Update on Acute Lung Injury and Critical Care Medicine 2009

Matthay, Michael A.; Idell, Steven

doi:10.1164/rccm.201001-0074up

Cited by 17 publications

(12 citation statements)

References 75 publications

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“…Reduced uPA activity in parallel with substantive elevations in PAI-1 in both bronchoalveolar lavage and blood were observed in acute respiratory diseases (4,30,31,62,81). The hallmark of these diseases is dysfunctional fluid homeostasis in the airways and alveolar compartment (29,40,54). Our novel findings demonstrate that uPA contributes to fluid resolution across the respiratory epithelial layer.…”

Section: Discussionmentioning

confidence: 56%

Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency

Chen

Zhao

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Epithelial sodium channels (ENaC) govern transepithelial salt and fluid homeostasis. ENaC contributes to polarization, apoptosis, epithelial-mesenchymal transformation, etc. Fibrinolytic proteases play a crucial role in virtually all of these processes and are elaborated by the airway epithelium. We hypothesized that urokinase-like plasminogen activator (uPA) regulates ENaC function in airway epithelial cells and tested that possibility in primary murine tracheal epithelial cells (MTE). Both basal and cAMP-activated Na(+) flow through ENaC were significantly reduced in monolayers of uPA-deficient cells. The reduction in ENaC activity was further confirmed in basolateral membrane-permeabilized cells. A decrease in the Na(+)-K(+)-ATPase activity in the basolateral membrane could contribute to the attenuation of ENaC function in intact monolayer cells. Dysfunctional fluid resolution was seen in uPA-disrupted cells. Administration of uPA and plasmin partially restores ENaC activity and fluid reabsorption by MTEs. ERK1/2, but not Akt, phosphorylation was observed in the cells and lungs of uPA-deficient mice. On the other hand, cleavage of γ ENaC is significantly depressed in the lungs of uPA knockout mice vs. those of wild-type controls. Expression of caspase 8, however, did not differ between wild-type and uPA(-/-) mice. In addition, uPA deficiency did not alter transepithelial resistance. Taken together, the mechanisms for the regulation of ENaC by uPA in MTEs include augmentation of Na(+)-K(+)-ATPase, proteolysis, and restriction of ERK1/2 phosphorylation. We demonstrate for the first time that ENaC may serve as a downstream signaling target by which uPA controls the biophysical profiles of airway fluid and epithelial function.

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Section: Discussionmentioning

confidence: 56%

Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency

Chen

Zhao

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Inflammation is a major contributor to the pathogenesis of various lung diseases including ALI (Matthay and Idell, 2010, Matthay and Zemans, 2011). Previous studies suggest that inhibition of the inflammasome complex suppresses the inflammatory response after thromboembolic stroke in mice, and neutralizing Abs against the inflammasome successfully inhibits inflammasome activation in multiple models of CNS injury (Abulafia, et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…The cytokine burst further leads to cytokine-dependent inflammation, apoptosis and injury at late stages of ALI. This can be particularly relevant in ALI, in which inflammatory processes increase from the early stages to the late stages of ALI ((Matthay and Idell, 2010, Matthay and Zemans, 2011)). The cytokine burst also causes epithelial permeability, epithelial barrier dysfunction, and cell death.…”

Section: Discussionmentioning

confidence: 99%

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NALP‐3 inflammasome silencing attenuates ceramide‐induced transepithelial permeability

