Biomedical subjects

E A Deitch

Publications and source records attributed to E A Deitch.

At least 19 recordsLinked to original sources

PubMed1998

Role of interleukin 8 in the genesis of acute respiratory distress syndrome through an effect on neutrophil apoptosis.

OBJECTIVE: To evaluate the role of interleukin 8 (IL-8) in the regulation of neutrophil (PMN) apoptosis in normal plasma and plasma from patients with early, fulminant acute respiratory distress syndrome (ARDS). DESIGN: Experimental study using cultured human PMNs. SETTING: University hospital, level I trauma center. PARTICIPANTS: Plasma was obtained from 6 patients with early, fulminant posttraumatic ARDS (mean Injury Severity Score, 26). All samples were drawn within 24 hours after injury. Plasma was also taken from 13 healthy control subjects. These controls were also used as sources of PMNs. MAIN OUTCOME MEASURES: Effect of early, fulminant ARDS and normal plasma on spontaneous apoptosis, CD16, and CD11-b expression in PMNs in vitro; levels of IL-8 in plasma; correlation of extracellular IL-8 concentration with rate of PMN apoptosis; and effect of IL-8 blockade on PMN apoptosis, CD16, and CD11-b expression in ARDS and normal plasma. RESULTS: Plasma from patients with early, fulminant ARDS inhibited spontaneous PMN apoptosis at 24 hours (35%+/-5% vs 54%+/-5%; P=.01). Neither CD16 nor CD1l-b differed significantly between the 2 groups. The mean plasma level of IL-8 in patients with early, fulminant ARDS was 359+/-161 pg/mL vs 3.0+/-0.4 pg/mL in healthy controls (P<.05). Interleukin 8 inhibited apoptosis in plasma-free medium at low doses (1-50 pg/mL) but had no significant effect at higher doses (100-5000 pg/mL) (P<.05). Interleukin 8 blockade with monoclonal antibody suppressed apoptosis in normal plasma (28%+/-5% with monoclonal antibody vs 51%+/-5% without monoclonal antibody; P=.008) but not in plasma from patients with early, fulminant ARDS (29%+/-5% with monoclonal antibody vs 34%+/-6% without monoclonal antibody; P=.67). It had no effect on CD16 or CD11-b expression in either plasma. CONCLUSIONS: Plasma from patients with early, fulminant ARDS contains soluble factors that inhibit PMN apoptosis in vitro. Low levels of IL-8 inhibit PMN apoptosis in normal plasma. Although plasma levels of IL-8 are markedly elevated in early, fulminant ARDS, IL-8 is not directly responsible for the antiapoptotic effect of plasma from patients with early, fulminant ARDS.

Apoptosis↗

PubMed1998

Gut-derived mesenteric lymph but not portal blood increases endothelial cell permeability and promotes lung injury after hemorrhagic shock.

OBJECTIVE: To determine whether gut-derived factors leading to organ injury and increased endothelial cell permeability would be present in the mesenteric lymph at higher levels than in the portal blood of rats subjected to hemorrhagic shock. This hypothesis was tested by examining the effect of portal blood plasma and mesenteric lymph on endothelial cell monolayers and the interruption of mesenteric lymph flow on shock-induced lung injury. SUMMARY BACKGROUND DATA: The absence of detectable bacteremia or endotoxemia in the portal blood of trauma victims casts doubt on the role of the gut in the generation of multiple organ failure. Nevertheless, previous experimental work has clearly documented the connection between shock and gut injury as well as the concept of gut-induced sepsis and distant organ failure. One explanation for this apparent paradox would be that gut-derived inflammatory factors are reaching the lung and systemic circulation via the gut lymphatics rather than the portal circulation. METHODS: Human umbilical vein endothelial cell monolayers, grown in two-compartment systems, were exposed to media, sham-shock, or postshock portal blood plasma or lymph, and permeability to rhodamine (10K) was measured. Sprague-Dawley rats were subjected to 90 minutes of sham or actual shock and shock plus lymphatic division (before and after shock). Lung permeability, pulmonary myeloperoxidase levels, alveolar apoptosis, and bronchoalveolar fluid protein content were used to quantitate lung injury. RESULTS: Postshock lymph increased endothelial cell monolayer permeability but not postshock plasma, sham-shock lymph/plasma, or medium. Lymphatic division before hemorrhagic shock prevented shock-induced increases in lung permeability to Evans blue dye and alveolar apoptosis and reduced pulmonary MPO levels. In contrast, division of the mesenteric lymphatics at the end of the shock period but before reperfusion ameliorated but failed to prevent increased lung permeability, alveolar apoptosis, and MPO accumulation. CONCLUSIONS: Gut barrier failure after hemorrhagic shock may be involved in the pathogenesis of shock-induced distant organ injury via gut-derived factors carried in the mesenteric lymph rather than the portal circulation.

