title: Phospholipase C-ε signaling mediates endothelial cell inflammation and barrier disruption in acute lung injury.
abstract: Phospholipase C-ε (PLC-ε) is a unique PLC isoform that can be regulated by multiple signaling inputs from both Ras family GTPases and heterotrimeric G proteins and has primary sites of expression in the heart and lung. Whereas the role of PLC-ε in cardiac function and pathology has been documented, its relevance in acute lung injury (ALI) is unclear. We used PLC-ε(-/-) mice to address the role of PLC-ε in regulating lung vascular inflammation and injury in an aerosolized bacterial LPS inhalation mouse model of ALI. PLC-ε(-/-) mice showed a marked decrease in LPS-induced proinflammatory mediators (ICAM-1, VCAM-1, TNF-α, IL-1β, IL-6, macrophage inflammatory protein 2, keratinocyte-derived cytokine, monocyte chemoattractant protein 1, and granulocyte-macrophage colony-stimulating factor), lung neutrophil infiltration and microvascular leakage, and loss of VE-cadherin compared with PLC-ε(+/+) mice. These data identify PLC-ε as a critical determinant of proinflammatory and leaky phenotype of the lung. To test the possibility that PLC-ε activity in endothelial cells (EC) could contribute to ALI, we determined its role in EC inflammation and barrier disruption. RNAi knockdown of PLC-ε inhibited NF-κB activity in response to diverse proinflammatory stimuli, thrombin, LPS, TNF-α, and the nonreceptor agonist phorbol 13-myristate 12-acetate (phorbol esters) in EC. Depletion of PLC-ε also inhibited thrombin-induced expression of NF-κB target gene, VCAM-1. Importantly, PLC-ε knockdown also protected against thrombin-induced EC barrier disruption by inhibiting the loss of VE-cadherin at adherens junctions and formation of actin stress fibers. These data identify PLC-ε as a novel regulator of EC inflammation and permeability and show a hitherto unknown role of PLC-ε in the pathogenesis of ALI.
authors.affiliation: Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Kaiser M
authors.initials: KM
authors.lastname: Bijli
authors.affiliation: Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Fabeha
authors.initials: F
authors.lastname: Fazal
authors.affiliation: Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Spencer A
authors.initials: SA
authors.lastname: Slavin
authors.affiliation: Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Antony
authors.initials: A
authors.lastname: Leonard
authors.affiliation: Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Valerie
authors.initials: V
authors.lastname: Grose
authors.affiliation: Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: William B
authors.initials: WB
authors.lastname: Alexander
authors.affiliation: Department of Pharmacology and Physiology, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York.
authors.forename: Alan V
authors.initials: AV
authors.lastname: Smrcka
authors.affiliation: Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York; Arshad_Rahman@URMC.Rochester.edu.
authors.forename: Arshad
authors.identifier: 0000-0002-5621-0512
authors.initials: A
authors.lastname: Rahman
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D054801:Phosphoinositide Phospholipase C / Q000502:physiology*; D015398:Signal Transduction; D022502:Stress Fibers / Q000378:metabolism; D014657:Vasculitis / Q000201:enzymology; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D016328:NF-kappa B; D054801:Phosphoinositide Phospholipase C; D000099152:Cadherin 5; C423320:phospholipase C epsilon
keywords: adhesion molecules; endothelial cells; lung inflammation; signal transduction; transcription factors