title: Role of platelet-activating factor in pneumolysin-induced acute lung injury.
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.
  
  
  METHODS
  Controlled, ex vivo laboratory study.
  
  
  METHODS
  Female Balb/C mice, 8-12 wks old.
  
  
  METHODS
  Ventilated and blood-free-perfused lungs of wild-type and PAF receptor-deficient mice were challenged with recombinant PLY.
  
  
  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.
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.forename: Birgitt
authors.initials: B
authors.lastname: Gutbier
authors.forename: John S
authors.initials: JS
authors.lastname: Owen
authors.forename: Bernd
authors.initials: B
authors.lastname: Schmeck
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishii
authors.forename: Simone
authors.initials: S
authors.lastname: Rosseau
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Hartwig
authors.initials: H
authors.lastname: Schütte
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010972:Platelet Activating Factor / Q000187:drug effects / Q000378:metabolism*; D011018:Pneumonia, Pneumococcal / Q000150:complications*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013301:Streptolysins / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism; D054460:rho-Associated Kinases
chemical_list: D001426:Bacterial Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010972:Platelet Activating Factor; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D013928:Thromboxane A2; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases