Early Growth Response-1 Worsens Ventilator-induced Lung Injury by Up-Regulating Prostanoid Synthesis

Ngiam, Nicola; Peltekova, Vanya; Engelberts, Doreen; Otulakowski, Gail; Post, Martin; Kavanagh, Brian P.

doi:10.1164/rccm.200908-1297oc

Cited by 30 publications

(28 citation statements)

References 60 publications

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“…Pressure-based VILI experiments yielded similar results (data not shown). VILI has been shown to be attenuated in Egr12/2 KO mice (22). Our microarray analysis demonstrated that expression of Egr1 was decreased 14.0-fold in C18 KO mice (Table E3), and this finding was confirmed by qRT-PCR, which showed a 22.5-fold decrease in lungs of C18 KO mice ( Figure 7B).…”

Section: Lower Sensitivity To Ventilatorinduced Lung Injury In C18 Kosupporting

confidence: 59%

“…Microarray and qRT-PCR gene expression analysis revealed a large decrease in expression of the transcription factor Egr-1 in C18 KO lungs. EGR-1 activates expression of the gene encoding prostaglandin E synthase, an enzyme that increases synthesis of prostaglandin E2, which exacerbates inflammation and lung injury by activating pulmonary prostaglandin E receptor subtype 1 (22). Accordingly, Egr-1 KO mice feature significantly lower levels of injury in response to VILI (22), suggesting that lower Egr-1 expression in C18 KO mice is protective.…”

Section: Changes In Expression/localization Of Other Tjs and Tj-assocmentioning

confidence: 99%

“…EGR-1 activates expression of the gene encoding prostaglandin E synthase, an enzyme that increases synthesis of prostaglandin E2, which exacerbates inflammation and lung injury by activating pulmonary prostaglandin E receptor subtype 1 (22). Accordingly, Egr-1 KO mice feature significantly lower levels of injury in response to VILI (22), suggesting that lower Egr-1 expression in C18 KO mice is protective. Previous studies have suggested that b-agonists enhance adherens junctions and integrin-mediated cell adhesion (50).…”

Section: Changes In Expression/localization Of Other Tjs and Tj-assocmentioning

confidence: 99%

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Knockout Mice Reveal Key Roles for Claudin 18 in Alveolar Barrier Properties and Fluid Homeostasis

Flodby

Luo

et al. 2014

Am J Respir Cell Mol Biol

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Claudin proteins are major constituents of epithelial and endothelial tight junctions (TJs) that regulate paracellular permeability to ions and solutes. Claudin 18, a member of the large claudin family, is highly expressed in lung alveolar epithelium. To elucidate the role of claudin 18 in alveolar epithelial barrier function, we generated claudin 18 knockout (C18 KO) mice. C18 KO mice exhibited increased solute permeability and alveolar fluid clearance (AFC) compared with wild-type control mice. Increased AFC in C18 KO mice was associated with increased b-adrenergic receptor signaling together with activation of cystic fibrosis transmembrane conductance regulator, higher epithelial sodium channel, and Na-K-ATPase (Na pump) activity and increased Na-K-ATPase b1 subunit expression. Consistent with in vivo findings, C18 KO alveolar epithelial cell (AEC) monolayers exhibited lower transepithelial electrical resistance and increased solute and ion permeability with unchanged ion selectivity. Claudin 3 and claudin 4 expression was markedly increased in C18 KO mice, whereas claudin 5 expression was unchanged and occludin significantly decreased. Microarray analysis revealed changes in cytoskeletonassociated gene expression in C18 KO mice, consistent with observed F-actin cytoskeletal rearrangement in AEC monolayers. These findings demonstrate a crucial nonredundant role for claudin 18 in the regulation of alveolar epithelial TJ composition and permeability properties. Increased AFC in C18 KO mice identifies a role for claudin 18 in alveolar fluid homeostasis beyond its direct contributions to barrier properties that may, at least in part, compensate for increased permeability.

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Section: Lower Sensitivity To Ventilatorinduced Lung Injury In C18 Kosupporting

confidence: 59%

Section: Changes In Expression/localization Of Other Tjs and Tj-assocmentioning

confidence: 99%

Section: Changes In Expression/localization Of Other Tjs and Tj-assocmentioning

confidence: 99%

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Knockout Mice Reveal Key Roles for Claudin 18 in Alveolar Barrier Properties and Fluid Homeostasis

Flodby

Luo

et al. 2014

Am J Respir Cell Mol Biol

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“…ERK may increase permeability by promoting apoptosis, oxidant production and activation of myosin-light chain kinase, which activates molecular motor myosin to promote endothelial cytoskeletal contraction and subsequent interendothelial gap formation [12,[41][42][43]. ERK is strongly activated in VILI experiments and has been used as an injury marker in VILI [44,45]. ERK inhibition by a small-molecule inhibitor has been effective in rescuing a mouse model of endotoxin-induced lung injury [46] and mixed models of VILI and bleomycin or hyperoxia [12,47].…”

mentioning

confidence: 99%

Inhaled Activated Protein C Protects Mice from Ventilator-Induced Lung Injury.

