Impaired Gut Contractility Following Hemorrhagic Shock is Accompanied by IL6 and G-CSF Production and Neutrophil Infiltration (original) (raw)
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American journal of physiology. Gastrointestinal and liver physiology, 2003
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.
Induced nitric oxide promotes intestinal inflammation following hemorrhagic shock
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
In hemorrhagic shock (HS), increased cytokine production contributes to tissue inflammation and injury through the recruitment of neutrophils [polymorphonuclear cells (PMN)]. HS stimulates the early expression of inducible nitric oxide synthase (iNOS) that modulates proinflammatory activation after hemorrhage. Experiments were performed to determine the contribution of iNOS to gut inflammation and dysmotility after HS. Rats subjected to HS (mean arterial pressure 40 mmHg for 2.5 h followed by resuscitation and death at 4 h) demonstrated histological signs of mucosal injury, impairment of intestinal smooth muscle contractility, extravasation of PMN, and increased gut mRNA levels of ICAM-1, IL-6, and granulocyte colony-stimulating factor (G-CSF). In addition, DNA binding activity of NF-κB and Stat3, an IL-6 signaling intermediate, was significantly increased. In shocked rats treated with the selective iNOS inhibitor l- N6-(1-iminoethyl)lysine at the time of resuscitation, histological...
IL-6 Release after Intestinal Ischemia/Reperfusion in Rats Is under Partial Control of TNF
Journal of Surgical Research, 1997
barrier may serve as potent inducers to stimulate the Although there is much evidence to substantiate the release of TNF, which would be critical in evoking the view that tumor necrosis factor (TNF) plays a pivotal deleterious effects of both local and systemic injury [9, role in the pathogenesis of multiple organ injury sub-10]. Moreover, prophylactic treatment with monoclonal sequent to intestinal ischemia/reperfusion (I/R), it is antibodies to TNFa protects against the development still unclear whether TNF is involved in triggering the of multiple organ or system dysfunction, including the release of other inflammatory mediators in this condilung, liver, intestines, and cardiovascular system, and tion. The current study was designed to determine the improves the survival rate following intestinal I/R inpotential effects of TNF blockade, by means of monosult [10-12].
Interaction of Hemorrhagic Shock and Subsequent Polymicrobial Sepsis on Gastrointestinal Motility
Shock, 2009
Understanding "two-hit" experimental models is crucial for the rational development of therapies for hemorrhagic shock (HS). We modeled the clinical scenario of HS followed by polymicrobial sepsis (cecal ligation and puncture [CLP]) to investigate the molecular and functional alterations that occur within the gastrointestinal tract. Control, HS, CLP, simultaneous HS + CLP, and HS + delayed CLP by 24 h groups of Sprague-Dawley rats were studied for gastrointestinal transit and in vitro colonic circular muscle contractility to bethanechol. Reverse transcription-polymerase chain reaction quantified IL-6, IL-10, and heme oxygenase 1 messenger RNA expression in the isolated colonic muscularis 6 h after insult. Myeloperoxidase-positive neutrophils were quantified in colonic muscularis whole mounts. Mortality at 24 h was significantly increased in simultaneous mild HS + CLP (88%) over control, mild HS, CLP alone, or HS + delayed CLP. Cecal ligation and puncture significantly delayed transit compared with controls and HS alone. Hemorrhagic shock + delayed CLP animals had normal transit. Colonic contractions were suppressed by 50% after CLP compared with controls and HS. In contrast, HS + delayed CLP displayed control levels of contractile responses to bethanechol. Cecal ligation and puncture and simultaneous HS + CLP caused significant inflammatory messenger RNA induction of IL-6, iNOS, IL-10, and heme oxygenase 1 compared with control and HS, and these responses were significantly suppressed in HS + delayed CLP colonic muscularis extracts. Neutrophils were significantly recruited into the colonic muscularis following CLP after 24 h compared with control and HS. This recruitment was significantly less in the HS + delayed CLP animals. These data demonstrate the ability of mild HS to precondition the animal and protect it against a delayed, but not simultaneous, polymicrobial event.
The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock
AJP: Gastrointestinal and Liver Physiology, 2006
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; t...
The Journal of Trauma: Injury, Infection, and Critical Care, 2004
Background: Serum elevations of interleukin-6 (IL-6) correlate with multiple organ dysfunction syndrome and mortality in critically injured trauma patients. Data from rodent models of controlled hemorrhage suggest that recombinant IL-6 (rIL-6) infusion protects tissue at risk for ischemia-reperfusion injury. Exogenous rIL-6 administered during shock appears to abrogate inflammation, providing a protective rather than a deleterious influence. In an examination of this paradox, the current study aimed to determine whether rIL-6 decreases inflammation in a clinically relevant large animal model of uncontrolled hemorrhagic shock, (UHS), and to investigate the mechanism of protection. Methods: Swine were randomized to four groups (8 animals in each): (1) sacrifice, (2) sham (splenectomy followed by hemodilution and cooling to 33°C), (3) rIL-6 infusion (sham plus UHS using grade 5 liver injury with packing and resuscitation plus blinded infusion of rIL-6 [10 mcg/kg]), and (4) placebo (UHS plus blinded vehicle). After 4 hours, blood was sampled, estimated blood loss determined, animals sacrificed, and lung harvested for RNA isolation. Quantitative reverse transcriptase-polymerase chain reaction was used to assess granulocyte colony-stimulating factor (G-CSF), IL-6, and tumor necrosis factor-␣ (TNF␣) messenger ribonucleic acid (mRNA) levels. Serum levels of IL-6 and TNF␣ were measured by enzyme-linked immunoassay (ELISA).
