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.

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Vanderbilt University Medical Center
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Simpson, Scott A; Zaccagni, Hayden; Bichell, David P et al. (2014) Acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass. Pediatr Crit Care Med 15:503-10
Shonesy, Brian C; Bluett, Rebecca J; Ramikie, Teniel S et al. (2014) Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation. Cell Rep 9:1644-53
Wu, Jing; Thabet, Salim R; Kirabo, Annet et al. (2014) Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res 114:616-25
Xu, Shu; Hermanson, Daniel J; Banerjee, Surajit et al. (2014) Oxicams bind in a novel mode to the cyclooxygenase active site via a two-water-mediated H-bonding Network. J Biol Chem 289:6799-808
Neau, David B; Bender, Gunes; Boeglin, William E et al. (2014) Crystal structure of a lipoxygenase in complex with substrate: the arachidonic acid-binding site of 8R-lipoxygenase. J Biol Chem 289:31905-13
Shuck, Sarah C; Wauchope, Orrette R; Rose, Kristie L et al. (2014) Protein modification by adenine propenal. Chem Res Toxicol 27:1732-42
Hermanson, Daniel J; Gamble-George, Joyonna C; Marnett, Lawrence J et al. (2014) Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation. Trends Pharmacol Sci 35:358-67
Dikalov, Sergey I; Nazarewicz, Rafal R; Bikineyeva, Alfiya et al. (2014) Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension. Antioxid Redox Signal 20:281-94
Kirabo, Annet; Fontana, Vanessa; de Faria, Ana P C et al. (2014) DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest 124:4642-56
Trott, Daniel W; Thabet, Salim R; Kirabo, Annet et al. (2014) Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension 64:1108-15

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