Hemeprotein-catalyzed lipid peroxidation contributes to the pathophysiology of diseases in which myoglobin and hemoglobin are released from the antioxidant environment of cells. These include a major contribution of myoglobin-catalyzed lipid peroxidation to the renal failure produced by rhabdomyolysis. Lipid peroxidation induced by hemoglobin is correlated with the pathophysiology of subarachnoid hemorrhage. Among the products of lipid peroxidation are the F2-isoprostanes, which are highly potent vasoconstrictors. We have demonstrated that lipid peroxidation catalyzed by the peroxidase-like function of oxidized hemoproteins is inhibited by acetaminophen. In a rat model of rhabdomyolysis in which Fa-isoprostanes generated intrarenally contribute to the renal failure, acetaminophen significantly reduced lipid peroxidation and markedly decreased the extent of renal failure. In a rabbit model of subarachnoid hemorrhage, an acetaminophen prodrug significantly reduced levels of F2-isoprostanes. Based on this evidence, the effect of acetaminophen will be evaluated in subarachnoid hemorrhage, in which evidence of lipid peroxidation correlates with time of delayed vasospasm and with severity of neurological deficits. This will be a pilot study in which acetaminophen based regimens will be tested for their ability to reduce lipid peroxidation assessed by measurement of F2-isoprostane levels in cerebrospinal fluid. Secondary endpoints will include vasospasm, as well as neurological outcome, but this pilot study is not powered for these. The results could provide a basis for a larger outcome study, and a rationale for development of even more potent regimens for inhibiting hemoprotein-catalyzed lipid peroxidation in subarachnoid hemorrhage. Acute kidney injury occurs in up to 30% of patients who undergo cardiac surgery with cardiopulmonary bypass, and is an independent predictor of morbidity and mortality. Elevated plasma levels of free hemoglobin and myoglobin correlate with acute kidney injury, and increased levels of the lipid peroxidation biomarkers, F2-isoprostanes and isofurans, are also associated with acute kidney injury. The concerted evidence supports a hypothesis that hemeprotein-catalyzed peroxidation of renal lipids is a major and potentially modifiable contributor to the acute kidney injury. Accordingly, a proof-of-concept investigation to assess the effect of acetaminophen on F2-isoprostanes and isofurans in patients undergoing cardiac surgery with cardiopulmonary bypass is proposed. Evidence that acetaminophen inhibited lipid peroxidation in these patients would provide a rationale for an outcome study evaluating its effect on acute kidney injury in these patients.

Public Health Relevance

Clinical investigations are proposed that aim to improve the treatment of subarachnoid hemorrhage, a form of stroke that can cause injury to the brain leading to disability or death. A related study will evaluate a treatment aimed at preventing the injury to the kidneys that can occur in patients undergoing cardiac surgery this kidney injury can lead to a loss of kidney function that complicates their recovery and can cause kidney failure or death.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM015431-45
Application #
8379501
Study Section
Special Emphasis Panel (ZGM1-PPBC-6)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
45
Fiscal Year
2012
Total Cost
$513,361
Indirect Cost
$198,494
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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