Posthemorrhagic Shock Mesenteric Lymph Primes Circulating Neutrophils and Provokes Lung Injury

Zallen, Garret; Moore, Ernest E.; Johnson, Jeffrey L.; Tamura, Douglas Y.; Ciesla, David J.; Silliman, Christopher C.

doi:10.1006/jsre.1999.5569

Cited by 102 publications

(57 citation statements)

References 31 publications

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“…The mechanisms of gut reperfusion-induced lung injury, while not completely elucidated, center on 1) infiltration and/or activation of lung neutrophils by circulating soluble factors (i.e., cytokines) induced by damaged cells/tissues (9, 16) and 2) infiltration and/or activation of lung neutrophils by factors derived from the mesenteric lymph (7,25,38). However, the effects of kidney IRI on subsequent lung dysfunction have not been studied extensively, and clearly, the potential molecular mechanisms involved remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy

Hassoun

Grigoryev²,

Lie

et al. 2007

American Journal of Physiology-Renal Physiology

189

168

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Hassoun HT, Grigoryev DN, Lie ML, Liu M, Cheadle C, Tuder RM, Rabb H. Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol 293: F30-F40, 2007. First published February 27, 2007 doi:10.1152/ajprenal.00023.2007.-Acute kidney injury (AKI) is associated with significant mortality, which increases further when combined with acute lung injury. Experiments in rodents have shown that kidney ischemia-reperfusion injury (IRI) facilitates lung injury and inflammation. To identify potential ischemia-specific lung molecular pathways involved, we conducted global gene expression profiling of lung 6 or 36 h following 1) bilateral kidney IRI, 2) bilateral nephrectomy (BNx), and 3) sham laparotomy in C57BL/6J mice. Bronchoalveolar lavage fluid analysis revealed increased total protein, and lung histology revealed increased cellular inflammation following IRI, but not BNx, compared with sham controls. Total RNA from whole lung was isolated and hybridized to 430MOEA (22,626 genes) GeneChips (n ϭ 3/group), which were analyzed by robust multichip average and significance analysis of microarrays and linked to gene ontology (GO) terms using MAPPFinder. The microarray power analysis predicted that the false discovery rate (q Ͻ 1%) and Ն50%-fold change compared with sham would represent significant changes in gene expression. Analysis identified 266 and 455 ischemia-specific, AKI-associated lung genes with increased expression and 615 and 204 with decreased expression at 6 and 36 h, respectively, compared with sham controls. Real-time PCR analysis validated select array changes in lung serum amyloid A3 and endothelin-1. GO analysis revealed significant activation (Z Ͼ 1.95) of several proinflammatory and proapoptotic biological processes. Ischemic AKI induces functional and transcriptional changes in the lung distinct from those induced by uremia alone. Further investigation using this lung molecular signature induced by kidney IRI will provide mechanistic insights and new therapies for critically ill patients with AKI.ischemia-reperfusion; lung injury; microarray ISCHEMIC ACUTE KIDNEY INJURY (AKI) occurs in various clinical settings including shock, sepsis, transplantation, and vascular surgery. Despite advances in renal replacement therapy, the mortality of patients with AKI has remained high over the past few decades, and renal insufficiency continues to be a sensitive marker for a poor outcome in critically ill patients (2, 22). Epidemiological studies have identified an association between AKI and dysfunction of extrarenal organs (4). Given the persistent AKI-associated poor clinical outcomes, there is a need to study the systemic and remote organ effects that occur in the context of AKI.Acute lung injury (ALI) is a significant cause of respiratory failure in the intensive care unit and carries a substantial mortality of 30 -40% (8). When combined with AKI, mortality approaches 80% (26). The clinical presentation of AKI-associate...

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Section: Discussionmentioning

confidence: 99%

Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy

Hassoun

Grigoryev²,

Lie

et al. 2007

American Journal of Physiology-Renal Physiology

189

168

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“…Such interaction may also have occurred in the present study. In addition, it has been proposed that PMN activation (''priming''), followed by their recruitment in various organs, notably the lung, was triggered by factors contained in mesenteric lymph (31)(32)(33), suggesting a critical link between gut dysfunction, PMN activation, and distant organ injury in HS. The suppression of lung PMN recruitment in PARP Ϫ͞Ϫ mice is consistent with this hypothesis, in view of the marked protection against gut barrier failure in these animals.…”