Animals↗

PubMed1998

Effect of acute-phase and heat-shock stress on apoptosis in intestinal epithelial cells (Caco-2).

OBJECTIVES: a) To determine if the sequence of exposure of intestinal epithelial cells to heat-shock or acute-phase stimuli would affect whether cellular protection or injury would occur; and b) to determine if the effects of a thermally induced heat-shock response can be mimicked by sodium arsenite, a nonthermal inducer of the heat-shock response. DESIGN: In vitro controlled study. SETTING: Institutional laboratories. SUBJECTS: Caco-2 human intestinal cell line. INTERVENTIONS: Human intestinal epithelial cells (Caco-2) were grown on 35-mm culture dishes, chamber slides, or in a bicameral culture system to confluence or until tight-junction integrity was established. The cells were examined for viability, apoptosis, and bacterial translocation after exposure to a series of insults. MEASUREMENTS AND MAIN RESULTS: Control Caco-2 cells (medium only) and cells exposed to arsenite or to LPS alone had an apoptotic cell rate of 5.7%, 7.9%, and 8.6%, respectively. However, Caco-2 cells exposed to the cytokines IL-1beta and IL-6 had a significantly higher rate of apoptosis (22.1%, p < .01 vs. other groups). Caco-2 cells exposed to arsenite followed by LPS had 6.7% apoptotic cells, while cells exposed to LPS followed by arsenite had a significantly greater number of apoptotic cells (19.7%, p < .05). In addition, cells exposed to cytokines followed by arsenite had a higher apoptotic rate than cells exposed to arsenite followed by cytokines (28.4% vs. 10.6%, p < .01). Similar results were seen when cell viability was quantitated. At 3 hrs after challenge with Escherichia coli, the cytokine-exposed Caco-2 monolayers had a significantly increased rate of bacterial passage across the Caco-2 monolayer than control monolayers (p < .05), while the Caco-2 monolayers exposed to arsenite followed by cytokines or arsenite alone had a decreased rate of bacterial passage (p < .05). Conversely, cells exposed to cytokines or LPS before arsenite had the highest number of bacteria crossing the monolayer (p < .05). CONCLUSIONS: These results indicate that preinduction of a heat-shock response (arsenite) can protect against cytokine or LPS-induced apoptosis and enterocyte dysfunction, as manifested by the passage of E. coli across an intact enterocyte monolayer. In contrast, the induction of a heat-shock response after exposure to acute-phase response inducers (cytokines and LPS) may result in decreased enterocyte viability, increased apoptosis, and cellular dysfunction.

Apoptosis↗

PubMed1998

The relationships among nitric oxide production, bacterial translocation, and intestinal injury after endotoxin challenge in vivo.

BACKGROUND: This study examines the hypothesis that there is a relationship among endotoxin-induced bacterial translocation (BT) and increased nitric oxide (NO) production and that inhibition of excessive NO production with NG-monomethyl-L-arginine (L-NMMA) is beneficial. METHODS: Rats received 0, 1, or 4 mg/kg endotoxin intraperitoneally, and 6 or 18 hours later, they were killed and BT, NO production (as reflected in nitrite/nitrate levels), and calcium-dependent nitric oxide synthase and calcium-independent nitric oxide synthase (iNOS) activities were measured in tissues (ileum, liver, and mesenteric lymph nodes) and blood. In a second set of experiments, the animals received the NOS inhibitor L-NMMA (100 mg/kg) intravenously either 15 minutes before or 2 hours after endotoxin challenge (4 mg/kg) and the same parameters were measured. RESULTS: The incidence of BT was higher in rats receiving 4 mg/kg endotoxin (62.5%) than in the control group (0%, p < 0.05), and the 1 mg/kg endotoxin group had intermediate incidence (25%). The animals receiving 4 mg/kg endotoxin had higher tissue (mesenteric lymph nodes, liver) and blood nitrite/nitrate levels than the control or 1 mg/kg endotoxin groups. The increased NO production was mainly attributable to an elevated level of iNOS activity. The administration of L-NMMA before but not after endotoxin challenge reduced iNOS activity, NO production, and BT to control levels at 6 hours but not 18 hours after endotoxin administration. CONCLUSION: Endotoxin-induced mucosal injury and BT are associated with iNOS activity and increased NO production. Inhibition of iNOS activity with L-NMMA before treatment prevented endotoxin-induced ileal mucosal injury and BT.

