These alterations in gut barrier function were not observed in IL-6 KO animals. HS/R increased ileal steady-state mRNA levels for IL-6, TNF, and IL-10 in WT but not in IL-6 KO mice. Ileal mucosal expression of the tight junction protein, ZO-1, decreased after HS/R in WT but not IL-6 KO mice. Collectively, these data support the view that expression of IL-6 is essential for the development of gut barrier dysfunction after HS/R.

The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock

2006 ◽  
Vol 291 (4) ◽  
pp. G556-G565 ◽  
Author(s):  
Kathleen G. Raman ◽  
Penny L. Sappington ◽  
Runkuan Yang ◽  
Ryan M. Levy ◽  
Jose M. Prince ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Bacterial Translocation ◽  
Intestinal Barrier ◽  
High Plasma ◽  
Mucosal Barrier ◽  
Barrier Dysfunction ◽  
Mesenteric Lymph Nodes ◽  
Mucosal Permeability ◽  
Intestinal Barrier Dysfunction ◽  
Soluble Rage

The receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of numerous conditions associated with excessive inflammation. To determine whether RAGE-dependent signaling is important in the development of intestinal barrier dysfunction after hemorrhagic shock and resuscitation (HS/R), C57Bl/6, rage−/−, or congenic rage+/+ mice were subjected to HS/R (mean arterial pressure of 25 mmHg for 3 h) or a sham procedure. Twenty-four hours later, bacterial translocation to mesenteric lymph nodes and ileal mucosal permeability to FITC-labeled dextran were assessed. Additionally, samples of ileum were obtained for immunofluorescence microscopy, and plasma was collected for measuring IL-6 and IL-10 levels. HS/R in C57Bl/6 mice was associated with increased bacterial translocation, ileal mucosal hyperpermeability, and high circulating levels of IL-6. All of these effects were prevented when C57Bl/6 mice were treated with recombinant human soluble RAGE (sRAGE; the extracellular ligand-binding domain of RAGE). HS/R induced bacterial translocation, ileal mucosal hyperpermeability, and high plasma IL-6 levels in rage+/+ but not rage−/− mice. Circulating IL-10 levels were higher in rage−/− compared with rage+/+ mice. These results suggest that activation of RAGE-dependent signaling is a key factor leading to gut mucosal barrier dysfunction after HS/R.

ICAM-1 and P-selectin expression in a model of NSAID-induced gastropathy

1998 ◽  
Vol 274 (2) ◽  
pp. G246-G252 ◽  
Author(s):  
Z. Morise ◽  
S. Komatsu ◽  
J. W. Fuseler ◽  
D. N. Granger ◽  
M. Perry ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Critical Role ◽  
Mucosal Blood Flow ◽  
Gastric Mucosal Blood Flow ◽  
Mucosal Injury ◽  
Gastric Mucosal Injury ◽  
Intercellular Adhesion Molecule ◽  
Sprague Dawley ◽  
Intercellular Adhesion Molecule 1 ◽  
Mucosal Permeability

A growing body of experimental evidence suggests that neutrophilic polymorphonuclear leukocyte (PMN)-endothelial cell interactions play a critical role in the pathophysiology of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. The objective of this study was to directly determine whether the expression of endothelial cell adhesion molecules is enhanced in a model of NSAID-induced gastropathy. Gastropathy was induced in male Sprague-Dawley rats via oral administration of indomethacin (Indo, 20 mg/kg). Lesion scores, blood-to-lumen clearance of 51Cr-EDTA (mucosal permeability), and histological analysis (epithelial necrosis) were used as indexes of gastric mucosal injury. Gastric mucosal vascular expression of intercellular adhesion molecule 1 (ICAM-1) or P-selectin were determined at 1 and 3 h after Indo administration using the dual radiolabeled monoclonal antibody (MAb) technique. For some experiments, a blocking MAb directed at either ICAM-1 (1A29) or P-selectin (RMP-1) or their isotype-matched controls was injected intravenously 10 min before Indo administration. We found that P-selectin expression was significantly increased at 1 h but not 3 h after Indo administration, whereas ICAM-1 expression was significantly increased at both 1 and 3 h after Indo treatment. The blocking ICAM-1 and P-selectin MAbs both inhibited Indo-induced increases in lesion score, mucosal permeability, and epithelial cell necrosis. However, the Indo-induced gastropathy was not associated with significant PMN infiltration into the gastric mucosal interstitium, nor did Indo reduce gastric mucosal blood flow. We propose that NSAID-induced gastric mucosal injury may be related to the expression of P-selectin and ICAM-1; however, this mucosal injury does not appear to be dependent on the extravasation of inflammatory cells or mucosal ischemia.

