Dissociation of Inflammatory Mediators and Function

Uematsu, Satoko; Engelberts, Doreen; Peltekova, Vanya; Otulakowski, Gail; Post, Martin; Kavanagh, Brian P.

doi:10.1097/ccm.0b013e318267606f

Cited by 11 publications

(6 citation statements)

References 32 publications

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“…above the definition threshold of ALI. Of note, we [ 8 , 51 ] and others [ 73 ] found a similar dissociation between significantly increased levels of inflammatory biomarkers in the lung and lacking effects on lung mechanics and gas exchange in mice after chest trauma [ 8 , 51 ] and poly-microbial sepsis [ 73 ]. Only few studies reported Horovitz-indices compatible with the definition of ALI (< 300 mmHg) in mechanically ventilated mice: animals were either ventilated with injurious tidal volumes (12–40 mL·kg -1 ) [ 74 – 78 ], or 24 hours after injection of endotoxin, i.e.…”

Section: Discussionsupporting

confidence: 56%

Blunt Chest Trauma in Mice after Cigarette Smoke-Exposure: Effects of Mechanical Ventilation with 100 % O2

Wagner

Gröger²,

McCook³

et al. 2015

PLoS ONE

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Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest trauma is due to the physical damage, the drop in alveolar PO2, and the consecutive hypoxemia and tissue hypoxia. Therefore, we tested the hypotheses that 1) CS exposure prior to blunt chest trauma causes more severe post-traumatic inflammation and thereby aggravates lung injury, and that 2) hyperoxia may attenuate this effect. Immediately after blast wave-induced blunt chest trauma, mice (n=32) with or without 3-4 weeks of CS exposure underwent 4 hours of pressure-controlled, thoraco-pulmonary compliance-titrated, lung-protective mechanical ventilation with air or 100 % O2. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1 (HO-1), activated caspase-3, and hypoxia-inducible factor 1-α (HIF-1α) expression, nuclear factor-κB (NF-κB) activation, nitrotyrosine formation, purinergic receptor 2X4 (P2XR4) and 2X7 (P2XR7) expression, and histological scoring. CS exposure prior to chest trauma lead to higher pulmonary compliance and lower PaO2 and Horovitz-index, associated with increased tissue IL-18 and blood MCP-1 concentrations, a 2-4-fold higher inflammatory cell infiltration, and more pronounced alveolar membrane thickening. This effect coincided with increased activated caspase-3, nitrotyrosine, P2XR4, and P2XR7 expression, NF-κB activation, and reduced HIF-1α expression. Hyperoxia did not further affect lung mechanics, gas exchange, pulmonary and systemic cytokine and chemokine concentrations, or histological scoring, except for some patchy alveolar edema in CS exposed mice. However, hyperoxia attenuated tissue HIF-1α, nitrotyrosine, P2XR7, and P2XR4 expression, while it increased HO-1 formation in CS exposed mice. Overall, CS exposure aggravated post-traumatic inflammation, nitrosative stress and thereby organ dysfunction and injury; short-term, lung-protective, hyperoxic mechanical ventilation have no major beneficial effect despite attenuation of nitrosative stress, possibly due to compensation of by regional alveolar hypoxia and/or consecutive hypoxemia, resulting in down-regulation of HIF-1α expression.

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Section: Discussionsupporting

confidence: 56%

Blunt Chest Trauma in Mice after Cigarette Smoke-Exposure: Effects of Mechanical Ventilation with 100 % O2

Wagner

Gröger²,

McCook³

et al. 2015

PLoS ONE

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“…Others have used lower VT ventilation after CLP and did not observe worsening of lung injury [ 9 ]. Uematsu et al [ 17 ] noted that high VT ventilation (40 ml/kg) after CLP increased mediator release but did not affect pulmonary function. Yehya et al [ 18 ] showed that high VT (30 ml/kg) accelerated lung injury secondary to previous CLP in rats but the endpoints of injury (lung compliance, pulmonary edema, oxygenation and computed tomography of micro-CT scans) reached the same pathophysiology as from CLP alone.…”

