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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Dunsmore, Sarah
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Feinstein Institute for Medical Research
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Aziz, Monowar; Ode, Yasumasa; Zhou, Mian et al. (2018) B-1a cells protect mice from sepsis-induced acute lung injury. Mol Med 24:26
Hirano, Yohei; Ode, Yasumasa; Ochani, Mahendar et al. (2018) Targeting junctional adhesion molecule-C ameliorates sepsis-induced acute lung injury by decreasing CXCR4+ aged neutrophils. J Leukoc Biol 104:1159-1171
Matsuo, Shingo; Sharma, Archna; Wang, Ping et al. (2018) PYR-41, A Ubiquitin-Activating Enzyme E1 Inhibitor, Attenuates Lung Injury in Sepsis. Shock 49:442-450
Hendricks, Louie; Aziz, Monowar; Yang, Weng-Lang et al. (2017) Milk fat globule-epidermal growth factor-factor VIII-derived peptide MSP68 is a cytoskeletal immunomodulator of neutrophils that inhibits Rac1. J Surg Res 208:10-19
Aziz, Monowar; Holodick, Nichol E; Rothstein, Thomas L et al. (2017) B-1a Cells Protect Mice from Sepsis: Critical Role of CREB. J Immunol 199:750-760
Khan, Mohammad Moshahid; Yang, Weng-Lang; Brenner, Max et al. (2017) Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress. Sci Rep 7:41363
Hirano, Yohei; Aziz, Monowar; Yang, Weng-Lang et al. (2016) Neutralization of Osteopontin Ameliorates Acute Lung Injury Induced by Intestinal Ischemia-Reperfusion. Shock 46:431-8
Idrovo, Juan Pablo; Yang, Weng-Lang; Jacob, Asha et al. (2016) Inhibition of lipogenesis reduces inflammation and organ injury in sepsis. J Surg Res 200:242-9
Hirano, Yohei; Aziz, Monowar; Wang, Ping (2016) Role of reverse transendothelial migration of neutrophils in inflammation. Biol Chem 397:497-506
Cen, Cindy; Aziz, Monowar; Yang, Weng-Lang et al. (2016) Milk fat globule-epidermal growth factor-factor VIII downregulates interleukin-17 expression in sepsis by modulating STAT3 activation. Surgery 159:560-9

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