Mitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injury

Dolinay, Tamás; Wu, Wei; Kaminski, Naftali; Ifedigbo, Emeka; Kaynar, A. Murat; Szilasi, Mária; Watkins, Simon C.; Ryter, Stefan W.; Hoetzel, Alexander; Choi, Augustine M.K.

doi:10.1371/journal.pone.0001601

Cited by 74 publications

(59 citation statements)

References 54 publications

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“…Use of apocynin blocks MAPK signal transduction and attenuates apoptotic cell death by blocking intrinsic and extrinsic signaling pathways during ischemia and reperfusion injury [30][31][32][33][34][35][36][37]. Several studies [21,38,39] have shown organ protective effects of apocynin by inhibition of cyclooxygenase metabolites in a variety of animal models.…”

Section: Discussionmentioning

confidence: 99%

Apocynin attenuates ventilator-induced lung injury in an isolated and perfused rat lung model

et al. 2011

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Rationale-Apocynin suppresses the generation of reactive oxygen species (ROS) that are implicated in ventilator-induced lung injury (VILI). We thus hypothesized that apocynin attenuates VILI.Methods-VILI was induced by mechanical ventilation with tidal volume (V t ) of 15 ml/kg in isolated and perfused rat lung. Apocynin was administered in the perfusate at onset of mechanical ventilation. A group ventilated with low V t of 5 ml/kg served as control. Hemodynamics, lung Results-There was an increase in lung permeability and lung weight gain after mechanical ventilation with high V t , compared with low V t . Levels of inflammatory cytokines including interleukin-1b (IL-1b), tumor necrosis factor-alpha (TNF-a), and macrophage inflammatory protein-2 (MIP-2) increased in lung lavage fluids; concentrations of carbonyl, thiobarbituric acid reactive substances, and H 2 O 2 were higher in perfusates and lung lavage fluids, and expression of myeloperoxidase, JNK, p38, and caspase-3 in lung tissue was greater in the high-Vt than in the low-Vt group. Administration of apocynin attenuated these inflammatory responses and lung permeability associated with decreased activation of nuclear factor-κB.Conclusions-VILI is associated with inflammatory responses including generation of ROS, cytokines, and activation of mitogen-activated protein kinase cascades. Administration of apocynin at onset of mechanical ventilation attenuates inflammatory responses and VILI in the isolated, perfused rat lung model.

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Section: Discussionmentioning

confidence: 99%

Apocynin attenuates ventilator-induced lung injury in an isolated and perfused rat lung model

et al. 2011

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“…novel target molecules potentially modulating VILI (24,25). We first performed gene expression profiling analysis of 10,000 mouse genes in an ex vivo model of experimental VILI using isolated, blood-free, perfused BALB/c mouse lungs subjected to high negative-pressure ventilation (225 cm H 2 O) versus low-pressure ventilation (210 cm H 2 O) (24).…”

Section: Vili Increases Inflammasome Gene Expressionmentioning

confidence: 99%

“…In a retrospective analysis of this study, we found significant changes in inflammasome-related gene expression, including interleukin1a (Il1a), caspase-activator domain-10 (Card10), and IL-1 receptor-1 and -2 (Il1r1 and 2) ( Table 1). Furthermore, members of the inflammasome complex family were significantly regulated in a microarray study of an in vivo model of VILI, using C57Bl/6 mice subjected to MV (10 ml/kg tidal volume for 8 h) (25). We identified caspase-activator domain-10, and -15, (Card10 and 15), IL-18 receptor-1 (Il18r1), Il1r2, and IL-1b (Il1b) as genes with significant expression change after MV (Table 2).…”

Section: Vili Increases Inflammasome Gene Expressionmentioning

confidence: 99%

Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

Dolinay

Kim

Howrylak

et al. 2012

Am J Respir Crit Care Med

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Rationale: Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation. Objectives: We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS. Methods: We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid. Measurements and Main Results: In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18-neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality. Conclusions: The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.

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“…Remarkably, several MAPKs, including p38 MAPK, may play a functional role in the initiation and propagation of the ventilator-induced lung injury (VILI) [141]. Mechanical ventilation at a moderate tidal volume causes a significant and time-dependent inflammatory response, reflected both by the infiltration of macrophages and neutrophils into the airways and by an increased production of cytokines and chemokines (i.e., IL-1b, MIP-1b, and MCP-1) [142,143].…”

Section: Co Signalingmentioning

confidence: 99%

CO metabolism, sensing, and signaling

et al. 2011

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Abstract.CO is a colorless and odorless gas produced by the incomplete combustion of hydrocarbons, both of natural and anthropogenic origin. Several microorganisms, including aerobic and anaerobic bacteria and anaerobic archaea, use exogenous CO as a source of carbon and energy for growth. On the other hand, eukaryotic organisms use endogenous CO, produced during heme degradation, as a neurotransmitter and as a signal molecule. CO sensors act as signal transducers by coupling a ''regulatory'' heme-binding domain to a ''functional'' signal transmitter. Although high CO concentrations inhibit generally heme-protein actions, low CO levels can influence several signaling pathways, including those regulated by soluble guanylate cyclase and/or mitogenactivated protein kinases. This review summarizes recent insights into CO metabolism, sensing, and signaling.

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Mitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injury

Cited by 74 publications

References 54 publications

Apocynin attenuates ventilator-induced lung injury in an isolated and perfused rat lung model

Apocynin attenuates ventilator-induced lung injury in an isolated and perfused rat lung model

Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

CO metabolism, sensing, and signaling

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