Objective: Sepsis-induced lung injury is a persisting clinical problem with no direct therapy. Recent work suggests that intravenously infused ascorbic acid improves the circulatory dysfunction of sepsis. We used a model of endotoxin-induced acute lung injury to determine whether parenteral ascorbic acid modulates the dysregulated proinflammatory, procoagulant state that leads to lung injury.
Design: C57BL/6 mice were exposed to lethal lipopolysaccharide doses (10 μg/g of body weight) to induce acute lung injury.
Setting: Laboratory investigation.
Subjects: Wild-type C57BL/6 mice.
Interventions: Ascorbic acid or its oxidized form (dehydroascorbic acid) was administered intraperitoneally at 200 mg/kg 30 mins after the lethal lipopolysaccharide dose.
Measurements and Main Results: We quantified survival, lung capillary leak, proinflammatory chemokine expression, and lung microvascular thrombosis. Lipopolysaccharide induced 100% lethality in mice within 28 hrs of exposure and in lung we observed intense neutrophil sequestration, loss of capillary barrier function, exuberant pulmonary inflammation, and extensive microthrombus formation. A time-delayed infusion protocol of both ascorbic acid and dehydroascorbic acid significantly prolonged survival. Both ascorbic acid and dehydroascorbic acid preserved lung architecture and barrier function while attenuating proinflammatory chemokine expression and microvascular thrombosis. Ascorbic acid and dehydroascorbic acid attenuated nuclear factor kappa B activation and normalized coagulation parameters.
Conclusions: Ascorbic acid administered in an interventional manner following lipopolysaccharide infusion attenuates proinflammatory, procoagulant states that induce lung vascular injury in an animal model of sepsis.
From the Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine (BJF, IMS, DK, NFV, AAF, RN) and Department of Medicinal Chemistry (JNT), Virginia Commonwealth University, Richmond, VA.
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This research was supported by a grant from the A.D. Williams Research Foundation (RN), by the Victoria Johnson Center for Obstructive Lung Disease and the Aubery Sage Mac Farlane Endowment for Acute Lung Injury Research.
Dr. Natarajan received funding from the A.D. Williams research foundation. The remaining authors have not disclosed any potential conflicts of interest.
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