title: Protein kinase C inhibition attenuates hypochlorite-induced acute lung injury.
abstract: Neutrophil-derived oxidative stress plays a crucial role in acute lung injury. Hypochlorite/hypochlorous acid (HOCl) is a major oxidant of neutrophils. Protein kinase C (PKC) may be an appropriate target for HOCl due to its functionally important thiols. This study investigates the role of PKC in HOCl-induced acute lung injury. Isolated lung preparations were from 30 rabbits. HOCl (1000 nmol min(-1)) or buffer (control) were infused into isolated rabbit lungs. Pulmonary artery pressure (PAP [Torr]) and lung weight were continuously measured. Capillary filtration coefficient (K(f,c)), was measured at baseline and at 30, 60, 90 min. Experiments were terminated at 105 min or when fluid retention exceeded 50 g. The non-selective protein kinase inhibitor staurosporin (100 nM) or the selective PKC inhibitor bisindolylmaleimide I (GF109203X, 10nM) were added to the perfusate 5 min prior to the start of the experiments. Staurosporin completely prevented the HOCl-induced increase in PAP (no change versus DeltaPAP(max) 5.2+/-0.78) but did not influence the increase in vascular permeability. GF109203X delayed the HOCl-induced increase in PAP and vascular permeability. PAP(max) was observed significantly later in the HOCl-GF109203X group (84.4+/-4.0 min) in comparison with the HOCl group (52.1+/-3.5 min). Termination of the experiments due to edema formation occurred significantly later in experiments with GF109203X (91.8+/-1.9 versus 79.2+/-4.1 min). Protein kinases are involved in HOCl-induced acute lung injury. Specifically PKC inhibition delayed HOCl-induced increases in PAP and vascular permeability.
authors.affiliation: Department of Respiratory Medicine, University of Leipzig, Leipzig, Germany. stefan.hammerschmidt@t-online.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Hammerschmidt
authors.forename: Tobias
authors.initials: T
authors.lastname: Vogel
authors.forename: Susan
authors.initials: S
authors.lastname: Jockel
authors.forename: Christian
authors.initials: C
authors.lastname: Gessner
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Seyfarth
authors.forename: Adrian
authors.initials: A
authors.lastname: Gillissen
authors.forename: Hubert
authors.initials: H
authors.lastname: Wirtz
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006997:Hypochlorous Acid / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011651:Pulmonary Artery / Q000503:physiopathology; D011817:Rabbits; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D016877:Oxidants; D006997:Hypochlorous Acid; D011493:Protein Kinase C; D019311:Staurosporine; C070515:bisindolylmaleimide I