title: Protein kinase C and acute respiratory distress syndrome.
abstract: The acute respiratory distress syndrome (ARDS) is a major public health problem and a leading source of morbidity in intensive care units. Lung tissue in patients with ARDS is characterized by inflammation, with exuberant neutrophil infiltration, activation, and degranulation that is thought to initiate tissue injury through the release of proteases and oxygen radicals. Treatment of ARDS is supportive primarily because the underlying pathophysiology is poorly understood. This gap in knowledge must be addressed to identify urgently needed therapies. Recent research efforts in anti-inflammatory drug development have focused on identifying common control points in multiple signaling pathways. The protein kinase C (PKC) serine-threonine kinases are master regulators of proinflammatory signaling hubs, making them attractive therapeutic targets. Pharmacological inhibition of broad-spectrum PKC activity and, more importantly, of specific PKC isoforms (as well as deletion of PKCs in mice) exerts protective effects in various experimental models of lung injury. Furthermore, PKC isoforms have been implicated in inflammatory processes that may be involved in the pathophysiologic changes that result in ARDS, including activation of innate immune and endothelial cells, neutrophil trafficking to the lung, regulation of alveolar epithelial barrier functions, and control of neutrophil proinflammatory and prosurvival signaling. This review focuses on the mechanistic involvement of PKC isoforms in the pathogenesis of ARDS and highlights the potential of developing new therapeutic paradigms based on the selective inhibition (or activation) of specific PKC isoforms.
authors.affiliation: Center for Inflammation, Translational and Clinical Lung Research, Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mondrinos
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kennedy
authors.forename: Melanie
authors.initials: M
authors.lastname: Lyons
authors.forename: Clifford S
authors.initials: CS
authors.lastname: Deutschman
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Kilpatrick
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D020556:Neutrophil Infiltration / Q000276:immunology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012128:Respiratory Distress Syndrome / Q000201:enzymology* / Q000209:etiology / Q000628:therapy; D057170:Translational Research, Biomedical / Q000379:methods
chemical_list: D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C