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Nonseptic Shock Properdin Deficiency in Murine Models Of Properdin Deficiency in Murine Models of Nonseptic Shock Nina D. Ivanovska, Petya A. Dimitrova, Jeni C. Luckett, Rana El-Rachkidy Lonnen, Wilhelm J. Schwaeble and This information is current as Cordula M. Stover of October 3, 2021. J Immunol 2008; 180:6962-6969; ; doi: 10.4049/jimmunol.180.10.6962 http://www.jimmunol.org/content/180/10/6962 Downloaded from References This article cites 28 articles, 6 of which you can access for free at: http://www.jimmunol.org/content/180/10/6962.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 3, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Properdin Deficiency in Murine Models of Nonseptic Shock1 Nina D. Ivanovska,2* Petya A. Dimitrova,2* Jeni C. Luckett,† Rana El-Rachkidy Lonnen,† Wilhelm J. Schwaeble,† and Cordula M. Stover3† Hereditary properdin deficiency is linked to susceptibility to meningococcal disease (Neisseria meningitidis serotypes Y and W-135) with high mortality. Its relative contribution toward the outcome of nonseptic shock has not been investigated. Using properdin- deficient C57BL/6 mice and their littermates, this study examines their survival of zymosan-induced and LPS-induced shock. Properdin-deficient mice were more resistant to zymosan shock compared with wild-type mice, which showed greater impairment of end-organ function 24 h after zymosan injection, higher TNF-␣ production by alveolar and peritoneal macrophages, higher TNF-␣, and, inversely, lower IL-10 levels in peritoneal lavage and circulation and higher plasma C5a levels. Properdin-deficient mice showed significantly higher mortality in LPS shock, elevated TNF-␣, and, inversely, reduced IL-10 production by peritoneal macrophages as well as lower plasma C5a levels compared with wild-type littermates. NO production by peritoneal macrophages ␣ and plasma 1-antitrypsin levels at 24 h after the injection of LPS or zymosan were decreased in properdin-deficient mice in both Downloaded from models, and fewer histopathologic changes in liver were observed in properdin-deficient animals. This study provides evidence that properdin deficiency attenuates zymosan-induced shock and exacerbates LPS-induced shock. The Journal of Immunology, 2008, 180: 6962–6969. omplement acts in the first line of the immune defense deficient mouse line in a model of cecal ligation and puncture that before the generation of a specific, adaptive immune re- leads to subacute polymicrobial sepsis and found that over an ob- http://www.jimmunol.org/ sponse because it recognizes and subsequently is acti- servation period of 14 days, properdin-deficient mice were signif- C 4 vated by pathogen-associated molecular patterns and immune icantly impaired in their survival compared with wild-type (WT) complexes involving preimmune Abs of the IgM type. These pat- littermates (9). Properdin participates in alternative pathway acti- terns can be heterogenous and activate one or the other or all three vation by stabilizing C3 and C5 convertases, thereby amplifying of the distinct complement activation pathways, namely the clas- ongoing complement activation initiated by any of the pathways. sical, lectin, and alternative pathways. LPS, a wall component en- Recently, the generation of another genetically engineered prop- dotoxin of Gram-negative bacteria, activates the classical and lec- erdin-deficient mouse line (on mixed background 129/C57BL/6) tin pathways of complement (1). Zymosan, a component of yeast was reported. In vitro analysis of this properdin-deficient serum cells, initiates the alternative and classical pathways of comple- using LPS revealed a deficiency in alternative pathway activation, by guest on October 3, 2021 ment (2, 3). C3- and C4-deficient mice are significantly impaired whereas alternative pathway activation induced by zymosan was in their clearance of LPS and show greater mortality in LPS-in- only marginally impaired and classical pathway-triggered alterna- duced shock (4), mirroring the significance of intact complement tive pathway amplification remained intact (10). activation pathways for the survival of this particular type of non- The purpose of the present study was to examine, in vivo, the septic shock. By contrast, C5-deficient mice show decreased mor- course of zymosan- and LPS-induced models of shock in WT and tality in zymosan-induced shock (5), suggesting that impairment of properdin-deficient C57BL/6 mice. complement activation involving the generation of C5a, an ana- phylatoxin, and C5b, the initiating component of the membrane Materials and Methods attack complex, could be beneficial for the survival of this type of Animals nonseptic shock. Experiments were performed using properdin-deficient