Kolliputi

Galam

Parthasarathy

et al. 2012

Journal Cellular Physiology

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The hallmark of acute lung injury (ALI) is the influx of proinflammatory cytokines into lung tissue and alveolar permeability that ultimately leads to pulmonary edema. However, the mechanisms involved in inflammatory cytokine production and alveolar permeability are unclear. Recent studies suggest that excessive production of ceramide has clinical relevance as a mediator of pulmonary edema and ALI. Our earlier studies indicate that the activation of inflammasome promotes the processing and secretion of proinflammatory cytokines and causes alveolar permeability in ALI. However, the role of ceramide in inflammasome activation and the underlying mechanism in relation to alveolar permeability is not known. We hypothesized that ceramide activates the inflammasome and causes inflammatory cytokine production and alveolar epithelial permeability. To test this hypothesis, we analyzed the lung ceramide levels during hyperoxic acute lung injury in mice. The effect of ceramide on activation of inflammasome and production of inflammatory cytokine was assessed in primary mouse alveolar macrophages and THP-1 cells. Alveolar transepithelial permeability was determined in alveolar epithelial type-II cells (AT-II) and THP-1 co-cultures. Our results reveal that ceramide causes inflammasome activation, induction of caspase-1, IL-1β cleavage and release of proinflammatory cytokines. In addition, ceramide further induces alveolar epithelial permeability. Short hairpin RNA silencing of inflammasome components abrogated ceramide-induced secretion of proinflammatory cytokines in vitro. Inflammasome silencing abolishes ceramide induced alveolar epithelial permeability in AT-II. Collectively, our results demonstrate for the first time that ceramide-induced secretion of proinflammatory cytokines and alveolar epithelial permeability occurs though inflammasome activation.

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“…Acute lung injury (ALI) and its more severe counterpart, acute respiratory distress syndrome (ARDS) are among the most common conditions encountered in the intensive care unit (ICU) (1, 2). In patients with sepsis, hypoproteinemia is a predictor of the development of ALI and subsequent clinical outcomes, including elevated hydrostatic pressures, fluid retention and weight gain, which are associated with mortality (3, 4).…”

Section: Introductionmentioning

confidence: 99%

Metabolic effects of albumin therapy in acute lung injury measured by proton nuclear magnetic resonance spectroscopy of plasma: A pilot study*

Park

Jones

Ziegler

et al. 2011

Critical Care Medicine

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Objectives Improved means to monitor and guide interventions could be useful in the intensive care unit (ICU). Metabolomic analysis with bioinformatics is used to understand mechanisms and identify biomarkers of disease development and progression. This pilot study evaluated plasma 1H-NMR spectroscopy as a means to monitor metabolism following albumin administration in acute lung injury (ALI) patients. Design This study was conducted on plasma samples from 6 albumin-treated and 6 saline-treated patients from a larger double-blind trial. The albumin group was administered 25 g of 25% human albumin in 0.9% saline every 8 h for a total of 9 doses over 72 h. 0.9% saline was used as placebo. Blood samples were collected immediately prior to, 1 h after and 4 h after the albumin/saline administration for the 1st, 4th, and 7th doses (first dose of each day for 3 days). Samples were analyzed by 1H-NMR spectroscopy, and spectra were analyzed by principal component analysis and biostatistical methods. Measurements and Main Results After 1 day of albumin therapy, changes in small molecules, including amino acids and plasma lipids, were evident with Principal Component Analysis (PCA). Differences remained 3 days after the last albumin administration. Analysis of data along with spectra from healthy controls showed that patients receiving albumin had a trajectory toward the spectra observed in healthy individuals while placebo controls did not. Conclusions The data suggest that metabolic changes detected by 1H-NMR spectroscopy and bioinformatics tool may be useful approach to clinical research especially in acute lung injury.

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Update on Acute Lung Injury and Critical Care Medicine 2009

Abstract: Support by grants NHLBI R37 HL51856, NHLBI R01 HL51854, and NIAID P01 A1053194 (M.A.M.) and NHLBI PO1 HL076406 and NHLBI XO-1NS063898 (S.I.).

Cited by 17 publications

References 75 publications

Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency

Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency

NALP‐3 inflammasome silencing attenuates ceramide‐induced transepithelial permeability

Metabolic effects of albumin therapy in acute lung injury measured by proton nuclear magnetic resonance spectroscopy of plasma: A pilot study*

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