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

Martin Witzenrath; Birgitt Gutbier; John S Owen; Bernd Schmeck; Timothy J Mitchell; Konstantin Mayer; Michael J Thomas; Satoshi Ishii; Simone Rosseau; Norbert Suttorp; Hartwig Schütte

doi:10.1097/01.CCM.0000269212.84709.23

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

Martin Witzenrath, Birgitt Gutbier, John S Owen, Bernd Schmeck, Timothy J Mitchell, Konstantin Mayer, Michael J Thomas, Satoshi Ishii, Simone Rosseau, Norbert Suttorp, Hartwig Schütte

Microbiology and Infection

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1756-62
Number of pages	7
Journal	Critical care medicine
Volume	35
Issue number	7
DOIs	https://doi.org/10.1097/01.CCM.0000269212.84709.23
Publication status	Published - Jul 2007

Keywords

Animals
Bacterial Proteins
Disease Models, Animal
Female
Humans
Hypertension, Pulmonary
Intracellular Signaling Peptides and Proteins
Mice
Mice, Inbred BALB C
Platelet Activating Factor
Pneumonia, Pneumococcal
Protein-Serine-Threonine Kinases
Respiratory Distress Syndrome, Adult
Signal Transduction
Streptolysins
Thromboxane A2
rho-Associated Kinases

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@article{e6deaf2501264e5aad93cffe40f06aab,

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.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.",

keywords = "Animals, Bacterial Proteins, Disease Models, Animal, Female, Humans, Hypertension, Pulmonary, Intracellular Signaling Peptides and Proteins, Mice, Mice, Inbred BALB C, Platelet Activating Factor, Pneumonia, Pneumococcal, Protein-Serine-Threonine Kinases, Respiratory Distress Syndrome, Adult, Signal Transduction, Streptolysins, Thromboxane A2, rho-Associated Kinases",

author = "Martin Witzenrath and Birgitt Gutbier and Owen, {John S} and Bernd Schmeck and Mitchell, {Timothy J} and Konstantin Mayer and Thomas, {Michael J} and Satoshi Ishii and Simone Rosseau and Norbert Suttorp and Hartwig Sch{\"u}tte",

year = "2007",

month = jul,

doi = "10.1097/01.CCM.0000269212.84709.23",

language = "English",

volume = "35",

pages = "1756--62",

journal = "Critical care medicine",

issn = "0090-3493",

publisher = "Lippincott Williams and Wilkins",

number = "7",

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T1 - Role of platelet-activating factor in pneumolysin-induced acute lung injury

AU - Witzenrath, Martin

AU - Gutbier, Birgitt

AU - Owen, John S

AU - Schmeck, Bernd

AU - Mitchell, Timothy J

AU - Mayer, Konstantin

AU - Thomas, Michael J

AU - Ishii, Satoshi

AU - Rosseau, Simone

AU - Suttorp, Norbert

AU - Schütte, Hartwig

PY - 2007/7

Y1 - 2007/7

N2 - 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.

AB - 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.

KW - Animals

KW - Bacterial Proteins

KW - Disease Models, Animal

KW - Female

KW - Humans

KW - Hypertension, Pulmonary

KW - Intracellular Signaling Peptides and Proteins

KW - Mice

KW - Mice, Inbred BALB C

KW - Platelet Activating Factor

KW - Pneumonia, Pneumococcal

KW - Protein-Serine-Threonine Kinases

KW - Respiratory Distress Syndrome, Adult

KW - Signal Transduction

KW - Streptolysins

KW - Thromboxane A2

KW - rho-Associated Kinases

U2 - 10.1097/01.CCM.0000269212.84709.23

DO - 10.1097/01.CCM.0000269212.84709.23

M3 - Article

C2 - 17522574

SN - 0090-3493

VL - 35

SP - 1756

EP - 1762

JO - Critical care medicine

JF - Critical care medicine

IS - 7

ER -

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

Abstract

Keywords

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