Ethyl Pyruvate Inhibits Nuclear Factor-κB-Dependent Signaling by Directly Targeting p65

2004 ◽  
Vol 312 (3) ◽  
pp. 1097-1105 ◽  
Author(s):  
Yusheng Han ◽  
Joshua A. Englert ◽  
Runkuan Yang ◽  
Russell L. Delude ◽  
Mitchell P. Fink
Keyword(s):  
Ethyl Pyruvate ◽  
Nuclear Factor Κb ◽  
Nuclear Factor

Role of leukocytes in indomethacin-induced small bowel injury in the rat

1994 ◽  
Vol 266 (2) ◽  
pp. G239-G246 ◽  
Author(s):  
H. M. Chmaisse ◽  
J. S. Antoon ◽  
P. R. Kvietys ◽  
M. B. Grisham ◽  
M. A. Perry
Keyword(s):  
Small Bowel ◽  
Morphological Changes ◽  
Mucosal Injury ◽  
Bowel Injury ◽  
Rat Jejunum ◽  
Small Bowel Injury ◽  
Mucosal Permeability ◽  
Quantitative Histology ◽  
51Cr Edta

This study assesses the role of neutrophils in indomethacin-induced small bowel injury and determines the influence of intestinal pH on the magnitude of this injury. Rat jejunum was perfused via the lumen with buffer, and mucosal injury was assessed by blood-to-lumen clearance of 51Cr-EDTA and quantitative histology. Reduction in luminal pH from 7.4 to 6.0 in the presence of indomethacin (1.0 mg/ml) increased 51Cr-EDTA clearance from 2.0 +/- 0.1 to 6.5 +/- 0.3 microliter.min-1.g-1. Indomethacin caused a reduction in villus length, an increase in villus width, and an increase in lesion score. Depletion of neutrophils with antiserum largely prevented the increase in 51Cr-EDTA clearance and morphological changes. Intravenous indomethacin given at a dose to mimic therapeutic plasma levels (1 mg/kg iv) had no significant effect on 51Cr-EDTA clearance but caused similar morphological changes to those observed following intraluminal administration. The data suggest that neutrophils play a role in acute indomethacin injury and that the drug given intravenously can cause morphological changes without necessarily altering mucosal permeability to 51Cr-EDTA.

Apocynin suppressed the nuclear factor-κB pathway and attenuated lung injury in a rat hemorrhagic shock model

2017 ◽  
Vol 82 (3) ◽  
pp. 566-574 ◽  
Author(s):  
Seok Ho Choi ◽  
Gil Joon Suh ◽  
Woon Yong Kwon ◽  
Kyung Su Kim ◽  
Min Ji Park ◽  
...  
Keyword(s):  
Lung Injury ◽  
Hemorrhagic Shock ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Shock Model ◽  
Hemorrhagic Shock Model

Role of neutrophils in hemorrhagic shock-induced gastric mucosal injury in the rat

1987 ◽  
Vol 93 (3) ◽  
pp. 466-471 ◽  
Author(s):  
S.Morgan Smith ◽  
Lena Holm-Rutili ◽  
Michael A. Perry ◽  
Matthew B. Grisham ◽  
Karl-E. Arfors ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Mucosal Injury ◽  
Gastric Mucosal Injury

Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo

2013 ◽  
Vol 305 (1) ◽  
pp. G95-G105 ◽  
Author(s):  
Anna Sommansson ◽  
Wan Salman Wan Saudi ◽  
Olof Nylander ◽  
Markus Sjöblom
Keyword(s):  
Nicotinic Receptor ◽  
Mucosal Injury ◽  
Paracellular Permeability ◽  
Ethanol Exposure ◽  
Mucosal Permeability ◽  
Duodenal Motility ◽  
Gastrointestinal Barrier ◽  
Induced Changes ◽  
Epithelial Inflammation

Increased intestinal permeability is often associated with epithelial inflammation, leaky gut, or other pathological conditions in the gastrointestinal tract. We recently found that melatonin decreases basal duodenal mucosal permeability, suggesting a mucosal protective mode of action of this agent. The aim of the present study was to elucidate the effects of melatonin on ethanol-, wine-, and HCl-induced changes of duodenal mucosal paracellular permeability and motility. Rats were anesthetized with thiobarbiturate and a ∼30-mm segment of the proximal duodenum was perfused in situ. Effects on duodenal mucosal paracellular permeability, assessed by measuring the blood-to-lumen clearance of 51Cr-EDTA, motility, and morphology, were investigated. Perfusing the duodenal segment with ethanol (10 or 15% alcohol by volume), red wine, or HCl (25–100 mM) induced concentration-dependent increases in paracellular permeability. Luminal ethanol and wine increased, whereas HCl transiently decreased duodenal motility. Administration of melatonin significantly reduced ethanol- and wine-induced increases in permeability by a mechanism abolished by the nicotinic receptor antagonists hexamethonium (iv) or mecamylamine (luminally). Signs of mucosal injury (edema and beginning of desquamation of the epithelium) in response to ethanol exposure were seen only in a few villi, an effect that was histologically not changed by melatonin. Melatonin did not affect HCl-induced increases in mucosal permeability or decreases in motility. Our results show that melatonin reduces ethanol- and wine-induced increases in duodenal paracellular permeability partly via an enteric inhibitory nicotinic-receptor dependent neural pathway. In addition, melatonin inhibits ethanol-induced increases in duodenal motor activity. These results suggest that melatonin may serve important gastrointestinal barrier functions.

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