title: Pulmonary endothelial protein kinase C-delta (PKCδ) regulates neutrophil migration in acute lung inflammation.
abstract: Excessive neutrophil migration across the pulmonary endothelium into the lung and release of oxidants and proteases are key elements in pathogenesis of acute lung injury. Previously, we identified protein kinase C-delta (PKCδ) as an important regulator of proinflammatory signaling in human neutrophils and demonstrated that intratracheal instillation of a TAT-conjugated PKCδ inhibitory peptide (PKCδ-TAT) is lung protective in a rat model of sepsis-induced indirect pulmonary injury (cecal ligation and puncture). In the present study, intratracheal instillation of this PKCδ inhibitor resulted in peptide distribution throughout the lung parenchyma and pulmonary endothelium and decreased neutrophil influx, with concomitant attenuation of sepsis-induced endothelial ICAM-1 and VCAM-1 expression in this model. To further delineate the role of PKCδ in regulating neutrophil migration, we used an in vitro transmigration model with human pulmonary microvascular endothelial cells (PMVECs). Consistent with in vivo findings, inhibition of PMVEC PKCδ decreased IL-1β-mediated neutrophil transmigration. PKCδ regulation was stimulus-dependent; PKCδ was required for transmigration mediated by IL-1β and fMLP (integrin-dependent), but not IL-8 (integrin-independent). PKCδ was essential for IL-1β-mediated neutrophil adherence and NF-κB-dependent expression of ICAM-1 and VCAM-1. In PMVECs, IL-1β-mediated production of ROS and activation of redox-sensitive NF-κB were PKCδ dependent, suggesting an upstream signaling role. Thus, PKCδ has an important role in regulating neutrophil-endothelial cell interactions and recruitment to the inflamed lung.
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania; Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania; Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mondrinos
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania; Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania; Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Shuang
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania; Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kennedy
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania; Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Devon J
authors.initials: DJ
authors.lastname: King
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania; Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Marla R
authors.initials: MR
authors.lastname: Wolfson
authors.affiliation: Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania; Department of Radiology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Knight
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania; Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Rosario
authors.initials: R
authors.lastname: Scalia
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania; Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, Pennsylvania; Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania. Electronic address: laurie.kilpatrick@temple.edu.
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Kilpatrick
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology*; D006801:Humans; D007154:Immune System Diseases / Q000201:enzymology*; D007150:Immunohistochemistry; D007960:Leukocyte Disorders / Q000201:enzymology*; D008297:Male; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D051745:Protein Kinase C-delta