Trauma and hemorrhagic shock activate molecular association of 5-lipoxygenase and 5-lipoxygenase–Activating protein in lung tissue

Nunns, Geoffrey R.; Stringham, James C.; Gamboni, Fabia; Moore, Ernest E.; Fragoso, Miguel; Stettler, Gregory R.; Silliman, Christopher C.; Banerjee, Anirban

doi:10.1016/j.jss.2018.03.023

Cited by 8 publications

(6 citation statements)

References 37 publications

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“…5-LO activation is considered to be an important regulator of the pathogenesis of multi-cellular organisms. [ 40 ] Monteiro et al 's study [ 41 ] have shown that IRI and even sepsis patients treated with 5-LO inhibitors are significantly protected from lung inflammation and injury. It can be seen that 5-LO products play an important role in lung injury caused by sepsis, and also suggest that the application of 5-LO inhibitors may have clinical therapeutic value.…”

Section: Bio-mechanismmentioning

confidence: 99%

Gut-lymph-lung pathway mediates sepsis-induced acute lung injury

Jin

Chen

et al. 2020

Chinese Medical Journal

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This review attempts to unveil the possible mechanisms underlying how gut lymph affects lung and further gives rise to acute respiratory distress syndrome, as well as potential interventional targets under the condition of ischemia-reperfusion injury. We searched electronic databases including PubMed, MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, Web of Science, and Embase to identify relevant literatures published up to December 2019. We enrolled the literatures including the Mesh Terms of “gut lymph or intestinal lymph and acute lung injury or acute respiratory distress syndrome.” Gut is considered to be the origin of systemic inflammation and the engine of multiple organ distress syndrome in the field of critical care medicine, whereas gut lymph plays a pivotal role in initiation of ischemia-reperfusion injury-induced acute respiratory distress syndrome. In fact, in the having been established pathologic model of sepsis leading to multiple organ dysfunction named by Gut Lymph theory, a variety of literatures showed the position and role of changes in gut lymph components in the initiation of systemic inflammatory response, which allows us to screen out potential intervention targets to pave the way for future clinic and basic research.

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Section: Bio-mechanismmentioning

confidence: 99%

Gut-lymph-lung pathway mediates sepsis-induced acute lung injury

Jin

Chen

et al. 2020

Chinese Medical Journal

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“…A reduction in neuronal 5-Lox following microglia ablation could therefore also be a sign for lesser need of anti-inflammatory stimuli due to a lower numbers of proinflammatory signals from microglia. However, the FLAP is widely expressed in peripheral organs, in particular associated with infiltrating leukocytes, such as in lung [62] and muscle tissue [63]. In the brain, we observed FLAP exclusively expressed in all microglia cells.…”

Section: Discussionmentioning

confidence: 59%

“…FLAP is widely expressed in peripheral organs, in particular associated with infiltrating leukocytes, such as in lung [ 62 ] and muscle tissue [ 63 ]. In the brain, we observed FLAP exclusively expressed in all microglia cells.…”

Section: Discussionmentioning

confidence: 99%

Microglia depletion diminishes key elements of the leukotriene pathway in the brain of Alzheimer’s Disease mice

