In the United States, traumatic injury accounts for a greater loss of productive life years than that of any other disease and has an estimated annual healthcare cost of 400 billion dollars per year. For patients that are injured, major bleeding accounts for the largest number of deaths that are potentially preventable both in civilian and military trauma. Mortality in patients that survive the initial insult is often due to the development of organ dysfunction and/or sepsis. Thus, understanding the cellular mechanisms that lead to tissue injury and the development of therapeutic adjuncts that can be instituted in the field early in the care of these patients has tremendous potential to significantly improve morbidity and mortality. Our investigations have focused on the understanding of the role of carbon monoxide (CO) in physiological and pathophysiological conditions, as well as the development of CO as a therapeutic. CO is produces endogenously in the breakdown of heme by heme oxygenase enzymes and has been shown to possess significant anti-inflammatory properties. Exogenous CO can be harnessed for its cytoprotective properties and we have been studying the use of inhaled CO as a therapeutic in pre-clinical models since 1999. Our strong preclinical data demonstrates that inhaled CO can protect against the development of shock, inflammation, organ injury, and death from hemorrhage. Importantly, cells and tissues must be able to adjust metabolism and intracellular processes to accommodate for the lack of oxygen and other vital cellular resources that characterize shock states. Only recently we have recognized a role for HO enzymes and CO in the control of cellular metabolism and bioenergetics. Our experiments are designed to study the mechanism(s) of HO signaling, as well as the protective mechanism(s) of CO when delivered exogenously as a therapeutic in models of acute severe hemorrhage and resuscitation. Our studies concentrate on the influence of HO enzymes and CO within the liver and hepatocytes, as hepatic injury has been a major area of investigation within our laboratory. Based on our published work and promising preliminary data we hypothesize that: Heme Oxygenase Enzymes/Carbon Monoxide protect against the development of shock/bioenergetic failure from hemorrhage or hypoxia. We shall test these hypotheses by addressing the following aims:
Specific Aim I : To determine the role and mechanism(s) of HO/CO in the regulation of respiration to protect against organ dysfunction from hemorrhagic shock.
Specific Aim II. To determine the protective role of mitochondria as signaling organelles in hemorrhage/resuscitation and the mechanisms of regulation by HO/CO.

Public Health Relevance

Traumatic injury results in the greatest loss of productive life years compared to all other diseases in the United States. The development of shock and multiple organ dysfunction secondary to hemorrhage accounts for a significant portion of these deaths;however, it has been exceedingly difficult to develop treatment strategies that effectively reverse the processes. In the proposed study, we will investigate the therapeutic effect of inhaled carbon monoxide as well as the role(s) of heme oxygenase enzymes in the regulation of cellular metabolism and adaptive bioenergetic signaling to limit hepatic and organ injury from hemorrhage.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM082830-04
Application #
8541029
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$282,234
Indirect Cost
$95,941
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nassour, Ibrahim; Kautza, Benjamin; Rubin, Mark et al. (2015) Carbon monoxide protects against hemorrhagic shock and resuscitation-induced microcirculatory injury and tissue injury. Shock 43:166-71
Escobar, Daniel A; Botero-Quintero, Ana M; Kautza, Benjamin C et al. (2015) Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation. J Surg Res 194:262-72
Wegiel, B; Hedblom, A; Li, M et al. (2014) Heme oxygenase-1 derived carbon monoxide permits maturation of myeloid cells. Cell Death Dis 5:e1139
Seymour, Christopher W; Yende, Sachin; Scott, Melanie J et al. (2013) Metabolomics in pneumonia and sepsis: an analysis of the GenIMS cohort study. Intensive Care Med 39:1423-34