Animals↗

PubMed1998

Animal models of sepsis and shock: a review and lessons learned.

Over the past decade, the biotechnology/pharmaceutical industry has been diligently working on the development of immunomodulatory agents for the treatment of shock and sepsis, and the literature is rife with descriptions of novel and innovative molecules that promise to become the panacea for these conditions. Unfortunately, despite promising preclinical evidence, dozens of these new agents have failed to demonstrate clinical efficacy in controlled, randomized clinical trials, abandoning the bedside physician to the traditional armamentarium of drugs and therapeutics for the treatment of patients with these complex, progressive, and life-threatening conditions. The reasons for this quandary are controversial, complex, and multifactorial. This review focuses on the concept that the preclinical trials of many of these agents were conducted using models of sepsis and shock that do not adequately reflect the clinical realities of these conditions. As a result, it is not surprising that clinical trials of agents based on clinically flawed models failed to demonstrate clinical efficacy. The lack of clinical insight during preclinical development of these agents has contributed to the current impasse of the development of safe, efficacious, and potentially lifesaving agents for the treatment of shock and sepsis. Thus, the goal of this review article is to review the advantages and disadvantages of commonly used sepsis and shock models in light of lessons learned from these clinical trials.

Animals↗

PubMed1998

Chemokine stimulation of human neutrophil [Ca2+]i signaling in biologic environments.

Clinical neutrophil (PMN) priming is the net result of multiple stimuli, with intracellular calcium ([Ca2+]i) being a key second messenger for PMN agonists such as the chemokines. Thus, [Ca2+]i measurement may be a robust tool for the assessment of global PMN activation. [Ca2+]i is difficult to measure in complex biologic environments, however, so data in this area are limited. We therefore developed an in vitro system to measure the effects of chemokines on PMN [Ca2+]i. PMN were isolated from volunteer blood. PMN [Ca2+]i responses to interleukin (IL)-8 and Growth-Related Oncogene (GRO)-alpha were studied by fura-2-acetoxymethyl ester fluorescence with or without reincubation in autologous plasma just prior to study. The effects of IL-8 and GRO-alpha on PMN [Ca2+]i at ascending doses, with or without plasma reincubation, given sequentially and in the presence or absence of extracellular calcium, were studied. PMN basal [Ca2+]i was increased by plasma, as were low-dose priming and higher-dose spike responses to IL-8. GRO-alpha caused a more pronounced priming of PMN [Ca2+]i than IL-8 at low doses, although significantly lower peak responses were observed with GRO-alpha than IL-8 at higher doses. Plasma suppressed both priming and spike responses to GRO-alpha. When given serially at clinically relevant agonist doses, GRO-alpha was permissive of IL-8 signaling, whereas IL-8 blocked GRO-alpha signaling. IL-8 generates high [Ca2+]i spikes using intracellular calcium stores only. GRO-alpha produces lower [Ca2+]i spikes despite using both intra- and extracellular stores. Plasma preincubation has profound effects on PMN [Ca2+]i responses to chemokines. These can be measured accurately, as described. In clinically relevant environments, IL-8 and GRO-alpha interact in a regulatory fashion. GRO-alpha may act as a priming agent, with IL-8 activating PMN functions requiring high [Ca2+]i. This cross-cooperation is probably terminated by IL-8 regulation of GRO-alpha activity at the C-X-C chemokine receptor 2.

Calcium↗

PubMed1998

Post-hemorrhagic shock mesenteric lymph is cytotoxic to endothelial cells and activates neutrophils.