Michael

Unger

Poupardin

et al. 2020

acta neuropathol commun

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Leukotrienes (LTs) contribute to the neuropathology of chronic neurodegenerative disorders including Alzheimer's Disease (AD), where they mediate neuroinflammation and neuronal cell-death. In consequence, blocking the action of Leukotrienes (LTs) ameliorates pathologies and improves cognitive function in animal models of neurodegeneration. Surprisingly, the source of Leukotrienes (LTs) in the brain is largely unknown. Here, we identified the Leukotriene (LT) synthesis rate-limiting enzyme 5-Lipoxygenase (5-Lox) primarily in neurons and to a lesser extent in a subpopulation of microglia in human Alzheimer´s Disease (AD) hippocampus brain sections and in brains of APP Swedish PS1 dE9 (APP-PS1) mice, a transgenic model for Alzheimer´s Disease (AD) pathology. The 5-Lipoxygenase (5-Lox) activating protein (FLAP), which anchors 5-Lipoxygenase (5-Lox) to the membrane and mediates the contact to the substrate arachidonic acid, was confined exclusively to microglia with the entire microglia population expressing 5-Lipoxygenase activating protein (FLAP). To define the contribution of microglia in the Leukotriene (LT) biosynthesis pathway, we ablated microglia using the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 in wildtype (WT) and APP-PS1 mice. Microglia ablation not only diminished the expression of FLAP and of the Leukotriene (LT) receptor Cysteinylleukotriene receptor 1 (CysLTR1), as expected based on their microglia cell type-specific expression, but also drastically reduced 5-Lipoxygenase (5-Lox) mRNA expression in the brain and its protein expression in neurons, in particular in wildtype (WT) mice. In conclusion i) microglia are key in Leukotriene (LT) biosynthesis, and ii) they regulate neuronal 5-Lipoxygenase (5-Lox) expression implying a yet unknown signaling mechanism between neurons and microglia.

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“…ALOX5 is a rate-limiting enzyme in leukotriene synthesis and associated with leukotriene-induced inflammation and post-traumatic lung injury, therefore, ALOX5 can accelerate the development of pulmonary dysfunction. 24 ALOX5 plays a crucial role in mediating inflammatory response to maintain homeostasis, but certain allele variants of ALOX5 may increase the risk of atherosclerosis and coronary heart disease. 25 Through RNA-seq, this study found that ALOX5 have high expression in sepsis group compared to normal group.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Panax Ginseng on Treating Sepsis by RNA-Seq Technology

Wang

Shen

et al. 2022

IDR

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Purpose To explore the potential active targets and mechanisms of Panax Ginseng in the treatment of sepsis using network pharmacology and RNA-seq technology. Patients and Methods Patients with sepsis and healthy volunteers were collected according to SEPSIS 3.0, and their peripheral blood was used for RNA-seq analysis. The active ingredients and targets of Panax Ginseng were obtained using the TCMSP database, PPI and GO analysis were performed for disease-drug intersection targets. Then, we used Meta-analysis to screen core genes. Finally, single-cell RNA-seq was used to perform cell localization analysis on core genes. Results RNA-seq analysis collected 4521 sepsis-related genes, TCMSP database obtained 86 Panax Ginseng active ingredients and their 294 active targets. PPI and GO analysis showed intersection targets were closely linked, and mainly involved in cellular response to chemical stress, response to drug and molecule of bacterial origin, etc. Then, core targets, IL1B, ALOX5, BCL2 and IL4R, were sorted by Meta-analysis, and all four genes have high expression in the sepsis survivor group compared to the sepsis non-survivor group; single-cell RNA-seq revealed that IL1B was mainly localized in macrophages, ALOX5 was mainly localized in macrophages and B cells, BCL2 was mainly localized in natural killer cells, T cells and B cells, IL4R was widely distributed in immune cells. Finally, according to the correspondence between the active ingredients and targets of Panax Ginseng in TCMSP database, we found that Ginsenoside rh2 regulates the expression of IL1B, Ginsenoside rf regulates the expression of IL1B and IL4R, Kaempferol regulates the expression of ALOX5 and BCL2, and β-sitosterol regulates the expression of BCL2. Conclusion Ginsenoside rh2, Ginsenoside rf, Kaempferol and β-sitosterol may produce anti-sepsis effects by regulating the expression of IL1B, ALOX5, BCL2 and IL4R, thus improving the survival rate of sepsis patients.

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Trauma and hemorrhagic shock activate molecular association of 5-lipoxygenase and 5-lipoxygenase–Activating protein in lung tissue

Abstract: These results suggest that the association of ALOX5/ALOX5AP contributes to leukotriene-induced inflammation and predisposes the T/HS animal to lung injury.

Cited by 8 publications

References 37 publications

Gut-lymph-lung pathway mediates sepsis-induced acute lung injury

Gut-lymph-lung pathway mediates sepsis-induced acute lung injury

Microglia depletion diminishes key elements of the leukotriene pathway in the brain of Alzheimer’s Disease mice

Mechanisms of Panax Ginseng on Treating Sepsis by RNA-Seq Technology

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