Hemorrhagic shock is a significant complication of surgical, gastrointestinal, and obstetric hemorrhage, but it is most commonly caused by severe trauma. Trauma is the leading cause of death in Americans 44 years-old or younger. During hemorrhagic responses, vascular endothelial cells (ECs) are activated and lose their integrity, contributing significantly to multi-organ failure and lethality. We have recently discovered that cold-inducible RNA-binding protein (CIRP) functions as a damage-associated molecular pattern (DAMP). In an animal model of hemorrhage, CIRP was upregulated in tissues and released into the circulation. Injection of healthy mice with recombinant murine CIRP (rmCIRP) caused an elevation of circulating tissue injury markers and vascular leakage in the lungs in association with increased expression of EC surface adhesion molecules. We then treated primary mouse lung vascular ECs with rmCIRP and observed increased ICAM-1 expression, NAD(P)H oxidase activation, inflammasome assembly and activation, and IL-1? release. We also demonstrated that rmCIRP induced EC pyroptosis. Based on these novel findings, we hypothesize that the CIRP released after hemorrhage causes EC activation and pyroptosis, leading to vascular EC dysfunction and organ damage. We have also identified a 15-mer peptide derived from human CIRP, named C23, which attenuated the expression of EC surface adhesion molecules and proinflammatory cytokines in the lungs as well as serum organ injury markers of hemorrhaged animals. Administration of C23 also reduced vascular leakage in the lungs after hemorrhage. Thus, we further hypothesize that CIRP antagonism by C23 represents a novel adjunct therapy for traumatic hemorrhage resuscitation via attenuation of EC damage. Accordingly, we plan to test the following four Specific Aims: (1) to confirm the pivotal role of CIRP in causing vascular EC injury after hemorrhage; (2) to determine the effect of CIRP on the activation of vascular ECs after hemorrhage; (3) to examine effects of CIRP on the induction of EC pyroptosis after hemorrhage; and (4) to develop an anti-CIRP peptide as a therapeutic adjunct for EC damage and mortality after hemorrhage. These proposed studies will lead to a new direction towards the development of innovative therapeutics as resuscitation adjuncts for patients suffering from trauma and hemorrhagic shock.

Public Health Relevance

Trauma-hemorrhage is a major cause of death worldwide. In the United States, hemorrhagic shock accounts for one third of mortality caused by traumatic injury, which is the main cause of death in individuals younger than 44 years of age. There is an unmet and critical need for a novel and effective therapy capable of improving hemorrhage survival and recovery. Our innovative and pioneering research led to the discovery that cold-inducible RNA-binding protein (CIRP) induces vascular endothelial dysfunction, and may thus contribute to hemorrhage-related morbidity and mortality. This project will lead to the development of a new class of therapeutic agents against CIRP to effectively manage trauma victims with major blood loss via attenuation of vascular endothelial damage.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076179-10
Application #
9225121
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Schwartz, Lisa
Project Start
2004-02-01
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
10
Fiscal Year
2017
Total Cost
$424,817
Indirect Cost
$133,636
Name
Feinstein Institute for Medical Research
Department
Type
Research Institutes
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
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Li, Zhi-Gang; Scott, Melanie J; Brzóska, Tomasz et al. (2018) Lung epithelial cell-derived IL-25 negatively regulates LPS-induced exosome release from macrophages. Mil Med Res 5:24
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Fan, Erica K Y; Fan, Jie (2018) Regulation of alveolar macrophage death in acute lung inflammation. Respir Res 19:50
Bolognese, Alexandra C; Sharma, Archna; Yang, Weng-Lang et al. (2018) Cold-inducible RNA-binding protein activates splenic T cells during sepsis in a TLR4-dependent manner. Cell Mol Immunol 15:38-47
McGinn, Joseph; Zhang, Fangming; Aziz, Monowar et al. (2018) The Protective Effect of A Short Peptide Derived From Cold-Inducible RNA-Binding Protein in Renal Ischemia-Reperfusion Injury. Shock 49:269-276
Li, Zhigang; Jiao, Yang; Fan, Erica K et al. (2017) Aging-Impaired Filamentous Actin Polymerization Signaling Reduces Alveolar Macrophage Phagocytosis of Bacteria. J Immunol 199:3176-3186
Zhang, Fangming; Yang, Weng-Lang; Brenner, Max et al. (2017) Attenuation of hemorrhage-associated lung injury by adjuvant treatment with C23, an oligopeptide derived from cold-inducible RNA-binding protein (CIRP). J Trauma Acute Care Surg :
Cen, Cindy; Aziz, Monowar; Yang, Weng-Lang et al. (2017) Osteopontin Blockade Attenuates Renal Injury After Ischemia Reperfusion by Inhibiting NK Cell Infiltration. Shock 47:52-60

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