Mechanisms of Endotoxin-Induced Intestinal Injury in a Hyperdynamic Model of Sepsis

Xu, Dazhong; Lu, Quan; Guillory, Dale; Cruz, Nestor Dela; Berg, Rodney D.; Deitch, Edwin A.

doi:10.1097/00005373-199305000-00010

Cited by 97 publications

(43 citation statements)

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“…For example, the chronic studies, where HIF-1 was protective, utilized conditional intestinal and colonic epithelial HIF-1␣ mice (28,37,56), whereas our studies were performed in mice with a partial HIF-1␣ deficiency that involves the entire gut. These differences may be important, since the segment of the gut that is susceptible to acute gut I/R-mediated injury is the distal small intestine (33,69). This increased susceptibility of the ileum to I/R-mediated injury is consistent with the observation that the levels of proinflammatory genes, such as iNOS, and apoptotic cell death were markedly increased after hemorrhagic shock in the ileum compared with duodenum, jejunum, and colon (33).…”

Section: Discussionsupporting

confidence: 66%

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Feinman

Deitch

Watkins

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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126

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mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 299: G833-G843, 2010. First published August 5, 2010 doi:10.1152/ajpgi.00065.2010.-Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) are major causes of death in trauma patients. Gut inflammation and loss of gut barrier function as a consequence of splanchnic ischemia-reperfusion (I/R) have been implicated as the initial triggering events that contribute to the development of the systemic inflammatory response, ALI, and MODS. Since hypoxia-inducible factor (HIF-1) is a key regulator of the physiological and pathophysiological response to hypoxia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Utilizing partially HIF-1␣-deficient mice in a global trauma hemorrhagic shock (T/HS) model, we found that HIF-1 activation was necessary for the development of gut injury and that the prevention of gut injury was associated with an abrogation of lung injury. Specifically, in vivo studies demonstrated that partial HIF-1␣ deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1␣ deficiency reduced TNF-␣, IL-1␤, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1␤ mRNA levels were reduced in the lung after T/HS. This study indicates that prolonged intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights. hemorrhagic shock; inflammation; multiple organ dysfunction syndrome; acute lung injury IN PATIENTS SUSTAINING major trauma, the development of the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction (MODS) is a major clinical problem resulting in 50 -80% of all deaths in surgical intensive care units. Since the pathophysiology of this syndrome remains incompletely understood and therapy remains largely supportive (16), studies focusing on the basic biology of traumainduced SIRS, organ injury/dysfunction, and MODS have been major areas of investigation. These mechanistic studies have generated several working hypotheses, one of which is the gut hypothesis of MODS. A key element in the gut hypothesis of MODS is that a splanchnic ischemia-reperfusion (I/R) insult leading to gut inflammation and loss of barrier function is the initial triggering event that turns the gut into the "motor" of MODS (19). However, the exact mechanisms by which gut I/R leads to intestinal injury and how an intestinal ischemic insult is transduced into a systemic inflammatory response remains incomplete. To date, the majority of the molecular and cellular studies investigating shock-induced gut injury and gut-induced MODS have focused pr...

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Section: Discussionsupporting

confidence: 66%

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Feinman

Deitch

Watkins

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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126

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“…We found 56 experiments performed in small animals [20, 24, 26, 27, 39, 42, 43, 44, 55, 57, 58, 59, 62, 63, 64, 67, 68, 72, 77, 79, 81, 82, 87, 88, 89, 90, 93, 94, 96, 97, 99, 100, 103, 104, 105, 110, 116, 120, 121, 122, 129, 132, 133, 134, 137, 138, 139, 141, 142, 143, 147, 148, 149, 150, 151] and 81 performed in large animals [21, 22, 23, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 56, 60, 61, 65, 66, 69, 70, 71, 73, 74, ...…”