Section: Discussionmentioning

confidence: 99%

“…Ventilating rodents after polymicrobial sepsis due to cecal ligation and puncture (CLP) [ 13 – 15 ] has produced equivocal results regarding sensitization to VILI. Mechanical ventilation with injurious high VT (30–40 ml/kg) exacerbated 48 h of CLP-induced lung injury in rats [ 16 ]; shorter periods of CLP were not associated with subsequent exacerbation of VILI in mice [ 17 ] or rats [ 9 , 18 ] although such overall injury was accelerated in the latter. Lower VT (15–20 ml/kg) did not exacerbate CLP-induced ALI in intact rats [ 9 ] or isolated perfused rat lungs [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanical ventilation enhances extrapulmonary sepsis-induced lung injury: role of WISP1–αvβ5 integrin pathway in TLR4-mediated inflammation and injury

et al. 2018

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BackgroundHigh tidal volume ventilation of healthy lungs or exacerbation of existing acute lung injury (ALI) by more moderate mechanical ventilation (MTV) produces ventilator-induced lung injury. It is less clear whether extrapulmonary sepsis sensitizes the lung to MTV.MethodsWe used a two-hit model of cecal ligation and puncture (CLP) followed 12 h later by MTV (10 ml/kg; 6 h) to determine whether otherwise noninjurious MTV enhances CLP-induced ALI by contrasting wildtype and TLR4−/− mice with respect to: alveolar-capillary permeability, histopathology and intrapulmonary levels of WNT-inducible secreted protein 1 (WISP1) and integrin β5; plasma levels of cytokines and chemokines (TNF-α, IL-6, MIP-2, MCP-1) and intrapulmonary neutrophil infiltration; and other inflammatory signaling via intrapulmonary activation of JNK, p38 and ERK. A separate cohort of mice was pretreated with intratracheal neutralizing antibodies to WISP1, integrin β5 or IgG as control and the presented phenotyping repeated in a two-hit model; there were 10 mice per group in these first three experiments. Also, isolated peritoneal macrophages (PM) from wildtype and TLR4−/−, MyD88−/− and TRIF−/− mice were used to identify a WISP1–TLR4–integrin β5 pathway; and the requisite role of integrin β5 in WISP1-induced cytokine and chemokine production in LPS-primed PM was examined by siRNA treatment.ResultsMTV, that in itself did not cause ALI, exacerbated increases in alveolar-capillary permeability, histopathologic scoring and indices of pulmonary inflammation in mice that previously underwent CLP; the effects of this two-hit model were abrogated in TLR4−/− mice. Attendant with these findings was a significant increase in intrapulmonary WISP1 and integrin β5 in the two-hit model. Anti-WISP1 or anti-integrin β5 antibodies partially inhibited the two-hit phenotype. In PM, activation of TLR4 led to an increase in integrin β5 expression that was MyD88 and NF-κB dependent. Recombinant WISP1 increased LPS-induced cytokine release in PM that was inhibited by silencing either TLR4 or integrin β5.ConclusionsThese data show for the first time that otherwise noninjurious mechanical ventilation can exacerbate ALI due to extrapulmonary sepsis underscoring a potential interactive contribution of common events (sepsis and mechanical ventilation) in critical care, and that a WISP1–TLR4–integrin β5 pathway contributes to this phenomenon.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2237-0) contains supplementary material, which is available to authorized users.

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“…Low levels of TNF-α and IL-1β have been correlated with septic shock and increased risk of bacterial infections. [12][13][14][15] High levels of circulating IL-6 are commonly implicated in inflammatory diseases, tissue damage, uncontrolled activation of macrophage cells, and increased rate of infections. 12,13,16 These observations may provide insight to the fulminant action of Ab-acquired pneumonia in which the patient typically presents with bacteremia and septic shock leading to death.…”

Section: Cr3 Ismentioning

confidence: 99%

Alcohol impairs J774.16 macrophage-like cell antimicrobial functions inAcinetobacter baumanniiinfection

et al. 2013

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Acinetobacter baumannii (Ab) is a common cause of community-acquired pneumonia (caP) in chronic alcoholics in tropical and sub-tropical climates and associated with a >50% mortality rate. We demonstrated that exposure of J774.16 macrophage-like cells to physiological alcohol (etOh) concentrations decreased phagocytosis and killing of Ab. etOh-mediated macrophage phagocytosis dysfunction may be associated with reduced expression of GtPase-rhoa, a key regulator of the actin polymerization signaling cascade. etOh inhibited nitric oxide (NO) generation via inducible NO-synthase inactivation, which enhanced Ab survival within macrophages. additionally, etOh alters cytokine production resulting in a dysregulated immune response. this study is a proof of principle which establishes that etOh might exacerbate Ab infection and be an important factor enhancing caP in individuals at risk.

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Dissociation of Inflammatory Mediators and Function

Cited by 11 publications

References 32 publications

Blunt Chest Trauma in Mice after Cigarette Smoke-Exposure: Effects of Mechanical Ventilation with 100 % O2

Blunt Chest Trauma in Mice after Cigarette Smoke-Exposure: Effects of Mechanical Ventilation with 100 % O2

Mechanical ventilation enhances extrapulmonary sepsis-induced lung injury: role of WISP1–αvβ5 integrin pathway in TLR4-mediated inflammation and injury

Alcohol impairs J774.16 macrophage-like cell antimicrobial functions inAcinetobacter baumanniiinfection

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