Candidate inhibitors of porcine complement

Thorgersen, Ebbe Billmann; Ghebremariam, Yohannes T.; Thurman, Joshua M.; Fung, Michael; Nielsen, Erik Waage; Holers, V. Michael; Kotwal, Girish J.; Mollnes, Tom Eirik

doi:10.1016/j.molimm.2006.10.004

Cited by 18 publications

(16 citation statements)

References 189 publications

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“…Several previous studies have demonstrated the beneficial effects of VCP as a complement inhibitor in rodent disease models, such as collagen-induced arthritis (16) and atherosclerosis (40). Recently, we showed that VCP is an efficient inhibitor of complement activation in porcine serum by several known complement activators (41). In the present study we first tested the ability of VCP to inhibit complement in porcine whole blood and found that VCP efficiently and in a dose-dependent manner inhibited E. coliinduced complement activation.…”

Section: Discussionmentioning

confidence: 88%

Inhibition of Complement and CD14 Attenuates theEscherichia coli-Induced Inflammatory Response in Porcine Whole Blood

et al. 2009

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The innate immune response is a double-edged sword in systemic inflammation and sepsis. Uncontrolled or inappropriate activation can damage and be lethal to the host. Several studies have investigated inhibition of downstream mediators, including tumor necrosis factor alpha (TNF-␣) and interleukin-1␤ (IL-1␤). Emerging evidence indicates that upstream inhibition is a better therapeutic approach for attenuating damaging immune activation. Therefore, we investigated inhibition of two central innate immune pathways, those of complement and CD14/Toll-like receptor 4 (TLR4)/myeloid differentiation protein 2 (MD-2), in a porcine in vitro model of Escherichia coli-induced inflammation. Porcine whole blood anticoagulated with lepuridin, which did not interfere with the complement system, was incubated with E. coli lipopolysaccharide (LPS) or whole bacteria. Inhibitors of complement and CD14 and thus the LPS CD14/TLR4/MD-2 receptor complex were tested to investigate the effect on the inflammatory response. A broad range of inflammatory readouts were used to monitor the effect. Anti-CD14 was found to saturate the CD14 molecule on granulocytes and completely inhibited LPS-induced proinflammatory cytokines in a dose-dependent manner. Anti-CD14 significantly reduced the levels of the E. coli-induced proinflammatory cytokines TNF-␣ and IL-1␤, but not IL-8, in a dose-dependent manner. No effect on bacterial clearance was seen. Vaccinia complement control protein and smallpox inhibitor of complement enzymes, two Orthopoxvirus-encoded complement inhibitors, completely inhibited complement activation. Furthermore, these agents almost completely inhibited the expression of wCD11R3, which is associated with CD18 as a ␤2 integrin, on porcine granulocytes and decreased IL-8 levels significantly in a dose-dependent manner. As expected, complement inhibition reduced bacterial clearance. We conclude that inhibition of complement and CD14 attenuates E. coli-induced inflammation and might be used as a therapeutic regimen in gram-negative sepsis along with appropriate treatment with antibiotics.

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Section: Discussionmentioning

confidence: 88%

Inhibition of Complement and CD14 Attenuates theEscherichia coli-Induced Inflammatory Response in Porcine Whole Blood

et al. 2009

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“…It cannot be fully excluded that there are differences between batches of C1-INH that may explain the difference, in addition to potential differences in the experimental settings. It should, however, be emphasized that although C1-INH is an efficient inhibitor of the autocatalytic activity of C1,29 recent data indicate that it is not similarly efficient in inhibiting exogenous activation of complement when induced on solid-phase,24 and it is also needed in high doses in order to reduce the formation of fluid-phase TCC efficiently 28,30…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of C1-Inhibitor in porcine and human whole blood are independent of its protease inhibition activity

et al. 2009

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C1-Inhibitor (C1-INH) is an important biological inhibitor, regulating several protein cascade systems. Recent research has shown that the molecule exhibits properties not dependent on its protease inhibition activity. Serum and whole blood from pigs and humans were pre-incubated with C1-INH, iC1-INH or the complement inhibitors SPICE or compstatin. Whole, live Escherichia coli were then added for further incubation. Complement activation, a range of cytokines, chemokines and growth factors, as well as the leukocyte activation markers wCD11R3 (pig) and CD11b (human) were measured. Both C1-INH and iC1-INH dose-dependently and significantly (P<0.05) reduced a range of E. coli-induced pro-inflammatory cytokines and chemokines in porcine and human whole blood, as well as growth factors in human whole blood. Differences between the two forms of C1-INH and between the two species were modest. Most of these anti-inflammatory effects could not be explained by complement inhibition, as specific complement inhibitors had minor effect on several of the mediators. C1-Inhibitor had no inhibitory effect on E. coli-induced complement activation, while iC1-INH enhanced complement activation. The presented data indicate that C1-INH has broad anti-inflammatory effects in E. coli-induced inflammation in pig and human whole blood. These effects are largely independent of the protease inhibition activity.

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“…Total complement activation was measured by the soluble terminal C5b-9 complement complex (TCC) by enzyme-linked immunosorbent assay, as described previously (18). The assay was developed for the detection of human TCC but shows cross-reactivity with porcine TCC (19,20).…”

Section: Inflammatory Mediatorsmentioning

confidence: 99%

A New Dynamic Porcine Model of Meningococcal Shock

Hellerud¹,

Thorgersen

Castellheim

et al. 2009

Shock

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The objective of this study was to establish a porcine analog of human meningococcal sepsis for pathophysiological investigations and possible future therapy in severe sepsis. Heat-killed Neisseria meningitidis was continuously infused in sublethal concentrations into 10 anesthetized 30-kg pigs (sepsis group). The dose was doubled every 30 min. Six pigs received saline only (control group). The changes described in the succeeding paragraphs were observed in the sepsis group but not in the control group. MAP was aimed to be kept normal by fluid infusion but declined after 3 h in parallel with a decrease in systemic vascular resistance. Pulmonary arterial pressure increased considerably after 30 to 45 min. A massive plasma extravasation was shown by increased hematocrit and a 50% reduction in plasma albumin content. Fluid accumulated in lungs, muscles, and jejunum, as shown by increased wet-dry ratios. Peak inspiratory pressures and fraction of inspired oxygen had to be increased. The cytokines TNF-alpha, IL-1beta, IL-6, IL-8, IL-10, and IL-12 increased markedly. Neutrophils fell to zero-levels, and platelets were markedly reduced. Thrombin-antithrombin complexes increased notably after 120 min. This is the first large animal model of sepsis using whole Neisseria meningitidis. The model simulates well central aspects of human meningococcal sepsis and could be used for future interventional studies.

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Candidate inhibitors of porcine complement

Cited by 18 publications

References 189 publications

Inhibition of Complement and CD14 Attenuates theEscherichia coli-Induced Inflammatory Response in Porcine Whole Blood

Inhibition of Complement and CD14 Attenuates theEscherichia coli-Induced Inflammatory Response in Porcine Whole Blood

Anti-inflammatory effects of C1-Inhibitor in porcine and human whole blood are independent of its protease inhibition activity

A New Dynamic Porcine Model of Meningococcal Shock

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