Severe hemorrhage as a result of traumatic injury is major cause of death in the United Stated. Because death from severe blood loss often occurs 'in the field' or within 4 hours of injury, early intervention and therapeutics that can delay or prevent the progression to irreversible hemorrhagic shock need to be elucidated. The insult from severe hemorrhage is a multifactorial global injury involving ischemia/reperfusion with inflammatory and autonomic dysfunction, which can result in microvascular dysfunction and circulatory collapse. The cellular and molecular responses to such an insult involve increased expression of antioxidant enzymes and stress response genes, including the stress-inducible gene heme oxygenase-1 (HO-1). HO-1 catalyzes the first and rate-limiting step in the catabolism of heme to yield equimolar quantities of biliverdin IXa, carbon monoxide (CO), and iron. Our laboratories and others have demonstrated that the induction of HO-1 provides cytoprotection both in vivo and in vitro against multiple modes of injury including endotoxemia, ischemia/reperfusion, and hemorrhage. Recent studies have illustrated that production of CO can mediate the cytoprotection seen with induction of HO-1. Bypassing the need to increase expression of HO-1, delivery of exogenous CO can also be cytoprotective. Our preliminary data in a murine model of hemorrhagic shock demonstrates that delivery of low dose inhaled CO can protect against the development of endorgan injury, decreases serum levels of inflammatory cytokines and increases serum levels of the anti-inflammatory cytokine IL-10. Additionally, we demonstrate that inhaled CO can decrease tissue hypoxia during hemorrhage. Further preliminary data suggests that these effects may be secondary to maintenance and regulation of the microcirculation as well as by protecting against multiple modes of cell death. CO, either by inhalation or controlled pharmacological release, represents a novel and feasible therapy that could be instituted rapidly and with ease as an out-of-hospital adjunct for severe blood loss and trauma. We hypothesize that carbon monoxide can protect against the onset of hypovolemic circulatory collapse and the development of irreversible hemorrhagic shock. Furthermore, that this protection is the result of the ability of CO to regulate and preserve microcirculatory blood flow and tissue perfusion by preventing endothelial cell activation and cell death. We shall test these hypotheses by addressing the following aims:
Specific Aim # l: To demonstrate that CO confers protection against the development of shock and circulatory collapse.
Specific Aim #2 : To test whether the protective effects of CO on shock and tissue hypoxia involve maintenance and/or regulation of the endothelium and microcirculation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076167-04
Application #
7060408
Study Section
Special Emphasis Panel (ZHL1-CSR-I (F1))
Program Officer
Liang, Isabella Y
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$415,013
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Schallner, Nils; Pandit, Rambhau; LeBlanc 3rd, Robert et al. (2015) Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1. J Clin Invest 125:2609-25
Otterbein, Leo E; Fan, Zhigang; Koulmanda, Maria et al. (2015) Innate immunity for better or worse govern the allograft response. Curr Opin Organ Transplant 20:8-12
Wegiel, Barbara; Larsen, Rasmus; Gallo, David et al. (2014) Macrophages sense and kill bacteria through carbon monoxide-dependent inflammasome activation. J Clin Invest 124:4926-40
Wegiel, Barbara; Gallo, David; Csizmadia, Eva et al. (2013) Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth. Cancer Res 73:7009-21
Andria, Barbara; Bracco, Adele; Attanasio, Chiara et al. (2013) Biliverdin protects against liver ischemia reperfusion injury in swine. PLoS One 8:e69972
Kuramitsu, Kaori; Gallo, David; Yoon, Myunghee et al. (2011) Carbon monoxide enhances early liver regeneration in mice after hepatectomy. Hepatology 53:2016-26
Wegiel, Barbara; Gallo, David J; Raman, Kathleen G et al. (2010) Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury. Circulation 121:537-48
Wegiel, Barbara; Baty, Catherine J; Gallo, David et al. (2009) Cell surface biliverdin reductase mediates biliverdin-induced anti-inflammatory effects via phosphatidylinositol 3-kinase and Akt. J Biol Chem 284:21369-78
Wegiel, Barbara; Chin, Beek Y; Otterbein, Leo E (2008) Inhale to survive, cycle or die? Carbon monoxide and cellular proliferation. Cell Cycle 7:1379-84
Scott, Jeffrey R; Chin, Beek Y; Bilban, Martin H et al. (2007) Restoring HOmeostasis: is heme oxygenase-1 ready for the clinic? Trends Pharmacol Sci 28:200-5

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