The inositol trisphosphate pathway mediates platelet-activating-factor-induced pulmonary oedema.
Platelet-activating factor (PAF) is a pro-inflammatory lipid mediator that increases vascular permeability by simultaneous activation of two pathways, one dependent on the cyclooxygenase metabolite prostaglandin E2 and the other on the sphingomyelinase metabolite ceramide. The hypothesis that part of the PAF-induced oedema is mediated via the inositol 1,4,5-trisphosphate (IP3) pathway or Rho kinase pathway was investigated. Oedema formation was induced in isolated perfused rat lungs by injection of 5 nmol PAF into the pulmonary artery. Lungs were pre-treated with specific inhibitors: edelfosine (L108) to block phosphatidyl-inositol-specific phospholipase C, xestospongin to block the IP3 receptor, 5-iodonaphthalene-1-sulphonyl-homopiperazine (ML-7) to block myosin light chain kinase, and (+)-R-trans-4-(aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide (Y27632) to block Rho-associated protein kinase. Pre-treatment with L108 or xestospongin reduced PAF-induced oedema formation by 58 and 56%, respectively. The effect of L108 was additive to that of the cyclooxygenase inhibitor acetyl salicylic acid (88% oedema reduction). PAF-induced oedema formation was also reduced if extracellular calcium concentrations were lowered. Furthermore, treatment with ML-7 reduced oedema formation by 54%, whereas Y27632 was without effect. It is concluded that platelet-activating-factor-triggered oedema is mediated by activation of the inositol 1,4,5-trisphosphate pathway, influx of extracellular calcium and subsequent activation of a myosin light chain kinase-dependent and Rho-associated-protein-kinase-independent mechanism.
Göggel
R
R
Division of Pulmonary Pharmacology, Research Centre Borstel, Leibniz Centre for Medicine and Biosciences, Parkallee 22, D-23845 Borstel, Germany.
Uhlig
S
S
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004727:Endothelium / Q000201:enzymology; D005260:Female; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000473:pathology; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D009929:Organ Size; D010972:Platelet Activating Factor; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D010972:Platelet Activating Factor; D015544:Inositol 1,4,5-Trisphosphate; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D002118:Calcium