Protein kinase C inhibition attenuates hypochlorite-induced acute lung injury

SummaryNeutrophil-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 (1000nmolmin−1) or buffer (control) were infused into isolated rabbit lungs. Pulmonary artery pressure (PAP [Torr]) and lung weight were continuously measured. Capillary filtration coefficient (Kf,c), was measured at baseline and at 30, 60, 90min. Experiments were terminated at 105min or when fluid retention exceeded 50g. The non-selective protein kinase inhibitor staurosporin (100nM) or the selective PKC inhibitor bisindolylmaleimide I (GF109203X, 10nM) were added to the perfusate 5min prior to the start of the experiments.Staurosporin completely prevented the HOCl-induced increase in PAP (no change versus ΔPAPmax 5.2±0.78) but did not influence the increase in vascular permeability. GF109203X delayed the HOCl-induced increase in PAP and vascular permeability. PAPmax was observed significantly later in the HOCl-GF109203X group (84.4±4.0min) in comparison with the HOCl group (52.1±3.5min). Termination of the experiments due to edema formation occurred significantly later in experiments with GF109203X (91.8±1.9 versus 79.2±4.1min).Protein kinases are involved in HOCl-induced acute lung injury. Specifically PKC inhibition delayed HOCl-induced increases in PAP and vascular permeability