Critical Care, 2007
Hydrogen sulfide is produced endogenously by a variety of enzymes involved in cysteine metabolism. Clinical data indicate that endogenous levels of hydrogen sulfide are diminished in various forms of cardiovascular diseases. The aim of the current study was to investigate the effects of hydrogen sulfide supplementation on cardiac function during reperfusion in a clinically relevant experimental model of cardiopulmonary bypass. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or the sodium sulfide infusion (1 mg/kg/hour, n = 6). Biventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and pulmonary blood flow, vasodilator responses to acetylcholine and sodiumnitroprusside and pulmonary function were also determined. Administration of sodium sulfide led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 minutes of reperfusion. Coronary blood flow was also significantly higher in the sodium sulfide-treated group (P < 0.05). Sodium sulfide treatment improved coronary blood flow, and preserved the acetylcholine-induced increases in coronary and pulmonary blood (P < 0.05). Myocardial ATP levels were markedly improved in the sulfide-treated group. Thus, supplementation of sulfide improves the recovery of myocardial and endothelial function and energetic status after hypothermic cardiac arrest during cardiopulmonary bypass. These beneficial effects occurred without any detectable adverse hemodynamic or cardiovascular effects of sulfide at the dose used in the current study.
The inflammatory basis of trauma/shock-associated multiple organ failure
Inflammation Research, 1998
Multiple alterations in inflammatory and immunologic function have been demonstrated in clinical and experimental situations after trauma and hemorrhage, in particular the activation of various humoral (e.g. complement, coagulation) and cellular systems (neutrophils, endothelial cells, macrophages). As a consequence of this activation process there is synthesis, expression and release of numerous mediators (toxic oxygen species, proteolytic enzymes, adherence molecules, cytokines), which may produce a generalized inflammation and tissue damage in the body. Mediators are responsible for ongoing interactions of different cell types and for amplification effects through their networks and feedback cycles, finally leading to a sustained inflammation and multiple organ damage in the body. In the setting of trauma/shock, many activators including bacterial as well as non-bacterial factors may be present that will induce local and systemic inflammatory responses. Although the potential role of bacteria/endotoxin translocation and its clinical relevance remains controversial, many lines of evidence support the concept that the gut may be the reservoir for systemic sepsis and subsequent MOF in a number of pathophysiologic states.
Shock, 2012
Interactions of Toll-like receptors (TLR) with non-microbial factors plays a major role in the pathogenesis of early trauma-hemorrhagic shock (T/HS)-induced organ injury and inflammation. Thus, we tested the hypothesis that TLR4 mutant (TLR4 mut) mice would be more resistant to T/ HS-induced gut injury and neutrophil (PMN) priming than their wild-type (WT) littermates and found that both were significantly reduced in the TLR4 mut mice. Additionally, the in vivo and ex vivo PMN priming effect of T/HS intestinal lymph observed in the WT mice was abrogated in TLR4 mut mice as well the TRIF mut deficient mice and partially attenuated in Myd88-/mice suggesting that TRIF activation played a more predominant role than MyD88 in T/HS lymphinduced PMN priming. PMN depletion studies showed that T/HS lymph-induced acute lung injury (ALI) was PMN-dependent, since lung injury was totally abrogated in PMN-depleted animals. Since the lymph samples were sterile and devoid of endotoxin or bacterial DNA, we investigated whether the effects of T/HS lymph was related to endogenous non-microbial TLR4 ligands. HMGB1, heat shock protein (Hsp)-70, Hsp27 and hyaluronic acid, since all have been implicated in ischemia-reperfusion-induced tissue injury. None of these 'danger' proteins appeared to be involved, since their levels were similar between the sham and shock lymph samples. In conclusion, TLR4 activation is important in T/HS-induced gut injury and in T/HS lymph-induced PMN priming and lung injury. However, the T/HS-associated effects of TLR4 on gut barrier dysfunction can be uncoupled from the T/HS lymph-associated effects of TLR4 on PMN priming.
Annals of Surgery, 2014
Objective-To test whether the mucus layer, luminal digestive enzymes, and intestinal mast cells are critical components in the pathogenesis of trauma-shock-induced gut and lung injury. Summary Background Data-Gut-origin sepsis studies have highlighted the importance of the systemic component (ischemia-repefusion) of gut injury while the intraluminal component is less well studied. Methods-In rats subjected to trauma-hemorrhagic shock (T/HS) or sham-shock (T/SS), the role of pancreatic enzymes in gut injury was tested by diversion of pancreatic enzymes via pancreatic duct exteriorization (PDE), while the role of the mucus layer was tested via the enteral administration of a mucus surrogate. Additionally the role of mast cells was assessed by measuring mast cell activation and the ability of pharmacologic inhibition of mast cells to abrogate gut and lung injury. Gut and mucus injury was characterized functionally, morphologically and chemically. Results-PDE abrogated T/HS-induced gut barrier loss and limited chemical mucus changes. The mucus surrogate prevented both T/HS-induced gut and lung injury. Lastly, pancreatic enzyme-induced gut and lung injury appears to involve mast cell activation, since T/HS activates mast cells and pharmacologic inhibition of intestinal mast cells prevented T/HS-induced gut and lung injury. Conclusions-These results indicate that gut and gut-induced lung injury after T/HS involves a complex process consisting of intraluminal digestive enzymes, the unstirred mucus layer, and a systemic ischemic-reperfusion injury. This suggests the possibility of intraluminal therapeutic strategies.