The goal of these experiments was to test the hypothesis that after a nonlethal episode of hemorrhagic shock, factors carried in the mesenteric lymph would promote endothelial cell injury and activate neutrophils to a greater extent than portal vein plasma. Catheters were placed in the efferent lymphatic duct draining the mesenteric lymph node complex, after which male rats were subjected to sham or actual shock (30 mmHg for 90 min), and lymph was collected. Portal vein plasma was collected from the sham-shock and shocked rats at 6 h post-shock or sham-shock. When the effect of lymph or portal blood plasma was tested on endothelial cell (HUVEC) monolayer permeability, it was found that post-shock lymph, but not post-shock portal vein plasma, increased HUVEC permeability to both 10 kDa and 40 kDa permeability probes. Subsequent experiments documented that only post-shock lymph was cytotoxic to endothelial cells as manifest both by decreased trypan blue dye exclusion and the increased release of Chromium-51 from chromium-loaded endothelial cells. Furthermore post-shock lymph induced a greater increase in neutrophil superoxide formation than pre-shock lymph, pre-shock, or post-shock portal vein plasma. Lastly, neutrophil-mediated endothelial cell injury was potentiated by the presence of post-shock lymph, and the magnitude of HUVEC injury was greater in endothelial cells incubated with post-shock lymph plus neutrophils than in monolayers incubated with post-shock lymph or neutrophils alone. These results suggest that post-shock lymph is cytotoxic to endothelial cells and activates neutrophils. Since the lung is the first organ that is exposed to mesenteric lymph, lung injury after hemorrhagic shock may be mediated by factors contained in mesenteric lymph.

Animals↗

PubMed1998

[Metabolism and nutritional support after burn injury].

The nutritional status of the burn patient plays a major role in the ability to ward off an infectious challenge. The immune and inflammatory systems can be modulated by nutritional support, and therefore this article focuses on the nutritional support after burn injury. The hypermetabolic response that occurs after burn injury is characterized by a greater magnitude than that observed after any other form of trauma. The hypothesis that gut-or wound-derived bacterial translocation is one of the major triggers of the hypermetabolic response has attracted attention recently. The first set of goals of nutritional support is to prevent starvation and nutrient deficiencies, and the second is to provide the correct amount of nutrients prevent injury-related adverse physiologic complications. The route and timing of nutritional support are most important. Enteral alimentation appears to preserve the host immune function and to attenuate the hypermetabolic response by preserving the intestinal mucosal barrier. Immediate enteral feeding is superior to delayed enteral feeding, even though only limited amounts of enterally administered nutrients are absorbed during the early days postburn.

Bacterial Infections↗

PubMed1997

Academic surgeons' knowledge of Food and Drug Administration regulations for clinical trials.

OBJECTIVES: To identify knowledge levels of academic surgeons about Food and Drug Administration (FDA) and Institutional Review Board (IRB) regulations for clinical research and to determine whether being a member in an IRB, conducting or participating in clinical trials, or being a member in surgical societies affected knowledge levels. DESIGN: Survey of surgical department faculty members in 20 universities. RESULTS: Sixty-five responses were received from 14 sites. Overall mean (+/- SEM) correct score was 6.7 +/- 0.2 of a possible 20 points. The best predictor of overall score was being a primary investigator of a clinical trial (P < .001), followed by being or having been a member of an IRB (P < or = .02). The total mean score of members of the Surgical Infection Society (8.2 +/- 0.5) was significantly higher (P < .001) than that of nonmembers (6.1 +/- 0.2), a phenomenon not observed with other surgical societies. In certain hypothetical clinical scenarios, all respondents were mistakenly willing to conduct clinical trials without obtaining appropriate approval from the FDA. Four (22%) of 18 IRB member respondents and 16 (25%) of the 65 respondents were willing to conduct human research without appropriate approval from patients, the IRB, or both. CONCLUSIONS: Knowledge deficits exist in the academic surgical community about the role and requirements of the FDA and local IRBs for conducting clinical research. Further study is required to determine the reasons for this deficit and to identify appropriate interventions.

Clinical Trials as Topic↗

PubMed1997

Bacterial translocation is inhibited in inducible nitric oxide synthase knockout mice after endotoxin challenge but not in a model of bacterial overgrowth.