Maniatis

Letsiou

Orfanos

et al. 2009

B106. Mechanisms of Ventilator Associated Lung Injury

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Introduction: Activated Protein C (APC), an endogenous anticoagulant, improves tissue microperfusion and endothelial cell survival in systemic inflammatory states such as sepsis, but intravenous administration may cause severe bleeding. We have thus addressed the role of APC delivered locally by inhalation in preventing acute lung injury from alveolar overdistention and the subsequent ventilator-induced lung injury (VILI). We also assessed the effects of APC on the activation status of Extracellular-Regulated Kinase 1/2 (ERK) pathway, which has been shown to be involved in regulating pulmonary responses to mechanical stretch. Methods:Inhaled APC (12.5 μg drotrecogin-α × 4 doses) or saline was given to tracheotomized C57/Bl6 mice starting 20 min prior to initiation of injurious mechanical ventilation with tidal volume 25 mL/Kg for 4 hours and then hourly thereafter; control groups receiving inhaled saline were ventilated with 8 mL/Kg for 30 min or 4 hr. We measured lung function (respiratory system elastance H), arterial blood gases, surrogates of vascular leak (broncho-alveolar lavage (BAL) total protein and angiotensin-converting enzyme (ACE)-activity), and parameters of inflammation (BAL neutrophils and lung tissue myeloperoxidase (MPO) activity). Morphological alterations induced by mechanical ventilation were examined in hematoxylin-eosin lung tissue sections. The activation status of ERK was probed in lung tissue homogenates by immunoblotting and in paraffin sections by immunohistochemistry. The effect of APC on ERK signaling downstream of the thrombin receptor was tested on A549 human lung epithelial cells by immunoblotting. Statistical analyses were performed using ANOVA with appropriate post-hoc testing. Results:In mice subjected to VILI without APC, we observed hypoxemia, increased respiratory system elastance and inflammation, assessed by BAL neutrophil counts and tissue MPO activity. BAL total protein levels and ACE activity were also elevated by VILI, indicating compromise of the alveolo-capillary barrier. In addition to preserving lung function, inhaled APC prevented endothelial barrier disruption and attenuated hypoxemia and the inflammatory response. Mechanistically, we found a strong activation of ERK in lung tissues by VILI, which was prevented by APC, suggestive of pathogenetic involvement of the Mitogen-Activated Kinase pathway. In cultured human lung epithelial cells challenged by thrombin, APC abrogated the activation of ERK and its downstream effector, cytosolic Phospholipase A 2 .Conclusions: Topical application of APC by inhalation may effectively reduce lung injury induced by mechanical ventilation in mice.

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“…Therefore, targeting this chemokine could be an effective approach to avoid VILI in this context. Other authors have used genomic studies to identify therapeutic targets, resulting in attenuation of VILI (26). However, it must .…”

Section: Sh3bgrl3mentioning

confidence: 99%

Exposure to mechanical ventilation promotes tolerance to ventilator-induced lung injury by Ccl3 downregulation

Blázquez-Prieto

López-Alonso

Amado-Rodríguez

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Our objectives were to demonstrate that tolerance to VILI can be induced by previous low-pressure ventilation, and to identify the molecular mechanisms responsible for this phenomenon. Intact 8-to 12-wk-old male CD1 mice were preconditioned with 90 min of noninjurious ventilation [peak pressure 17 cmH2O, positive end-expiratory pressure (PEEP) 2 cmH2O] and extubated. Seven days later, preconditioned mice and intact controls were submitted to injurious ventilation (peak pressure 20 cmH2O, PEEP 0 cmH2O) for 2 h to induce VILI. Preconditioned mice showed lower histological lung injury scores, bronchoalveolar lavage albumin content, and lung neutrophilic infiltration after injurious ventilation, with no differences in Il6 or Il10 expression. Microarray analyses revealed a downregulation of Calcb, Hspa1b, and Ccl3, three genes related to tolerance phenomena, in preconditioned animals. Among the previously identified genes, only Ccl3, which encodes the macrophage inflammatory protein 1 alpha (MIP-1␣), showed significant differences between intact and preconditioned mice after high-pressure ventilation. In separate, nonconditioned animals, treatment with BX471, a specific blocker of CCR1 (the main receptor for MIP-1␣), decreased lung damage and neutrophilic infiltration caused by high-pressure ventilation. We conclude that previous exposure to noninjurious ventilation induces a state of tolerance to VILI. Downregulation of the chemokine gene Ccl3 could be the mechanism responsible for this effect.

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Early Growth Response-1 Worsens Ventilator-induced Lung Injury by Up-Regulating Prostanoid Synthesis

Abstract: This is the first demonstration of a mechanism whereby expression of a novel gene (Egr1) can contribute to VILI via a prostanoid-mediated pathway.

Cited by 30 publications

References 60 publications

Knockout Mice Reveal Key Roles for Claudin 18 in Alveolar Barrier Properties and Fluid Homeostasis

Knockout Mice Reveal Key Roles for Claudin 18 in Alveolar Barrier Properties and Fluid Homeostasis

Inhaled Activated Protein C Protects Mice from Ventilator-Induced Lung Injury.

Exposure to mechanical ventilation promotes tolerance to ventilator-induced lung injury by Ccl3 downregulation

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