Section: Role Of Parp In the Multiple Organ Damage Associated With Hsmentioning

confidence: 99%

Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase

Liaudet

Soriano

Szabó

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

183

117

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Hemorrhagic shock (HS) and resuscitation leads to widespread production of oxidant species. Activation of the enzyme poly(ADPribose) polymerase (PARP) has been shown to contribute to cell necrosis and organ failure in various disease conditions associated with oxidative stress. We tested the hypothesis whether PARP activation plays a role in the multiple organ dysfunction complicating HS and resuscitation in a murine model of HS and resuscitation by using mice genetically deficient in PARP (PARP ؊͞؊ ) and their wild-type littermates (PARP ؉͞؉ ). Animals were bled to a mean blood pressure of 45 mmHg (1 mmHg ‫؍‬ 133 Pa) and resuscitated after 45 min with isotonic saline (2؋ volume of shed blood). There was a massive activation of PARP, detected by poly(ADP-ribose) immunohistochemistry, which localized to the areas of the most severe intestinal injury, i.e., the necrotic epithelial cells at the tip of the intestinal villi, and colocalized with tyrosine nitration, an index of peroxynitrite generation. Intestinal PARP activation resulted in gut hyperpermeability, which developed in PARP ؉͞؉ but not PARP ؊͞؊ mice. PARP ؊͞؊ mice were also protected from the rapid decrease in blood pressure after resuscitation and showed an increased survival time, as well as reduced lung neutrophil sequestration. The beneficial effects of PARP suppression were not related to a modulation of the NO pathway nor to a modulation of signaling through IL-6, which similarly increased in both PARP ؉͞؉ and PARP ؊͞؊ mice exposed to HS. We propose that PARP activation and associated cell injury (necrosis) plays a crucial role in the intestinal injury, cardiovascular failure, and multiple organ damage associated with resuscitated HS.gut ͉ knockout H emorrhagic shock (HS) and resuscitation trigger the expression of a cascade of inflammatory mediators, resulting in tissue damage, multiple organ dysfunction, and eventually death. Regional hypoxia associated with hemorrhage and oxidative stress during resuscitation contribute to the development of this systemic inflammatory response (1). In recent years, evidence has accumulated that an important mechanism of tissue injury during oxidative stress was the activation of PARP [also termed poly(ADP-ribose) (PAR) synthetase or PARS], an enzyme abundantly present in the nucleus of eukaryotic cells (2). Activation of PARP is triggered by oxidant-mediated DNA single-strand breaks and initiates an energy-consuming futile intracellular cycle, leading to the rapid depletion of the cellular stores of NAD ϩ (the substrate of PARP) and ATP, resulting in cell dysfunction and necrotic-type cell death (3, 4). DNA single-strand breakage, PARP activation, and cell death have been demonstrated in vitro in cells exposed to various oxygencentered free radicals (2), as well as to peroxynitrite, a reactive nitrogen species formed from the rapid reaction of NO with superoxide radical (5). In vivo, PARP activation has also been convincingly shown to act as a common effector of oxidantdependant damage in various pathophysiologi...

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“…A factor (or factors) in the PSML provokes acute lung injury following hemorrhagic shock, and in the absence of PSML due to ligation of the mesenteric duct, acute lung injury does not occur. 6,7 2. The inflammatory mediator must be isolated from a diseased organism and maintain activity in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 This is supported by the fact that lymphatic diversion prior to trauma/hemorrhagic shock (T/HS) prevents remote organ injury. 6,7 Tissue injury and hypoperfusion unleash a number of products which appear in the lymph: cytokines, 8 inflammatory lipids, coagulation factors, 9 and cellular breakdown products. 10 The lymphatic system collects the extravasated fluid and cellular breakdown products, proteins, and lipids from the interstitial space and returns them to the blood circulation via the subclavian vein.…”

Section: Introductionmentioning

confidence: 99%

Cross-transfusion of Postshock Mesenteric Lymph Provokes Acute Lung Injury

Wohlauer

Fragoso

Harr

et al. 2011

Journal of Surgical Research

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Objective-Substantial investigation has implicated mesenteric lymph as the mechanistic link between gut ischemia/reperfusion (I/R) and distant organ injury. Specifically, lymph diversion prevents acute lung injury (ALI) in vitro and bioactive lipids and proteins isolated from postshock mesenteric lymph (PSML), maintain bioactivity in vitro. However, Koch's postulates remain to be satisfied via direct cross-transfusion into a naïve animal. We therefore hypothesized that real time cross-transfusion of postshock mesenteric lymph provokes acute lung injury.Methods-One set of Sprague-Dawley rats (lymph donors) was anesthetized, with the mesenteric lymph ducts cannulated and exteriorized to drain freely into a siliconized plastic cup; concurrently, a second group of rats (lymph recipients) was anesthetized, with a cannula inserted into the animal's right internal jugular vein. Blood was removed from the donor rats to induce hemorrhagic shock (MAP of 35 mmHg × 45 minutes). The recipient rats were positioned 10 cm below the plastic cup which emptied into the jugular vein cannula. Thus, mesenteric lymph from the shocked donor rat was delivered to the recipient rat at the rate generated during shock and the subsequent 3 hours of resuscitation. Conclusion-Cross-transfusion of PSML into a naïve animal leads to PMN accumulation and provokes ALI. These data provide evidence that postshock agents released into mesenteric lymph are capable of provoking distant organ injury. Results-Neutrophil

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Posthemorrhagic Shock Mesenteric Lymph Primes Circulating Neutrophils and Provokes Lung Injury

Cited by 102 publications

References 31 publications

Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy

Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy

Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase

Cross-transfusion of Postshock Mesenteric Lymph Provokes Acute Lung Injury

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