BACKGROUND: Studies have shown that nitric oxide (NO) and NO synthase (NOS) inhibitors injure and protect organs after endotoxin (lipopolysaccharide [LPS]) challenge. OBJECTIVE: To test the hypothesis that LPS-induced gut injury and bacterial translocation (BT) are mediated through activation of inducible NOS (iNOS). DESIGN: A randomized, controlled study using genetically altered, iNOS gene knockout mice. SETTING: University research laboratory. METHODS: Forty-five wild-type (iNOS+/+) or homozygous mutant (iNOS-/-) mice weighing 25 to 35 g were challenged with Escherichia coli LPS or saline (10 mg/ kg) intraperitoneally (n = 8/group). In a second set of experiments, a bacterial overgrowth model of BT (E coli monoassociation) was tested (n = 6-7/group). The mesenteric lymph nodes and cecums were cultured, and liver, ileal, and blood nitrite and nitrate levels measured 24 hours after LPS or E coli monoassociation. RESULTS: After LPS challenge, 87.5% of the iNOS+/+ mice but 0% of the iNOS-/- mice had BT to their mesenteric lymph nodes (P < .01; chi 2 analysis). Nitrite and nitrate levels of the liver, ileum, and blood were higher in the iNOS+/+ mice (P < .05). In the E coli overgrowth model, BT to mesenteric lymph nodes occurred in 100% of iNOS-/- and iNOS+/+ mice. CONCLUSIONS: In this limited study, LPS-induced BT did not occur in iNOS-deficient mice, suggesting that LPS induction of increased iNOS activity is necessary for LPS-induced BT to occur. In contrast, iNOS activation does not seem to be necessary in a bacterial overgrowth model of BT.

Animals↗

PubMed1997

Role of bacterial adherence and the mucus barrier on bacterial translocation: effects of protein malnutrition and endotoxin in rats.

OBJECTIVE: The purpose of the study was to investigate the potential relations between mucosal bacterial adherence, intestinal mucus and mucin content, and bacterial translocation. SUMMARY BACKGROUND DATA: The attachment of bacteria to mucosal surfaces is the initial event in the pathogenesis of most bacterial infections that originate at mucosal surfaces, such as the gut. The intestinal mucus layer appears to function as a defensive barrier limiting micro-organisms present in the intestinal lumen from colonizing enterocytes. Consequently, studies focusing on the biology of bacterial adherence to the intestinal mucosa likely are to be important in clarifying the pathogenesis of gut origin sepsis. METHODS: To explore the relations between intestinal bacterial adherence, mucus bacterial binding, and bacterial translocation, two models were used. One (protein malnutrition) in which profound alterations in intestinal morphology occurs in the absence of significant translocation and one (endotoxin challenge) in which bacterial translocation occurs and intestinal morphology is relatively normal. RESULTS: Protein malnutrition was not associated with bacterial translocation and measurement of enteroadherent, mucosally associated bacterial population levels documented that the total number of gram-negative enteric bacilli adherent to the ileum and cecum was less in the protein-malnourished rats than in the normally nourished animals (p < 0.01). Furthermore, there was an inverse relation between the duration of protein malnutrition and bacterial adherence to the intestinal mucosa (r = 0.62, p < 0.002). In contrast, after endotoxin challenge, the level of enteroadherent bacteria was increased and bacterial translocation was observed. The binding of Escherichia coli to immobilized ileal mucus in vitro was decreased significantly in protein-malnourished rats, whereas E. coli binding to insoluble ileal mucus was increased in the rats receiving endotoxin. CONCLUSIONS: This study indicates that the adherence of bacteria to the intestinal mucosal surface is an important factor in bacterial translocation, that intestinal mucus modulates bacterial adherence, and that increased levels of mucosally associated bacteria are associated with a loss intestinal barrier function to bacteria.

Animals↗

PubMed1997

Interleukin-6 and tumor necrosis factor production in an enterocyte cell model (Caco-2) during exposure to Escherichia coli.

