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Inhibition of pulmonary microvascular chemokine production by human Laktoferrin and Phosphatidylethanolamine

Chemokines, a large family of structurally related chemotactic cytokines, are essential for the migration of leukocytes during inflammatory processes. The release of neutrophil attractant chemokines such as MCP-1, Groα, ENA-78, GCP-2 and NAP-2 as well as fractalkine by lung microvascular endothelial cells (LMVEC) is dramatically increased upon stimulation with LPS. The present study was performed to investigate, whether human Lactoferrin (hLf) or Phospholipase A2-inhibitor Phosphatidylethanolamine (PE) can intervene with the release of these chemokines by LMVEC under LPS stimulation.

LMVEC were protreated with hLf for various time intervals prior to stimulation with LPS or with LPS in the presence of hLf. In other experiments, cell impermeable PE, Cyclooxygenase-inhibitors (Col) (indomethacine, acetyl-salicylic acid) and a platelet activating factor (PAF)-antagonist, were added to LPS stimulated LMVEC. Chemokine release was measured by ELISA and detection of chemokine mRNA by means of RT-PCR.

HLf added to LMVEC at the time of stimulation did not influence chemokine production. However, when hLf was added prior to LPS stimulation, a significant inhibition of MCP-1 (P < 0.001) and ENA-78 (P < 0.01) but not of Groα production was observed. In order to investigate if LPS induced chemokine production was dependent on PAF, Arachidonic acid (AA) or its metabolites, LMVEC were treated with PE, Col and PAF-antagonist either after or at the time of LPS stimulation. Treatment of LMVEC with PE completely inhibited the LPS induced chemokine production of MCP-1, ENA-78 and Groα in a time and dose dependent fashion. This was still observed, when LMVEC were pretreated with LPS. Col and PAF-antagonist could partly reduce LPS induced chemokine production. Furthermore mRNA expression of ENA-78, Groα, GCP-2 and fractalkine was decreased after LPS stimulation in the presence of PE. Our data demonstrate, that hLf and PE are potent agents to counteract LPS induced chemokine produktion by LMVEC. These findings may have clinical implications in the treatment of acute lung injury during sepsis.

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Beck, G., Yard, B., van der Woude, F. et al. Inhibition of pulmonary microvascular chemokine production by human Laktoferrin and Phosphatidylethanolamine. Crit Care 3 (Suppl 1), P048 (2000).

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