Endotoxemia Following Multiple Trauma

Charbonney, Emmanuel; Tsang, Jennifer Y.; Li, Yangmei; Klein, David J.; Duque, Patricia; Romaschin, Alexander D.; Marshall, John C.

doi:10.1097/ccm.0000000000001404

Cited by 35 publications

(21 citation statements)

References 31 publications

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“…Endotoxemia frequently results in cardiac dysfunction and has a significant impact on post-surgery outcomes [1, 24, 25]. Thus, understanding of the impact of endotoxemia on tissue inflammatory responses and organ function in aging subjects is helpful for improving clinical outcomes in the elderly undergoing major surgery.…”

Section: Discussionmentioning

confidence: 99%

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Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice

Huang

Zhai

et al. 2017

Oncotarget

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BackgroundAging augments endotoxemic cardiac dysfunction, but the mechanism remains unclear. Anti-aging protein Klotho has been found to modulate tissue inflammatory responses. We tested the hypothesis that a reduced Klotho level in aging heart plays a role in the augmented endotoxemic cardiac dysfunction.Materials and MethodsEndotoxin (0.5 mg/kg, iv) was injected to adults (4-6 months) and aging (18-20 months) C57BL/6 mice. Recombinant Klotho (10 μg/kg, iv) was administered to a group of aging mice after endotoxin injection. Cardiac function was analyzed using a microcatheter at 24 and 48 h after endotoxin administration. Myocardial levels of Klotho and heat shock protein 70 (HSP70) were determined by immunoblotting, and plasma and myocardial cytokines were analyzed using ELISA.ResultsMore severe cardiac dysfunction in aging mice were accompanied by greater cytokine levels in the plasma and myocardium. Klotho was detected in the myocardial tissue. Klotho levels were lower in aging hearts and were further reduced during endotoxemia. Myocardial HSP70 levels were correlated with Klotho levels. Recombinant Klotho increased myocardial HSP70, inhibited NF-κB activation, reduced cytokine levels, and improved cardiac function in aging endotoxemic mice. Delivery of HSP70 into cultured macrophages suppressed endotoxin-induced NF-κB activation.ConclusionsAging-related augmentation of inflammatory responses and cardiac dysfunction is associated with relative Klotho deficiency. Post-treatment with recombinant Klotho suppresses the inflammatory responses and improves cardiac function in aging endotoxemic mice. Klotho modulates HSP70 levels and HSP70 appears to be involved in the anti-inflammatory mechanism of Klotho. Klotho may have therapeutic potential in amelioration of aging-related endotoxemic cardiac dysfunction.

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Section: Discussionmentioning

confidence: 99%

“…Trauma and stress associated with major surgery can result in endotoxemia and the systemic inflammatory response by eliciting gut bacteria translocation [1]. It is well known that endotoxemia causes cardiovascular dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice

Huang

Zhai

et al. 2017

Oncotarget

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Section: Posttraumatic Immune Response and Breakdown Of Protective Cementioning

confidence: 99%

“…Some groups have found no evidence of endotoxemia early after multiple trauma, either in the portal vein or systemically 164 , whereas others have detected endotoxemia systemically 165,166 . These differences are still unresolved and probably reflect differences in technical approaches 164–166 . In principle, either bacterial pathogens and related PAMPs can directly penetrate the damaged intestinal tissue to induce local inflammation and cause further damage by activating leukocytes, or they can be translocated to the intestinal lymph nodes via dendritic cells and intestinal macrophages.…”

Section: Posttraumatic Immune Response and Breakdown Of Protective Cementioning

confidence: 99%

Innate immune responses to trauma

2018

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Trauma can affect any individual at any location and at any time over a lifespan. The disruption of macrobarriers and microbarriers induces instant activation of innate immunity. The subsequent complex response, designed to limit further damage and induce healing, also represents a major driver of complications and fatal outcome after injury. This Review aims to provide basic concepts about the posttraumatic response and is focused on the interactive events of innate immunity at frequent sites of injury: the endothelium at large, and sites within the lungs, inside and outside the brain and at the gut barrier.

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“…Major surgery and trauma can cause endotoxemia [1]. Excessive production of pro-inflammatory mediators caused by bacterial lipopolysaccharide (LPS) frequently leads to cardiac dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-37 suppresses the inflammatory response to protect cardiac function in old endotoxemic mice

Zhai

et al. 2017

Cytokine

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Myocardial inflammatory responses to endotoxemia are enhanced in old mice, which results in worse cardiac dysfunction. Anti-inflammatory cytokine interleukin (IL)-37 has a broad effect on innate immunoresponses. We hypothesized that IL-37 suppresses myocardial inflammatory responses to protect cardiac function during endotoxemia in old mice. Old (20–24 month) wild-type (WT), and IL-37 transgenic (IL-37tg) mice were treated with lipopolysaccharide (LPS, 0.5 mg/kg, iv) or normal saline (0.1 ml/mouse, iv). Six hours later, left ventricle (LV) function was assessed using a pressure-volume microcatheter. Levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in plasma and myocardial tissue, as well as mononuclear cell density in the myocardium, were examined. Cardiac microvascular endothelial cells isolated from WT and IL-37tg mice were treated with LPS (0.2 μg/ml) for 0.5–24 hours. Nuclear factor-kappa B (NF-κB) p65 phosphorylation was examined by immunoblotting, and MCP-1 levels in cell culture supernatant was determined using enzyme-linked immunosorbent assay. LV dysfunction in old WT endotoxemic mice was accompanied by up-regulated MCP-1, myocardial accumulation of mononuclear cells and production of TNF-α, IL-1β and IL-6. Expression of IL-37 suppressed myocardial inflammatory responses to endotoxemia in old mice, resulting in improved LV function. Treatment of old WT endotoxemic mice with recombinant IL-37 also improved LV function. In vitro experiments revealed that cardiac microvascular endothelial cells from IL-37tg mice had attenuated NF-κB activation and MCP-1 production following LPS stimulation. In conclusion, IL-37 is potent to suppress myocardial inflammation and protects against cardiac dysfunction during endotoxemia in old mice.

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Endotoxemia Following Multiple Trauma

Cited by 35 publications

References 31 publications

Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice

Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice

Innate immune responses to trauma

Interleukin-37 suppresses the inflammatory response to protect cardiac function in old endotoxemic mice

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