Traumatic injury is a major, largely unrecognized public health problem in North America that cuts across age, race, gender, and economic boundaries. The resulting loss of productive life years exceeds that of any other diseases in the US, with societal costs of over $260 billion each year. Most trauma deaths result from insufficient tissue perfusion due to excessive blood loss or from the development of inflammation, infection, and organ damage after seemingly "adequate" resuscitation. Clinical management of hemorrhagic shock relies on massive and rapid infusion of fluids to maintain blood pressure. However, the majority of victims with severe blood loss do not respond well to fluid restoration. Development of effective strategies for resuscitation of traumatic blood loss, therefore, is urgently needed. In this proposal, we will continue our discovery of a novel proinflammatory mediator/cytokine, cold-inducible RNA-binding protein (CIRP). We have shown that CIRP expression is upregulated in an animal model of hemorrhage and in surgical ICU patients. By using newly-expressed and purified recombinant murine CIRP (rmCIRP), we have demonstrated that administration of rmCIRP in healthy animals induces acute inflammation and causes tissue injury. In addition, anti-rmCIRP antibodies attenuate hemorrhage-induced proinflammatory cytokines, neutrophil accumulation, and tissue injury. Anti-rmCIRP antibodies also improve the survival rate from 43% to 85% after hemorrhage and fluid resuscitation. Moreover, hemorrhage-induced mortality is much lower in CIRP knockout mice (CIRP-/-) than that of wild-type mice. By using GFP-CIRP expression plasmid, we were able to show CIRP translocation from the nucleus to cytoplasm under hypoxic conditions. We have determined that TLR4, rather than TLR2 or RAGE, serves as CIRP receptor. Biacore(R) biosensor assay showed a high binding affinity (Kd =1.55M) between human CIRP and human TLR4/MD2 complex. Based on these novel findings, we hypothesize that CIRP plays an important role in hemorrhage-induced tissue injury and mortality, and that CIRP antagonists should provide a novel adjunct therapy for traumatic hemorrhage resuscitation. Accordingly, three specific aims are proposed: (1) to study the mechanism responsible for hemorrhage-induced upregulation of CIRP;(2) to define the mechanism by which CIRP produces inflammation and tissue injury;and (3) to determine whether delayed CIRP inhibition after hemorrhage with crystalloid versus blood resuscitation is also beneficial. These proposed studies should open up a new research field for the development of innovative therapeutic agents as resuscitation adjuncts for victims with traumatic hemorrhage.

Public Health Relevance

Trauma and hemorrhagic shock are common, expensive, and frequently fatal conditions with a mortality rate as high as 80%. The resulting loss of productive life is very significant, with societal costs greater than $260 billion each year in the US alone. It is obvious that there is an urgent unmet medical need for an effective novel therapy for patients with trauma and hemorrhage. Our innovative approach to pioneer a new research field of the proinflammatory mediator (i.e., cold shock proteins) will promote the discovery of a new class of effective therapeutic agents for the treatment of this critical clinical condition.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076179-07
Application #
8473262
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Schwartz, Lisa
Project Start
2004-02-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$395,080
Indirect Cost
$157,080
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
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Kuncewitch, Michael; Yang, Weng-Lang; Corbo, Lana et al. (2015) WNT Agonist Decreases Tissue Damage and Improves Renal Function After Ischemia-Reperfusion. Shock 43:268-75
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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
Qiang, Xiaoling; Yang, Weng-Lang; Wu, Rongqian et al. (2013) Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med 19:1489-95
Zhou, Mian; Wang, Christie M; Yang, Weng-Lang et al. (2013) Microglial CD14 activated by iNOS contributes to neuroinflammation in cerebral ischemia. Brain Res 1506:105-14
Kuncewitch, Michael; Yang, Weng-Lang; Molmenti, Ernesto et al. (2013) Wnt agonist attenuates liver injury and improves survival after hepatic ischemia/reperfusion. Shock 39:3-10

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