%0 Journal Article %1 Nielsen:2007fy %A Nielsen, Erik Waage %A Waage, Christian %A Fure, Hilde %A Brekke, Ole L %A Sfyroera, Georgia %A Lambris, John D. %A Mollnes, Tom E. %D 2007 %J Molecular Immunology %K imported %N 8 %P 1819--1826 %R 10.1016/j.molimm.2006.10.003 %T Effect of supraphysiologic levels of C1-inhibitor on the classical, lectin and alternative pathways of complement. %U http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=17101176&retmode=ref&cmd=prlinks %V 44 %X C1-inhibitor is increasingly used experimentally and clinically in inflammatory conditions like septicemia and ischemia-reperfusion injury. Several mechanisms may account for the anti-inflammatory effects of C1-inhibitor, including inhibition of complement. The aim of the present study was to investigate and compare the supraphysiologic effect of C1-inhibitor on the three complement pathways. Novel assays for specific evaluation of the classical, lectin and alternative pathways were employed using normal human serum supplemented with increasing concentrations of C1-inhibitor. Solid-phase classical- and lectin pathway activation was dose-dependently and significantly reduced up to 85% in the range of 2-28 times physiologic C1-inhibitor concentration. The lectin pathway was more potently inhibited than the classical at low doses. A functional lectin pathway assay demonstrated a significant reduction of C4 deposition up to 86% even at low concentration of C1-inhibitor and documented the effect to be at the level of MBL/MASPs. In contrast, C1-inhibitor had no effect on solid-phase alternative pathway activation, but significantly reduced cobra venom factor-induced fluid-phase activation up to 88%. The negative controls albumin and IgG had no effect on complement activation. The positive inhibitory controls compstatin (C3 inhibition), EDTA- or MBL-deficient sera reduced complement activation by 82-100%. We conclude that C1-inhibitor in high physiologic doses differentially inhibits all three-complement pathways. The inhibition pattern was strikingly different in the classical and lectin pathway, compared to the alternative. Previous studies interpreting the effects of C1-inhibitor as only due to classical pathway inhibition needs reconsideration. The data has implications for the therapeutic use of C1-inhibitor.

@article{Nielsen:2007fy, abstract = {C1-inhibitor is increasingly used experimentally and clinically in inflammatory conditions like septicemia and ischemia-reperfusion injury. Several mechanisms may account for the anti-inflammatory effects of C1-inhibitor, including inhibition of complement. The aim of the present study was to investigate and compare the supraphysiologic effect of C1-inhibitor on the three complement pathways. Novel assays for specific evaluation of the classical, lectin and alternative pathways were employed using normal human serum supplemented with increasing concentrations of C1-inhibitor. Solid-phase classical- and lectin pathway activation was dose-dependently and significantly reduced up to 85% in the range of 2-28 times physiologic C1-inhibitor concentration. The lectin pathway was more potently inhibited than the classical at low doses. A functional lectin pathway assay demonstrated a significant reduction of C4 deposition up to 86% even at low concentration of C1-inhibitor and documented the effect to be at the level of MBL/MASPs. In contrast, C1-inhibitor had no effect on solid-phase alternative pathway activation, but significantly reduced cobra venom factor-induced fluid-phase activation up to 88%. The negative controls albumin and IgG had no effect on complement activation. The positive inhibitory controls compstatin (C3 inhibition), EDTA- or MBL-deficient sera reduced complement activation by 82-100%. We conclude that C1-inhibitor in high physiologic doses differentially inhibits all three-complement pathways. The inhibition pattern was strikingly different in the classical and lectin pathway, compared to the alternative. Previous studies interpreting the effects of C1-inhibitor as only due to classical pathway inhibition needs reconsideration. The data has implications for the therapeutic use of C1-inhibitor.}, added-at = {2017-12-08T05:18:19.000+0100}, affiliation = {Department of Anesthesiology, Nordland Hospital, N-8092 Bod{\o}, Norway; University of Troms{\o}, Norway. erikwn@fagmed.uit.no}, author = {Nielsen, Erik Waage and Waage, Christian and Fure, Hilde and Brekke, Ole L and Sfyroera, Georgia and Lambris, John D. and Mollnes, Tom E.}, biburl = {https://www.bibsonomy.org/bibtex/2122381dab456ef219e1a742c47377275/lambris}, date-added = {2012-03-27T20:49:02GMT}, date-modified = {2017-12-08T04:17:02GMT}, doi = {10.1016/j.molimm.2006.10.003}, interhash = {b29b3f6a26a0ad503374a085ef548196}, intrahash = {122381dab456ef219e1a742c47377275}, journal = {Molecular Immunology}, keywords = {imported}, language = {English}, month = mar, number = 8, pages = {1819--1826}, pmid = {17101176}, rating = {0}, read = {Yes}, timestamp = {2017-12-08T05:18:19.000+0100}, title = {{Effect of supraphysiologic levels of C1-inhibitor on the classical, lectin and alternative pathways of complement.}}, uri = {\url{papers3://publication/doi/10.1016/j.molimm.2006.10.003}}, url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=17101176&retmode=ref&cmd=prlinks}, volume = 44, year = 2007 }