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. )

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097747-03
Application #
8466739
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dunsmore, Sarah
Project Start
2011-08-02
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$502,824
Indirect Cost
$146,404
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Hajishengallis, George; Hajishengallis, Evlambia; Kajikawa, Tetsuhiro et al. (2016) Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application. Semin Immunol 28:285-91
Mastellos, D C; Ricklin, D; Hajishengallis, E et al. (2016) Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention. Mol Oral Microbiol 31:3-17
Frej, Cecilia; Linder, Adam; Happonen, Kaisa E et al. (2016) Sphingosine 1-phosphate and its carrier apolipoprotein M in human sepsis and in Escherichia coli sepsis in baboons. J Cell Mol Med 20:1170-81
Silasi-Mansat, Robert; Zhu, Hua; Georgescu, Constantin et al. (2015) Complement inhibition decreases early fibrogenic events in the lung of septic baboons. J Cell Mol Med 19:2549-63
Sfyroera, Georgia; Ricklin, Daniel; Reis, Edimara S et al. (2015) Rare loss-of-function mutation in complement component C3 provides insight into molecular and pathophysiological determinants of complement activity. J Immunol 194:3305-16
Zhang, Yuzhou; Shao, Dingwu; Ricklin, Daniel et al. (2015) Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy. Immunobiology 220:993-8
Mastellos, Dimitrios C; Yancopoulou, Despina; Kokkinos, Petros et al. (2015) Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. Eur J Clin Invest 45:423-40
Lin, Zhuoer; Schmidt, Christoph Q; Koutsogiannaki, Sophia et al. (2015) Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria. Blood 126:891-4
Chaaban, Hala; Keshari, Ravi S; Silasi-Mansat, Robert et al. (2015) Inter-α inhibitor protein and its associated glycosaminoglycans protect against histone-induced injury. Blood 125:2286-96
Hajishengallis, George; Chavakis, Triantafyllos; Hajishengallis, Evlambia et al. (2015) Neutrophil homeostasis and inflammation: novel paradigms from studying periodontitis. J Leukoc Biol 98:539-48

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