Ramesh Natarajan, PhD

Professor of Medicine, Department of Internal Medicine,
Division of Pulmonary Disease and Critical Care Medicine
Virginia Commonwealth University, Richmond, VA

image of Dr. Ramesh Natarajan

Abstract: Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Sepsis-induced acute lung injury (ALI) is a persisting clinical problem with no direct therapy. We used various models of sepsis in wild type and knockout mice to determine whether parenteral vitamin C modulates the dysregulated pro-inflammatory, pro-coagulant state that leads to sepsis-induced lung injury. Male C57BL/6 wild type mice and mice lacking functional L-gulono-γ-lactone oxidase (Gulo−/−) were exposed to bacterial lipopolysaccharide (endotoxin) or a fecal stem solution (polymicrobial sepsis) to induce abdominal peritonitis 30 min prior to parenterally receiving either reduced vitamin C (ascorbic acid, 200 mg/kg) or oxidized vitamin C (dehydroascorbic acid, 200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers, bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression, tight junction protein expression, cytoskeletal rearrangements, neutrophil extracellular trap formation (NETosis), multiple organ failure and various coagulation parameters in septic blood. Sepsis induced ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, increased formation of NETs, significant coagulation abnormalities, and increased mortality due to multiple organ failure. A single infusion of parenteral vitamin C protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the NFκB driven pro-inflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, prevention of sepsis-associated coagulation abnormalities, attenuation of NETosis, and normalization of physiological functions that attenuated the development of multiple organ dysfunction. These pre-clinical studies using parenteral vitamin C were central to the completed PHASE I trial of intravenous vitamin C in sepsis and the ongoing PHASE II multi-center trial examining the efficacy of intravenous vitamin C infusion in human sepsis-associated ALI.

New data from a model of hemorrhagic shock and polytrauma show that IV vitamin C may mitigate the pro-inflammatory/pro-coagulant response that contributes to multiple organ failure following acute severe polytrauma.