Data linking interactions between bacteria and the intestine with elevated serum cytokine levels has led to the concept of the gut as a cytokine-producing organ. An in vitro cell culture model was used to investigate the potential role of intestinal mucosa within this paradigm. Polarized monolayers of human enterocytes (Caco-2) were grown in a two compartment system where the apical and basal aspects of the membrane could be studied. Supernatant was collected at 0, 1, 3, 6, and 24 h after the monolayer was exposed (apically or basally) to 10(2), 10(5), or 10(8) colony-forming units of Escherichia coli C25/mL and saved for interleukin (IL)-6 and tumor necrosis factor (TNF) bioassay analysis. Caco-2 cells (not bacterially challenged) secreted significant amounts of constitutive IL-6, but not TNF, into the apical and basal chambers. Both cytokines levels were increased in a dose-dependent fashion (p < .05) after the E. coli challenge. This stimulated cytokine response was polar, in that the highest cytokine levels were at the side of the bacterial challenge and were most notable at the highest dose (10(8) colony-forming units/mL) of E. coli C25 tested. Caco-2 cells produce IL-6 and TNF in a dose-dependent fashion in response to E. coli C25 and the magnitude of this response is maximal on the side of the bacterial challenge. This data supports the hypothesis that bacterially challenged human enterocytes may be important producers of cytokines.

Caco-2 Cells↗

PubMed1996

Effect of heat shock and endotoxin stress on enterocyte viability apoptosis and function varies based on whether the cells are exposed to heat shock or endotoxin first.

BACKGROUND: Stress-gene responses, including the heat shock (HS) response and the acute phase response, are protective mechanisms for cells after exposure to stress. Both responses cannot occur simultaneously, and, in endothelial cells, the sequence of stress-gene expression seems to be a critical factor in whether cellular protection or injury occurs. OBJECTIVE: To determine if the sequence of stress-gene expression affects cellular protection or injury in epithelial cells. DESIGN: Randomized controlled in vitro study. SETTING: University research laboratory. SUBJECTS: Rat intestinal epithelial cell-6 (IEC-6) cells were grown on 35-mm culture dishes, chamber slides, or in a bicameral system to confluence or until tight junction integrity was established. INTERVENTIONS: Rat IEC-6 cells were examined for viability, apoptosis, and bacterial translocation (BT) after exposure to 25-micrograms/mL lipopolysaccharide (LPS) for 18 hours to HS (43 degrees C) for 90 minutes, to LPS followed by HS, or to HS followed by LPS. MAIN OUTCOME MEASURES: The IEC-6 cells were stained for viability and apoptosis using trypan blue and a direct immunoperoxidase detection of digoxigenin-labeled genomic DNA (Apop Tag Plus In Situ Apoptosis Detection Kit, Oncor, Gaithersburg, Md), respectively. Bacterial translocation was measured by culturing the bacteria (ie, Escherichia coli) that crossed the IEC-6 cell monolayer in the bicameral system. RESULTS: Control cells (medium only) and cells exposed to LPS alone, HS alone, or HS followed by LPS had a viability from 92% to 98%, and the percentage of apoptotic cells ranged from 2.2% to 5.7%. In contrast, IEC-6 cells exposed to LPS followed by HS had a significantly lower viability (83%, P < .05 vs all other groups) and a higher percentage of apoptotic cells (12.2%, P < .01). At 3 hours after challenge with E coli, the LPS-exposed IEC-6 cell monolayers had significantly increased BT vs control monolayers (P < .05), while the IEC-6 cell monolayers exposed to HS followed by LPS had decreased BT (P < .05). Conversely, cells exposed to LPS followed by HS had the highest magnitude of BT (P < .01 vs all other groups). CONCLUSIONS: These results indicate that preinduction of HS response can diminish LPS-induced cell injury, while induction of HS response after the LPS challenge (ie, the acute phase response) may lead to decreased enterocyte viability, increased apoptosis, and cellular dysfunction as manifested by BT.

Acute-Phase Reaction↗

PubMed1996

Role of the gut in multiple organ failure: bacterial translocation and permeability changes.

It is clear that increased gut permeability and bacterial translocation play a role in multiple organ failure (MOF). Failure of the gut barrier remains central to the hypothesis that toxins escaping from the gut lumen contribute to activation of the host's immune inflammatory defense mechanisms, subsequently leading to the autointoxication and tissue destruction seen in the septic response characteristic of MOF. However, the role of the gut is more than that of a sieve, which simply allows passage of bacteria and endotoxin from the gut lumen to the portal or systemic circulation. It appears, in addition, that the translocation of bacteria and endotoxin may lead to local activation of the immune inflammatory system and the local production of cytokines and other immune inflammatory mediators. These intestinally derived mediators may then exacerbate the systemic inflammatory response and potentially lead to a further increase in gut permeability. A vicious cycle of increased intestinal permeability, leading to toxic mediator release, resulting in a further increase in gut permeability is generated. Additionally, the systemic and local inflammatory cells that become activated in the gut contribute to the systemic response characteristic of the sepsis syndrome and MOF. Thus even if the immune inflammatory system, rather than the gut, is the "motor of" MOF, the gut remains one of the major pistons that turns the motor.

