Severe sepsis leads to systemic inflammation, wherein coagulation and complement activation play critical roles. Evidence from patients and animal models suggest that sepsis is a multi-stage, multi-factorial disease in which the early fulminate inflammatory response to the invading bacteria leads to hypo-perfusion and ischemia-reperfusion (IR) injury that evolves to multiple organ failure (MOF) and ultimately to death. Work from our lab has demonstrated that severe sepsis induced in animals by using sublethal doses of E. coli develops as two-stage series of events, each stage being driven by different pathophysiologies. First stage events are caused by the direct effects of the pathogen, whereas the second stage occurs as result of an aberrant host recovery after IR. The objectives of this proposal are to investigate whether inhibition of complement activation alone or as combination therapies could prevent MOF and improve the outcome of sepsis.
Aim 1 will use a C3 convertase inhibitor to determine the role of complement during each of the two stages of sepsis, assess complement activation as a potential cause of thrombocytopenia in sepsis and identify organ- specific protective effects of complement inhibition during sepsis progression. This research will employ cDNA microarray, immunocytochemistry, electron microscopy and biochemical analysis of vital organs to identify the effect of complement activation products on the dominant pathophysiologic processes controlling the progression of sepsis.
Aim 2 will determine if, and through what mechanisms, complement inhibition by the recombinant lectin-like domain of thrombomodulin (TM-LLD) could prevent organ failure and improve outcome in our sepsis model.
Aim 3 will determine whether combining complement blockade with immunological inhibition of CD14 or extracellular histones could provide superior/additional effects therapeutic effects on E. coli sepsis as compared to complement inhibition alone. This project has potential to advance our understanding of the role of complement activation in sepsis progression and to test whether complement inhibition could be used as effective therapy for sepsis-induced organ failure. )

Public Health Relevance

Sepsis is a multi-factorial disorder whose underlying pathophysiologic mechanisms are not yet known;therefore the quest for effective life-saving therapies remains elusive. In an attempt to bridge the gap between basic research on small animals and clinical research, this application addresses the use of a model with relevance to human disease to investigate whether inhibition of complement activation alone or as a combination therapy could prevent organ dysfunction and improve clinical outcome of sepsis. Owing to the resemblance with the human disease, the proposed studies have the potential to facilitate the translation of the mechanisms and therapies into the clinic and lead to a true bench-to-bed approach. )

National Institute of Health (NIH)
Research Project (R01)
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Innate Immunity and Inflammation (III)
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Dunsmore, Sarah
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Oklahoma Medical Research Foundation
Oklahoma City
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Keshari, Ravi S; Silasi-Mansat, Robert; Zhu, Hua et al. (2014) Acute lung injury and fibrosis in a baboon model of Escherichia coli sepsis. Am J Respir Cell Mol Biol 50:439-50
Huang, Yijun; Reis, Edimara S; Knerr, Patrick J et al. (2014) Conjugation to albumin-binding molecule tags as a strategy to improve both efficacy and pharmacokinetic properties of the complement inhibitor compstatin. ChemMedChem 9:2223-6
Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia et al. (2014) Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis. J Immunol 192:6020-7
Lupu, Florea; Keshari, Ravi S; Lambris, John D et al. (2014) Crosstalk between the coagulation and complement systems in sepsis. Thromb Res 133 Suppl 1:S28-31
Pieretti, Alberto C; Ahmed, Alwiya M; Roberts Jr, Jesse D et al. (2014) A novel in vitro model to study alveologenesis. Am J Respir Cell Mol Biol 50:459-69
Risitano, Antonio M; Ricklin, Daniel; Huang, Yijun et al. (2014) Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 123:2094-101
Oikonomopoulou, Katerina; DeAngelis, Robert A; Chen, Hui et al. (2013) Induction of complement C3a receptor responses by kallikrein-related peptidase 14. J Immunol 191:3858-66
Lupu, C; Herlea, O; Tang, H et al. (2013) Plasmin-dependent proteolysis of tissue factor pathway inhibitor in a mouse model of endotoxemia. J Thromb Haemost 11:142-8
Kourtzelis, Ioannis; Rafail, Stavros; DeAngelis, Robert A et al. (2013) Inhibition of biomaterial-induced complement activation attenuates the inflammatory host response to implantation. FASEB J 27:2768-76
Qu, Hongchang; Ricklin, Daniel; Bai, Hongjun et al. (2013) New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties. Immunobiology 218:496-505

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