Amiloride moderates increased gut permeability and diminishes mesenteric lymph-mediated priming of neutrophils in trauma/hemorrhagic shock

Fujiyoshi, Naohiko; Feketeova, Eleonora; Lu, Quan; Xu, Da-Zhong; Haskó, György; Deitch, Edwin A.

doi:10.1016/j.surg.2006.03.003

Cited by 21 publications

(12 citation statements)

References 36 publications

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“…The therapeutic implications of this work are that clinical strategies designed to limit gut injury and/or neutralize the biologic activity of T/HS lymph could limit the development or magnitude of ARDS and MODS. Although more work is necessary to test putative therapeutic strategies, we have found that certain resuscitative and pharmacologic strategies by limiting gut injury 43, 47, 48 or neutralizing T/HS lymph 49 protect against T/HS‐induced lung injury and MODS.…”

Section: Resultsmentioning

confidence: 99%

Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction

Deitch

2010

Annals of the New York Academy of Sciences

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167

143

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Major trauma, shock, sepsis, and other conditions can lead to the acute respiratory distress syndrome (ARDS), which may progress to the highly lethal multiple organ dysfunction syndrome (MODS). Although a number of therapeutic strategies have been initiated, their success has been limited largely due to an incomplete understanding of the biology of MODS. However, recent studies indicate that the intestinal lymphatics serve as the primary route for nonbacterial, tissue injurious gut-derived factors, which can induce acute ARDS and MODS. The gut lymph hypothesis of ARDS and MODS thus helps clarify several important issues. First, because the lung is the first organ exposed to mesenteric lymph and not the liver (i.e., mesenteric lymph enters the subclavian vein via the thoracic duct, which, in turn, empties directly into the heart and lungs), it would explain the clinical observation that the lung is generally the first organ to fail. Second, this hypothesis provides new pathophysiologic information, thereby providing a basis for novel therapies. Finally, by studying the composition of lymph, MODS-inducing factors can be isolated and identified.

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Section: Resultsmentioning

confidence: 99%

Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction

Deitch

2010

Annals of the New York Academy of Sciences

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167

143

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“…The assay of intestinal paracellular permeability was slightly modified from the previously described methods [11]–[13]. Briefly, a laparotomy was carried out under anesthesia before the animals were sacrificed at the end of experiment.…”

Section: Methodsmentioning

confidence: 99%

Myosin Light Chain Kinase Mediates Intestinal Barrier Disruption following Burn Injury

Chen

Wang

et al. 2012

PLoS ONE

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BackgroundSevere burn injury results in the loss of intestinal barrier function, however, the underlying mechanism remains unclear. Myosin light chain (MLC) phosphorylation mediated by MLC kinase (MLCK) is critical to the pathophysiological regulation of intestinal barrier function. We hypothesized that the MLCK-dependent MLC phosphorylation mediates the regulation of intestinal barrier function following burn injury, and that MLCK inhibition attenuates the burn-induced intestinal barrier disfunction.Methodology/Principal FindingsMale balb/c mice were assigned randomly to either sham burn (control) or 30% total body surface area (TBSA) full thickness burn without or with intraperitoneal injection of ML-9 (2 mg/kg), an MLCK inhibitor. In vivo intestinal permeability to fluorescein isothiocyanate (FITC)-dextran was measured. Intestinal mucosa injury was assessed histologically. Tight junction proteins ZO-1, occludin and claudin-1 was analyzed by immunofluorescent assay. Expression of MLCK and phosphorylated MLC in ileal mucosa was assessed by Western blot. Intestinal permeability was increased significantly after burn injury, which was accompanied by mucosa injury, tight junction protein alterations, and increase of both MLCK and MLC phosphorylation. Treatment with ML-9 attenuated the burn-caused increase of intestinal permeability, mucosa injury, tight junction protein alterations, and decreased MLC phosphorylation, but not MLCK expression.Conclusions/SignificanceThe MLCK-dependent MLC phosphorylation mediates intestinal epithelial barrier dysfunction after severe burn injury. It is suggested that MLCK-dependent MLC phosphorylation may be a critical target for the therapeutic treatment of intestinal epithelial barrier disruption after severe burn injury.

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“…[87] Administration of the sodium hydrogen exchange inhibitor amiloride has been demonstrated to ameliorate increased intestinal permeability in hemorrhagic shock and improves lung injury when combined with hypertonic saline resuscitation. [88, 89] Additionally, NHE inhibition in a colitis model has been shown to ameliorate disease activity and decrease IL-8 activation. [86] NHE inhibition has been shown to improve cardiac contractility in ischemia reperfusion injury.…”

Section: Mechanotransductionmentioning

confidence: 99%

Resuscitation-Induced Intestinal Edema and Related Dysfunction: State of the Science

Shah¹,

Uray

Stewart

et al. 2011

Journal of Surgical Research

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High volume resuscitation and damage control surgical methods, while responsible for significantly decreasing morbidity and mortality from traumatic injuries, are associated with pathophysiological derangements that lead to subsequent end organ edema and dysfunction. Alterations in hydrostatic and oncotic pressures frequently result in intestinal edema and subsequent dysfunction. The purpose of this review is to examine the principles involved in the development of intestinal edema, current and historical models for the study of edema, effects of edema on intestinal function (particularly ileus), molecular mediators governing edema-induced dysfunction, potential role of mechanotransduction, and therapeutic effects of hypertonic saline. We review the current state of the science as it relates to resuscitation induced intestinal edema and resultant dysfunction.

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Amiloride moderates increased gut permeability and diminishes mesenteric lymph-mediated priming of neutrophils in trauma/hemorrhagic shock

Cited by 21 publications

References 36 publications

Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction

Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction

Myosin Light Chain Kinase Mediates Intestinal Barrier Disruption following Burn Injury

Resuscitation-Induced Intestinal Edema and Related Dysfunction: State of the Science

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