Animals↗

PubMed1996

Infection, the gut and the development of the multiple organ dysfunction syndrome.

It has been hypothesised that failure of the gut is an important pathophysiological phenomenon of the generalised inflammatory response that leads to the multiple organ dysfunction syndrome (MODS). Abnormal colonisation, infections of gut origin, bacterial translocation are all signs of gut failure that have been implicated in the pathogenesis of MODS. We have concluded after summarising published experimental and clinical studies that have tried to correlate the occurrence or prevention (by selective decontamination of the digestive tract) of these phenomena with the development of MODS, it seems that in some patients it is clear that loss of intestinal barrier function or the onset of infection precedes the development of MODS. In other patients, however, this relationship is not so clear and it seems that these phenomena may reflect a failure of the host's immune and mechanical defence systems and are epiphenoma of critical illness. The causal relation between those phenomena and the development of MODS are complex and need further clarification.

Animals↗

PubMed1996

Trauma, shock, and gut translocation.

This article reviews the scientific and clinical evidence that supports trauma and shock as potential etiologies for translocation of intestinal microorganisms and their by-products. The potential for loss of intestinal barrier function to cause the eventual septic deaths observed in such patients, as well as possible mechanisms for preventing and treating this entity is also discussed.

Animals↗

PubMed1996

The relationship between gut-derived bacteria and the development of the multiple organ dysfunction syndrome.

Abnormal colonisation, infections of gut origin and bacterial translocation are all signs of gut failure that have been hypothesised as being implicated in the pathogenesis of the multiple organ dysfunction syndrome (MODS). We have summarised published experimental and clinical studies that have tried to correlate the occurrence or prevention of these phenomena with the development of MODS. We conclude that in some patients loss of intestinal barrier function or the onset of infection precedes the development of MODS. In other patients, however, this relationship is not so clear and it seems that these are epiphenoma of critical illness and may reflect a failure of the host's immune and mechanical defence systems. The causal relationship between these phenomena and the development of MODS is complex and needs further clarification.

Animals↗

PubMed1995

Elemental diet and IV-TPN-induced bacterial translocation is associated with loss of intestinal mucosal barrier function against bacteria.

OBJECTIVE: The goal of the current study was to directly assess the role of loss of mucosal barrier function in nutritionally induced bacterial translocation. BACKGROUND: Parenteral and certain elemental enteral diets have been shown to promote bacterial translocation. The mechanisms underlying this observation, especially the question of whether nutritionally induced bacterial translocation is primarily related to loss of intestinal barrier function, versus an impaired immune system, remain to be fully elucidated. METHODS: Bacterial translocation was measured in vivo, ileal mucosal membranes were harvested, and their electrophysiologic properties and barrier function were measured ex vivo in the Ussing chamber system 7 days after receiving total parenteral nutrition solution parenterally (IV-TPN) or enterally (elemental diet). Chow-fed rats served as control subjects. RESULTS: The incidence of bacterial translocation was significantly increased both to the mesenteric lymph nodes in vivo and across the in vitro Ussing chamber-mounted ileal mucosal membranes of the elemental diet-fed and IV-TPN-fed rats. The magnitude of Escherichia coli and phenol red transmucosal passage in the Ussing chamber was significantly higher in the IV-TPN-fed rats than in the elemental diet-fed or chow-fed animals. The potential differences across the ileal membrane were similar between the three groups at all time points. However, the specific resistances of the ileal membranes of the IV-TPN and elemental diet groups were significantly less than the chow-fed animals, indicating increased membrane permeability. CONCLUSIONS: Loss of intestinal barrier function plays a major role in nutritionally induced bacterial translocation, and the loss of mucosal barrier function to both E. coli and phenol red appeared greater in the IV-TPN than the elemental diet-fed rats.

Animals↗