Intestinal Mucus Layer Preservation in Female Rats Attenuates Gut Injury After Trauma-Hemorrhagic Shock

Sheth, Sharvil U.; Lu, Quan; Twelker, Kate; Sharpe, Susan; Qin, Xiaofa; Reino, Diego; Lee, Marlon A.; Xu, Da-Zhong; Deitch, Edwin A.

doi:10.1097/ta.0b013e3181caa6bd

Cited by 14 publications

(10 citation statements)

References 42 publications

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“…A 3-cm segment of terminal ileum was harvested, fixed in Carnoy’s fixative and stained with 3% alcian blue for mucus visualization16. Four-μm sections of gut were fixed to slides and stained with hematoxylin and eosin for villus injury determinations.…”

Section: Methodsmentioning

confidence: 99%

Loss of the Intestinal Mucus Layer in the Normal Rat Causes Gut Injury But Not Toxic Mesenteric Lymph nor Lung Injury

Sharpe

Qin

et al. 2010

Shock

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Background and Aims There is substantial evidence that gut barrier failure is associated with distant organ injury and systemic inflammation. After major trauma or stress, the factors and mechanisms involved in gut injury are unknown. Our primary hypothesis is that loss of the intestinal mucus layer will result in injury of the normal gut that is exacerbated by the presence of luminal pancreatic proteases. Our secondary hypothesis is that the injury produced in the gut will result in the production of biologically active mesenteric lymph and consequently distant organ (i.e., lung) injury. Methods To test this hypothesis, five groups of rats were studied: 1) un-instrumented naïve rats; 2) control rats, in which a ligated segment of distal ileum was filled with saline; 3) rats with pancreatic proteases placed in their distal ileal segments; 4) rats with the mucolytic N-acetylcysteine (NAC) placed in their distal ileal segments and 5) rats exposed to NAC and pancreatic proteases in their ileal segments. The potential systemic consequences of gut injury induced by NAC and proteases were assessed by measuring the biologic activity of mesenteric lymph as well as gut-induced lung injury. Results Exposure of the normal intestine to NAC, but not saline or proteases, led to increased gut permeability, loss of mucus hydrophobicity, a decrease in the mucus layer as well as morphologic evidence of villous injury. Although proteases themselves did not cause gut injury, the combination of pancreatic proteases with NAC caused more severe injury than NAC alone, suggesting that once the mucus barrier is impaired, luminal proteases can injure the now vulnerable gut. Since comparable levels of gut injury caused by systemic insults are associated with gut-induced lung injury which is mediated by biologically active factors in mesenteric lymph, we next tested whether this local model of gut injury would produce active mesenteric lymph or lead to lung injury. It did not, suggesting that gut injury by itself may not be sufficient to induce distant organ dysfunction. Conclusions Loss of the intestinal mucus layer, especially in the presence of intra -luminal pancreatic proteases, is sufficient to lead to injury and barrier dysfunction of the otherwise normal intestine, but not to produce gut-induced distant organ dysfunction.

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Section: Methodsmentioning

confidence: 99%

Loss of the Intestinal Mucus Layer in the Normal Rat Causes Gut Injury But Not Toxic Mesenteric Lymph nor Lung Injury

Sharpe

Qin

et al. 2010

Shock

Self Cite

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“…Similarly, T/HS induces breakdown of the mucus layer, and there is a direct correlation between loss of mucus layer and severity of villus injury (63). Interestingly, this is gender-dependent, as mucus is better preserved in female rats, associated to some degree with the estrus cycle (64). Although the mechanisms underlying mucus degradation are not fully elucidated, it is known that I/R breaks down mucus, at least in part, by degrading mucin 2 and fragmenting mucin 13 (58).…”

Section: The Mucus Layermentioning

confidence: 99%

Redefining the gut as the motor of critical illness

Mittal

Coopersmith

2014

Trends in Molecular Medicine

271

194

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The gut is hypothesized to play a central role in the progression of sepsis and multiple organ dysfunction syndrome. Critical illness alters gut integrity by increasing epithelial apoptosis and permeability and by decreasing epithelial proliferation and mucus integrity. Additionally, toxic gut-derived lymph induces distant organ injury. Although the endogenous microflora ordinarily exist in a symbiotic relationship with the gut epithelium, severe physiologic insults alter this relationship, leading to induction of virulence factors in the microbiome, which, in turn, can perpetuate or worsen critical illness. This review highlights newly discovered ways in which the gut acts as the motor that perpetuates the systemic inflammatory response in critical illness.

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“…There is relatively little information regarding inflammatory signaling in the lumen of the intestine. Recent studies suggest that loss of the intestinal mucus layer after injury exacerbates the intestinal inflammatory response and that pancreatic proteases in the lumen damage the gut mucosa (13, 14). In addition, it is known that the bacteria in the gut contribute to the inflammatory response, some through complex quorum sensing mechanisms (15).…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory Chemokines in the Intestinal Lumen Contribute to Intestinal Dysfunction During Endotoxemia

Sonnier

Bailey

Schuster

et al. 2012

Shock

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Intestinal failure is common in patients with septic shock, with dysfunction of the gut often manifesting as both a cause and consequence of their critical illness. Most studies investigating the pathogenesis of intestinal failure focus on the systemic aspect, although few data examine the inflammatory signaling in the intestinal lumen. Having previously demonstrated apical/luminal chemokine secretion in an in vitro model of intestinal inflammation, we hypothesized that endotoxemia would induce secretion of proinflammatory chemokines into the intestinal lumen. In addition, we examined the contribution of these mediators to intestinal dysmotility. C57/BL6 male mice were injected intraperitoneally with LPS. Serum, intestinal tissue, and intestinal luminal contents were harvested for cytokine analysis. For intestinal motility studies, a transit assay was performed after oral gavage of chemokines. Caco-2 cells grown on Transwell culture inserts were used to examine the role of the intestinal epithelium in chemokine secretion. Monocyte chemoattractant protein 1 (MCP-1/CCL2) and macrophage-derived chemokine (MDC/CCL22) were secreted into the lumen of multiple segments of the gut during endotoxemia in mice. In vitro work showed that the intestinal epithelium participates in monocyte chemoattractant protein 1 and MDC secretion and expresses the CCR2 and CCR4 receptors for these chemokines. Intestinal transit studies show that oral gavage of MDC results in impaired gut motility. This study demonstrates that the intestinal lumen is an active compartment in the gut's inflammatory response. Proinflammatory chemokines are secreted into the intestinal lumen during endotoxemia. These intraluminal chemokines contribute to intestinal dysmotility, complicating intestinal failure.

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Intestinal Mucus Layer Preservation in Female Rats Attenuates Gut Injury After Trauma-Hemorrhagic Shock

Abstract: Background-We tested the hypothesis that females are more resistant to trauma-hemorrhagic shock (T/HS)-induced gut injury than males, and this is related to better preservation of their intestinal mucus layer, which is influenced in turn by the estrus cycle stage at the time of injury.

Cited by 14 publications

References 42 publications

Loss of the Intestinal Mucus Layer in the Normal Rat Causes Gut Injury But Not Toxic Mesenteric Lymph nor Lung Injury

Loss of the Intestinal Mucus Layer in the Normal Rat Causes Gut Injury But Not Toxic Mesenteric Lymph nor Lung Injury

Redefining the gut as the motor of critical illness

Proinflammatory Chemokines in the Intestinal Lumen Contribute to Intestinal Dysfunction During Endotoxemia

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