P349	Influence of the platelet activating factor (PAF) - PAF-receptor - system on vascular changes and inflammation: effects in a murine model of acute lung injury (ALI).
1J.Ott, 1M.Schaefer, 1M.H.Bi, 1A.Mohr, 2S.Ishii, 2T.Shimizu, 1F.Grimminger, 1W.Seeger, 1K.Mayer
1Uniklinikum Giessen, University of Giessen Lung Center, Gießen, DE; 2University of Tokyo, Department of Biochemistry, Tokyo, JP.

Lipid mediators as eicosanoids and PAF are crucial for the regulation of inflammatory interactions of leukocytes and endothelial cells. In contrast to pro-inflammatory prostanoids derived from arachidonic acid (AA), anti-inflammatory potential of fish oil (FO) derived n-3 fatty acids (FA) has been demonstrated. N-3 FA have been shown to reduce PAF generation and subsequent leukocyte adhesion and transmigration. We examined the effects of lipid emulsions used for parenteral nutrition in a murine model of ALI. To differentiate effects of PAF, mice with targeted disruption of their PAF-receptor (PAF-R-/-) or injection of a PAF-receptor antagonist were used. A catheter was inserted into the jugular vein of mice connected to an exchangeable mini-osmotic pump (ALZET®). Mice were subjected to intratracheal instillation of lipopolysaccharide (LPS). Mice undergoing pharmacologic PAF-receptor inhibition, BN 52021 (BN) was injected i.v. 30 min prior to LPS-application. 24 h after stimulation, broncho-alveolar lavage (BAL) was performed. In BAL, leukocytes were counted and cytokines were measured by ELISA. In wild type (WT) mice, LPS stimulation induced a massive increase in transmigrated leukocytes as compared to unstimulated controls. Pre-infusion of n-6 lipids lead to a further increase in leukocyte invasion but FO-based lipids reduced leukocyte influx into the lung. When LPS was instilled in PAF-R-/- mice or mice receiving BN, leukocyte invasion was comparable to WT mice. However, the diverging effect of lipid emulsions was lost. In WT mice, LPS instillation induced an increase in TNF-a and MIP2. Again lipid emulsions differentially influenced cytokine generation. In PAF-R-/- mice undergoing LPS-stimulation, TNF-a was comparable to WT but MIP2 was more than doubled. When BN was used, TNF-a and MIP2 both were clearly reduced. In both models with interruption of the PAF-signaling, diverging effects of lipid emulsions were not detectable. Lipid emulsions differentially influence transmigration of leukocytes and cytokine generation in a murine model of ALI. This effect is linked to a functional PAF-PAF-receptor signalling system. PAF-R-/- mice but not mice with acute pharmacologic inhibition of the PAF-receptor show an upregulation of the MIP2 cytokine response possibly compensating the loss of PAF-PAF-receptor signalling.

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