John Owen - Role of platelet-activating factor in pneumolysin-induced acute lung injury.

Version 1

      Publication Details (including relevant citation   information):

      Crit Care Med 35:1756-1762

      Abstract:

      OBJECTIVE:

      Acute respiratory failure is a major complication of severe   pneumococcal pneumonia, characterized by impairment of pulmonary   microvascular barrier function and pulmonary hypertension. Both   features can be evoked by pneumolysin (PLY), an important   virulence factor of Streptococcus pneumoniae. We hypothesized   that platelet-activating factor (PAF) and associated downstream   signaling pathways play a role in the PLY-induced development of   acute lung injury.

      DESIGN:

      Controlled, ex vivo laboratory study.

      SUBJECTS:

      Female Balb/C mice, 8-12 wks old.

      INTERVENTIONS:

      Ventilated and blood-free-perfused lungs of wild-type and PAF   receptor-deficient mice were challenged with recombinant PLY.

      MEASUREMENTS AND MAIN RESULTS:

      Intravascular PLY, but not the pneumolysoid Pd-B (PLY with a   Trp-Phe substitution at position 433), caused an impressive   dose-dependent increase in pulmonary vascular resistance and   increased PAF in lung homogenates, as detected by reversed-phase   high-performance liquid chromatography coupled to tandem mass   spectrometry. The pressor response was reduced in lungs of PAF   receptor-deficient mice and after PAF receptor blockade by BN   50730. PLY and exogenous PAF increased thromboxane B2 in lung   effluate, and thromboxane receptor inhibition by BM 13505   diminished the pressor response to PLY. Differential inhibition   of intracellular signaling steps suggested significant   contribution of phosphatidylcholine-specific phospholipase C and   protein kinase C and of the Rho/Rho-kinase pathway to PLY-induced   pulmonary vasoconstriction. Unrelated to the pulmonary arterial   pressor response, microvascular leakage of PLY was diminished in   lungs of PAF receptor-deficient mice as well.

      CONCLUSIONS:

      PAF significantly contributed to PLY-induced acute injury in   murine lungs. The PAF-mediated pressor response to PLY depends on   thromboxane and on the downstream effectors   phosphatidylcholine-specific phospholipase C, protein kinase C,   and Rho-kinase.

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