Calcium Oxalate Monohydrate is Associated with Endothelial Cell Toxicity But Not with Reactive Oxygen Species Accumulati
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Calcium Oxalate Monohydrate is Associated with Endothelial Cell Toxicity But Not with Reactive Oxygen Species Accumulation Brian L. Crenshaw1 · Kenneth E. McMartin1
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract One characteristic of ethylene glycol overdose is a cardiopulmonary syndrome including hypertension and pulmonary edema with pathology indicating damage to the endothelium of heart, lung and brain vessels. The mechanism of the cardiopulmonary toxicity is unknown, but has been linked with accumulation of the metabolite calcium oxalate monohydrate (COM) in the endothelium. These studies have evaluated the hypothesis that COM or the oxalate ion produces endothelial damage in vitro and that damage is linked with induction of reactive oxygen species (ROS). In cultured human umbilical vein endothelial cells (HUVEC), COM, but not the oxalate ion, produced cytotoxicity in a dose- and time-dependent manner. Using three ROS-sensitive dyes, HUVEC exposed to COM did not significantly increase ROS production. Additionally, co-treatment with three antioxidants that operate by different mechanisms did not reduce COM cytotoxicity. As such, an increase in ROS production does not explain cell death in endothelial cells. Aluminum citrate, uniquely among citrate compounds, significantly reduced COM cytotoxicity to endothelial cells and thus may act as an adjunct therapy for ethylene glycol poisoning to reduce endothelial damage. These results imply that accumulation of COM in endothelial cells is an important aspect of the cardiopulmonary toxicity from ethylene glycol. Keywords Oxidative stress · Oxalate crystals · Ethylene glycol poisoning · HUVEC · Antioxidants · Citrate therapy
Introduction Overdose ingestion of ethylene glycol (EG), whether intentional or accidental, can lead to serious morbidity, including central nervous system (CNS) depression, cardiopulmonary collapse, and acute kidney injury (AKI), due to conversion of EG to toxic metabolites. The cardiopulmonary stage includes symptoms of hypertension, tachycardia, pulmonary edema, and eventually cardiac failure [14]. Autopsies have shown edema, hemorrhage, and perivascular inflammation near small blood vessels in the brain, lungs, and heart [15, 16], findings that suggest exudative damage to the endothelial cells. The mechanism of the cardiopulmonary toxicity from EG is unknown, but is probably associated with Handling Editor: Michael Tranter. * Kenneth E. McMartin [email protected] 1
Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA 71130‑3932, USA
metabolite accumulation in the endothelium. Oxalate, the end metabolite of EG, readily complexes with free Ca2+ to precipitate as calcium oxalate monohydrate (COM). Deposition of COM crystals in blood vessels of the brain, heart and lungs has been observed at post mortem examination of EG patients [15, 20]. Primary hyperoxaluria (PH), an elevated plasma oxalate disease, also leads to systemic deposition of COM
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