Claude H. Organ, Jr. Memorial Lecture: Splanchnic hypoperfusion provokes acute lung injury via a 5-lipoxygenase–dependent mechanism

Moore, Ernest E.

doi:10.1016/j.amjsurg.2010.05.010

Cited by 29 publications

(20 citation statements)

References 122 publications

(96 reference statements)

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“…Unregulated calcium influx, oxidative stress and cell swelling associated with ischemia/hypoxia activate PLA 2 , which is particularly highly concentrated in the gut [15], [16]. Moore and his collaborators have already pointed out that PLA 2 is extremely active following mesenteric artery occlusion and plays a pivotal role in the pathogenesis of intestinal ischemia-reperfusion injury [17], [18], [19].…”

Section: Discussionmentioning

confidence: 99%

Polyunsaturated Fatty Acid Metabolism Signature in Ischemia Differs from Reperfusion in Mouse Intestine

et al. 2013

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Polyunsaturated fatty acid (PUFA) metabolites are bioactive autoacoids that play an important role in the pathogenesis of a vast number of pathologies, including gut diseases. The induction and the resolution of inflammation depend on PUFA metabolic pathways that are favored. Therefore, understanding the profile of n-6 (eicosanoids)/n-3 (docosanoids) PUFA-derived metabolites appear to be as important as gene or protein array approaches, to uncover the molecules potentially implicated in inflammatory diseases. Using high sensitivity liquid chromatography tandem mass spectrometry, we characterized the tissue profile of PUFA metabolites in an experimental model of murine intestinal ischemia reperfusion. We identified temporal and quantitative differences in PUFA metabolite production, which correlated with inflammatory damage. Analysis revealed that early ischemia induces both pro-inflammatory and anti-inflammatory eicosanoid production. Primarily, LOX- (5/15/12/8-HETE, LTB4, LxA4) and CYP- (5, 6-EET) metabolites were produced upon ischemia, but also PGE3, and PDx. This suggests that different lipids simultaneously play a role in the induction and counterbalance of ischemic inflammatory response from its onset. COX-derived metabolites were more present from 2 to 5 hours after reperfusion, fitting with the concomitant inflammatory peaks. All metabolites were decreased 48 hours post-reperfusion except for to the pro-resolving RvE precursor 18-HEPE and the PPAR−γαμμα agonist, 15d-PGJ2. Data obtained through the pharmacological blockade of transient receptor potential vanilloid-4, which can be activated by 5, 6-EET, revealed that the endogenous activation of this receptor modulates post-ischemic intestinal inflammation. Altogether, these results demonstrate that different lipid pathways are involved in intestinal ischemia-reperfusion processes. Some metabolites, which expression is severely changed upon intestinal ischemia-reperfusion could provide novel targets and may facilitate the development of new pharmacological treatments.

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Section: Discussionmentioning

confidence: 99%

Polyunsaturated Fatty Acid Metabolism Signature in Ischemia Differs from Reperfusion in Mouse Intestine

et al. 2013

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“…The Alox5 encodes arachidonate 5-lipoxygenase, an enzyme that converts arachidonate (or eiosatetraenoic acid) to leukotriene A4, which can be converted to leukotrienes B4, C4, and D4. The resulting leukotrienes are elevated in ALI (45). In gene-targeted deficient mice or in animals treated with ALOX5 inhibitors, neutrophil infiltration and lavage protein are decreased after various forms of lung injury (89)(90)(91)(92)(93)(94).…”

Section: Discussionmentioning

confidence: 98%

Functional Genomic Assessment of Phosgene-Induced Acute Lung Injury in Mice

Leikauf

Concel

Bein

et al. 2013

Am J Respir Cell Mol Biol

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In this study, a genetically diverse panel of 43 mouse strains was exposed to phosgene and genome-wide association mapping performed using a high-density single nucleotide polymorphism (SNP) assembly. Transcriptomic analysis was also used to improve the genetic resolution in the identification of genetic determinants of phosgene-induced acute lung injury (ALI). We prioritized the identified genes based on whether the encoded protein was previously associated with lung injury or contained a nonsynonymous SNP within a functional domain. Candidates were selected that contained a promoter SNP that could alter a putative transcription factor binding site and had variable expression by transcriptomic analyses. The latter two criteria also required that >10% of mice carried the minor allele and that this allele could account for >10% of the phenotypic difference noted between the strains at the phenotypic extremes. This integrative, functional approach revealed 14 candidate genes that included Atp1a1, Alox5, Galnt11, Hrh1, Mbd4, Phactr2, Plxnd1, Ptprt, Reln, and Zfand4, which had significant SNP associations, and Itga9, Man1a2, Mapk14, and Vwf, which had suggestive SNP associations. Of the genes with significant SNP associations, Atp1a1, Alox5, Plxnd1, Ptprt, and Zfand4 could be associated with ALI in several ways. Using a competitive electrophoretic mobility shift analysis, Atp1a1 promoter (rs215053185) oligonucleotide containing the minor G allele formed a major distinct faster-migrating complex. In addition, a gene with a suggestive SNP association, Itga9, is linked to transforming growth factor b1 signaling, which previously has been associated with the susceptibility to ALI in mice.

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“…Arachidonic acid is abundant in PSML, and leukotrienes are increased in the lungs of animals following T/HS, making these lipids the current focus of intensive investigation in our lab. 37 Postshock mesenteric lymph may be toxic through a variety of mechanisms, including endothelial inflammation, 6,26 neutrophil priming, 38,39,40 enhanced apoptosis, 41 pulmonary epithelial inflammation, 42 and RBC hemolysis. 43,32 …”

Section: Discussionmentioning

confidence: 99%

Cross-Transfusion of Postshock Mesenteric Lymph Provokes Acute Lung Injury

Wohlauer

Moore

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. Results Neutrophil (PMN) accumulation in the lungs was substantially elevated in the postshock lymph cross-transfusion group compared to both sham lymph cross-transfusion and instrumented control (MPO: 9.42±1.55 vs. 2.81±0.82 U/mg lung tissue in postshock vs. sham lymph cross-transfusion, n=6 in each group, p=0.02). Additionally, cross-transfusion of PSML induced oxidative stress in the lung (0.21±0.03 vs. 0.10±0.01 micromoles MDA per mg lung tissue in lymph cross-transfusion vs. instrumented control, n=6 in each group, p = 0.046). Furthermore, transfusion of PSML provoked lung injury (BAL protein 0.77±0.18 vs. 0.15±0.02 mg/ml protein in BALF, postshock vs. sham lymph cross-transfusion, n=6 in each group, p=0.004). 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.

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Claude H. Organ, Jr. Memorial Lecture: Splanchnic hypoperfusion provokes acute lung injury via a 5-lipoxygenase–dependent mechanism

Cited by 29 publications

References 122 publications

Polyunsaturated Fatty Acid Metabolism Signature in Ischemia Differs from Reperfusion in Mouse Intestine

Polyunsaturated Fatty Acid Metabolism Signature in Ischemia Differs from Reperfusion in Mouse Intestine

Functional Genomic Assessment of Phosgene-Induced Acute Lung Injury in Mice

Cross-Transfusion of Postshock Mesenteric Lymph Provokes Acute Lung Injury

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