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The inositol trisphosphate pathway mediates platelet-activating-factor-induced pulmonary oedema

Division of Pulmonary Pharmacology, Research Centre Borstel, Leibniz Centre for Medicine and Biosciences, Borstel, Germany

CORRESPONDENCE: S. Uhlig, Division of Pulmonary Pharmacology, Research Centre Borstel, Leibniz Centre for Medicine and Biosciences, Parkallee 22, D-23845 Borstel, Germany. Fax: 49 4537188778. E-mail: suhlig@fz-borstel.de

Keywords: Calcium, myosin light chain kinase, phosphatidyl-inositol-specific phospholipase C, Rho kinase

Received: June 11, 2004
Accepted December 27, 2004

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.

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