Complement and CD14 : Roles in Escherichia coli-induced inflammation in the pig
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AbstractSepsis is a systemic inflammatory response syndrome caused by infection. The morbidity and mortality in sepsis is high despite of modern treatment with broad-spectrum antibiotics and supportive therapy. This fact reflects our poor understanding of the complex inflammatory response in sepsis. A range of biomarkers have been shown to correlate with disease activity and death in sepsis. However, targeting single downstream mediators in clinical sepsis trials, like the central proinflammatory cytokine TNF-α, have been disappointing. A better approach may be inhibition of upstream inducers instead of downstream mediators of inflammation.
The aims of this Thesis were to find effective inhibitors of complement and CD14/TLR4/MD2, two key upstream innate immunity inducers of inflammation, and to investigate the effect in a pig model of sepsis. The initial studies were conducted in vitro in porcine serum and whole blood, and a pig whole animal model was developed in parallel to mimic the human clinical situation. The pig is a well suited animal for studying human diseases. The anatomy and physiology is quite similar to humans, the same surveillance may be used as in humans, and pigs are LPS sensitive in contrast to rodents.
Upstream inhibition of both complement (in vitro) and CD14/TLR4 (in vitro and in vivo) were found to be effective in reduction of E. coli-induced inflammation in the pig. Induction of central proinflammatory cytokines and chemokines, activation of hemostasis, and activation of granulocytes, by E. coli, were reduced. The findings in this Thesis suggest that inhibition of complement and CD14/TLR4/MD2 should be regarded as an early treatment approach in sepsis.
List of papers
I Thorgersen EB, Ghebremariam YT, Thurman JM, Fung M, Nielsen EW, Holers VM, Kotwal GJ, Mollnes TE. Candidate inhibitors of porcine complement. Mol Immunol. 2007 Mar; 44(8):1827-34. doi:10.1016/j.molimm.2006.10.004
II Thorgersen EB, Pharo A, Haverson K, Axelsen AK, Gaustad P, Kotwal GJ, Sfyroera G, Mollnes TE. Complement- and CD14-inhibition attenuate Escherichia coli-induced inflammatory response in porcine whole blood. Infect Immun. 2009 Feb; 77 (2): 725-732. doi:10.1128/IAI.01305-08
III Thorgersen EB, Macagno A, Rossetti C, Mollnes TE. Cyanobacterial LPS antagonist (CyP)-a novel and efficient inhibitor of Escherichia coli LPS-induced cytokine response in the pig. Mol Immunol. 2008 Aug; 45(13):3553-7. doi:10.1016/j.molimm.2008.05.005
IV Castellheim A, Thorgersen EB, Hellerud BC, Pharo A, Johansen HT, Brosstad F, Gaustad P, Brun H, Fosse E, TÃ¸nnessen TI, Nielsen EW, Mollnes TE. New biomarkers in an acute model of live Escherichia coliinduced sepsis in pigs. Scand J Immunol. 2008 Jul; 68(1):75-84. doi: 10.1111/j.1365-3083.2008.02122.x
V Thorgersen EB, Hellerud BC, Nielsen EW, Barratt-Due A, Fure H, Lindstad JK, Pharo A, Fosse E, TÃ¸nnessen TI, Johansen HT, Castellheim A, Mollnes TE. CD14-inhibition efficiently attenuates early inflammatory and hemostatic responses in Escherichia coli-sepsis in pigs. Submitted.