mice (9) that were In previous work, we have shown that an inhibitor of classical backcrossed for 9–12 generations onto C57BL/6 background and WT lit- and alternative pathways of complement (fangchinoline) improves termates (all males) weighing 30–35 g. The animals had free access to the outcome of zymosan-induced nonseptic multiorgan dysfunc- water and standard chow. The study protocols were approved by the Eth- tion syndrome (6–8). We have further characterized a properdin- ical Animal Commission of the Institute of Microbiology, Sofia, Bulgaria. These properdin-deficient mice were generated by gene-specific targeting and have recently been characterized as being completely impaired in prop- *Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sci- erdin-dependent rabbit erythrocyte lysis compared with their WT litter- ences, Sofia, Bulgaria; and †Department of Infection, Immunity and Inflammation, mates; however, they do not differ in their serum levels of C3 and IgM (9). University of Leicester, Leicester, United Kingdom Zymosan- and LPS-induced nonseptic shock Received for publication June 19, 2007. Accepted for publication March 7, 2008. The costs of publication of this article were defrayed in part by the payment of page Zymosan (1 mg/kg body weight; Sigma-Aldrich) was suspended in sterile charges. This article must therefore be hereby marked advertisement in accordance water and autoclaved for 30 min. WT and properdin-deficient mice were with 18 U.S.C. Section 1734 solely to indicate this fact. injected i.p. with 1 or 0.8 (low dose) mg/g body weight of this suspension ␮ 1 This study was supported by Medical Research Council Grant G0400300 (to (0.5 ml) or with 400 g of LPS (Escherichia coli serotype 055:B5, Sigma- C.M.S.). Aldrich) per mouse, a dose that elicits severe shock in mice of this genetic 2 N.D.I. and P.A.D. contributed equally to this work. 3 Address correspondence and reprint requests to Dr. Cordula Stover, Lecturer in 4 Abbreviations used in this paper: WT, wild type; aM␾, alveolar macrophage; pM␾, Immunology, Department of Infection, Immunity and Inflammation, University of peritoneal macrophage. Leicester, University Road, Leicester LE1 9HN, U.K. E-mail address: cms13@ leicester.ac.uk Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 www.jimmunol.org The Journal of Immunology 6963 FIGURE 1. Properdin-deficient mice are significantly impaired in their FIGURE 2. Properdin-deficient and WT mice differ in their liver his- survival of acute LPS-induced shock. Properdin-deficient mice (n ϭ 11) tology at day 7 after LPS-injection. Liver sections were stained with H&E and WT littermates (n ϭ 10) were injected with LPS (400 ␮g i.p.) and (original magnification ϫ400), and are representative for three mice of p Ͻ 0.001; two-way ,ءءء .mortality was recorded over seven days each genotype. ANOVA. background (11), and tested in a pilot experiment to achieve such pheno- NO production by macrophages type in C57BL/6 control mice. Mice injected i.p. with 0.5 ml of saline Downloaded from served as controls. Peritoneal macrophages were harvested as described above. The cells were washed once and plated at a density of 1 ϫ 106 cells/ml in 200 ␮l of RPMI Organ weights Mice were bled at various time points, culled, and liver, spleen, and kid- neys were removed and weighed. To correct for differences in body weight between animals, organ weights were calculated as a percentage of total body weight. http://www.jimmunol.org/ Histopathologic evaluation of liver Livers were fixed in formaldehyde and paraffin embedded. Sections (7 ␮m) were deparaffinized with xylene and stained with H&E. TUNEL analysis to detect apoptotic cells was performed using TdT-FragEL DNA fragmenta- tion detection kit following the manufacturer’s (Merck Chemicals) instruc- tions and evaluated blind by two assessors. Measurement of coagulation time by guest on October 3, 2021 Blood was collected in a microcapillary pipette (10 cm ϫ 1 mm) contain- ing a horse hair of 20 cm in length as described (12). Every 30 s, 5 mm of the hair was pulled out of the tube manually and formation of a clot was recorded visually. Quantification of liver and renal injury and the concentration of glucose in plasma At day 7 of zymosan inflammation heparinized blood samples were col- lected and plasma was separated. All samples were analyzed immediately by standard laboratory kits (Dialab), measuring the following biochemical markers of organ dysfunction: alanine aminotransferase (a specific marker for hepatic parenchymal injury), aspartate aminotransferase (a nonspecific marker for hepatic injury), bilirubin (a predictor of liver failure), creatinine (an indicator of reduced glomerular filtration ability), and glucose level.
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