Section: Resultsmentioning

confidence: 99%

Renal Vascular Resistance in Sepsis

et al. 2006

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Aims: To assess changes in renal vascular resistance (RVR) in human and experimental sepsis and to identify determinants of RVR. Methods: We performed a systematic interrogation of two electronic reference libraries using specific search terms. Subjects were animals and patients involved in experimental and human studies of sepsis and septic acute renal failure, in which the RVR was assessed. We obtained all human and experimental articles reporting RVR during sepsis. We assessed the role of various factors that might influence the RVR during sepsis using statistical methods. Results: We found no human studies, in which the renal blood flow (and, therefore, the RVR) was measured with suitably accurate direct methods. Of the 137 animal studies identified, 52 reported a decreased RVR, 16 studies reported no change in RVR, and 69 studies reported an increased RVR. Consciousness of animals, duration of measurement, method of induction of sepsis, and fluid administration had no effect on the RVR. On the other hand, on univariate analysis, size of the animals (p<0.001), technique of measurement (p = 0.017), recovery after surgery (p = 0.004), and cardiac output (p <0.001) influenced the RVR. Multivariate analysis, however, showed that only cardiac output (p = 0.028) and size of the animals (p = 0.031) remained independent determinants of the RVR. Conclusions: Changes in RVR during sepsis in humans are unknown. In experimental sepsis, several factors not directly related to sepsis per se appear to influence the RVR. A high cardiac output and the use of large animals predict a decreased RVR, while a decreased cardiac output and the use of small animals predict an increased RVR.

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“…29 In our study blood flow to the distal small intestine and cecum was significantly diminished in both blood flow to the bowel is not the only important determinant of barrier function, but other factors, such as experimental groups, whereas the blood flow to the proximal part of the small intestine was unchanged cytokines, may play an important role in this process. 30 The host's immune function is most important of the compared with control rats. This pattern of change has also been observed after endotoxin challenge, 30 and the extraintestinal factors.…”

Section: Discussionmentioning

confidence: 99%

“…30 The host's immune function is most important of the compared with control rats. This pattern of change has also been observed after endotoxin challenge, 30 and the extraintestinal factors. 10 The process of bacterial translocation is frequently observed in immune-altered or present finding suggests involvement of similar mechanisms in the blood flow changes observed in acute liver immunocompromised patients.…”

Section: Discussionmentioning

confidence: 99%

Bacterial translocation in acute liver injury induced by d- galactosamine

Kasravi

Wang

et al. 1996

Hepatology

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Acute liver injury and hepatic failure are serious Acute liver injury is associated with a high rate of infectious and septic complications. Most of these infec-clinical conditions that are sometimes observed in extions are produced by gram negative enteric bacteria. tensive hepatic surgery and in patients with multiple We evaluated bacterial translocation, intestinal perme-system organ failure. 1,2 Bacterial infection and sepsis ability, blood flow, portal pressure, and intestinal mi-are recognized as dangerous complications of this remcroflora after induction of liver injury and 70% liver re-edy with significant share in its morbidity and mortalsection in the rat. The rate of translocation to both portal ity. [3][4][5] Gram-negative enteric bacteria are frequent and arterial blood was 100% at 24 hours and 50% at 48 causative organisms in most of the published studies. 6-8 hours after liver resection compared with 83% to portal It has been shown that the gut, as a reservoir of enteric vein and 50% to aortic blood at both time points after bacteria in the body, plays an important role in many acute liver injury. Translocation to intraabdominal orcritical clinical situations, such as major burns, hemorgans (liver, spleen, and mesenteric lymph nodes) was rhagic shock, and so on. 9 Under normal conditions a 100% in both groups at both 24 and 48 hours. The rate series of protective measures, such as mucosal barrier of translocation increased after liver injury at 48 hours with progression of the liver injury but was decreased function, immunoglobulin secretion, and local and sysin the 70% liver resection group with improvement of temic macrophage system prevent translocation of liver function. ''Total aerobic'' and ''total anaerobic'' bac-these potential pathogens to the extraintestinal sites. 10 terial counts in small intestine and cecum were not af-Severe clinical disorders may disrupt these normal profected. Pulmonary, distal small intestine, and cecal tective mechanisms and make it possible for the intestiblood flow were decreased in both groups, whereas nal bacteria to translocate. Translocation of endotoxin blood flow in the proximal small intestine was unaf-and intestinal bacteria in acute liver injury may intenfected. Portal pressure and flow were increased after sify the extent of injury and may also be responsible 70% liver resection, but they were decreased in acute for the high rate of associated infection and sepsis obliver injury. After acute liver injury, permeability of both served in these patients. So far, little attention has MATERIALS AND METHODSgery, Lund University, 221 85 Lund, Sweden. Experimental Groups.One hundred eight Sprague-

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Mechanisms of Endotoxin-Induced Intestinal Injury in a Hyperdynamic Model of Sepsis

Cited by 97 publications

References 0 publications

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Renal Vascular Resistance in Sepsis

Bacterial translocation in acute liver injury induced by d- galactosamine

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