Despite advances in the management of sepsis patients, a large number of those patients die from the ensuing septic shock and multiple organ failure. Thus, there is an urgent unmet medical need for a novel and effective therapy for sepsis. Excessive recruitment of activated neutrophils into various tissues is a major contributing factor for organ injury in sepsis. In the previous cycle of this project, we have demonstrated the beneficial effect of milk fat globule epidermal growth factor-factor VIII (MFG-E8) in reducing inflammatory responses and organ injury, and improving survival in an animal model of sepsis induced by cecal ligation and puncture (CLP). We have recently discovered a novel property of MFG-E8 in inhibiting the infiltration of activated neutrophils into tissues. By analyzing the proten structure of human MFG-E8 for its binding to integrins, we have screened a large number of human MFG-E8-derived peptides. We have identified a short peptide, named MSP68, which inhibited neutrophil adhesion and migration. In this renewal application, we will focus on further characterization of MSP68 in alleviating tissue injury in sepsis and the development of MSP68 as a new anti-sepsis therapy. Post-treatment with MSP68 significantly decreased the inflammatory responses and attenuated organ damage in sepsis mice induced by CLP. MSP68 treatment reduced the number of neutrophils infiltrating into the lungs and liver of sepsis mice. The ten-day survival of sepsis mice was markedly improved with MSP68 treatment. MSP68 had a direct effect on regulating neutrophil adhesion and chemotaxis. Using surface plasmon resonance (SPR) analysis, we further demonstrated that MSP68 bound to integrins directly. Based on these novel findings, we hypothesize that the human MFG-E8-derived peptide MSP68 inhibits neutrophil infiltration into tissues during sepsis, leading to the attenuation of tissue ijury and improvement in survival of sepsis animals. Accordingly, three specific aims are proposed: (1) to further investigate the role of MSP68 in inhibiting neutrophil infiltration in sepsis;(2) t determine the molecular mechanism responsible for such an inhibitory effect of MSP68;and (3) to evaluate the efficacy and safety of MSP68 as a therapeutic agent for sepsis. The proposed studies will lead to a new direction for the development of innovative therapeutics for patients with sepsis. Through this innovative research, it is expected that MSP68 will be developed as a novel drug to treat sepsis and septic shock.

Public Health Relevance

Sepsis is one of the leading causes of death in the intensive care unit (ICU). More than 750,000 people in the US develop sepsis annually, out of which over 210,000 people succumb to this overwhelming inflammatory reaction associated with infection. Given the intensive and prolonged care necessary to treat patients with sepsis, it costs $16.7 billion nationally for treatment and this economic burden is profound. Thus, there is an urgent unmet medical need for an effective therapy for treating patients with sepsis. Our innovative and pioneering research led to the discovery that rhMFG-E8-derived peptide MSP68 prevents excessive neutrophil infiltration into tissues, which reduces sepsis-induced injury and mortality. This novel finding will lead to the development of new therapeutic agents modulating neutrophils for effectively treating sepsis and septic shock.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM057468-14A1
Application #
8761161
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
1998-05-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
14
Fiscal Year
2014
Total Cost
$345,425
Indirect Cost
$140,425
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Aziz, M; Jacob, A; Wang, P (2014) Revisiting caspases in sepsis. Cell Death Dis 5:e1526
Zhou, Mian; Yang, Weng-Lang; Ji, Youxin et al. (2014) Cold-inducible RNA-binding protein mediates neuroinflammation in cerebral ischemia. Biochim Biophys Acta 1840:2253-61
Sharma, Archna; Matsuo, Shingo; Yang, Weng-Lang et al. (2014) Receptor-interacting protein kinase 3 deficiency inhibits immune cell infiltration and attenuates organ injury in sepsis. Crit Care 18:R142
Matsuda, Akihisa; Yang, Weng-Lang; Jacob, Asha et al. (2014) FK866, a visfatin inhibitor, protects against acute lung injury after intestinal ischemia-reperfusion in mice via NF-*B pathway. Ann Surg 259:1007-17
Aziz, Monowar; Yang, Weng-Lang; Matsuo, Shingo et al. (2014) Upregulation of GRAIL is associated with impaired CD4 T cell proliferation in sepsis. J Immunol 192:2305-14
Matsuo, Shingo; Yang, Weng-Lang; Aziz, Monowar et al. (2014) Fatty acid synthase inhibitor C75 ameliorates experimental colitis. Mol Med 20:1-9
Khader, Adam; Yang, Weng-Lang; Kuncewitch, Michael et al. (2014) Sirtuin 1 activation stimulates mitochondrial biogenesis and attenuates renal injury after ischemia-reperfusion. Transplantation 98:148-56
Giangola, Matthew D; Yang, Weng-Lang; Rajayer, Salil R et al. (2013) Growth arrest-specific protein 6 attenuates neutrophil migration and acute lung injury in sepsis. Shock 40:485-91
Aziz, Monowar; Yang, Weng-Lang; Wang, Ping (2013) Measurement of phagocytic engulfment of apoptotic cells by macrophages using pHrodo succinimidyl ester. Curr Protoc Immunol Chapter 14:Unit 14.31.
Matsuda, Akihisa; Jacob, Asha; Wu, Rongqian et al. (2013) Milk fat globule--EGF factor VIII ameliorates liver injury after hepatic ischemia-reperfusion. J Surg Res 180:e37-46

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