Vitamin C: Rationale for Its Use in Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)

Abstract

Acute respiratory distress syndrome (ARDS) is a life-threatening event that occurs in patients suffering from bacterial, fungal, or viral sepsis. Research performed over the last five decades showed that ARDS is a consequence of severe unrestrained systemic inflammation, which leads to injury of the lung's microvasculature and alveolar epithelium. ARDS leads to acute hypoxic/hypercapnic respiratory failure and death in a significant number of patients hospitalized in intensive care units worldwide. Basic and clinical research performed during the time since ARDS was first described has been unable to construct a pharmacological agent that will combat the inflammatory fire leading to ARDS. In-depth studies of the molecular pharmacology of vitamin C indicate that it can serve as a potent anti-inflammatory agent capable of attenuating the pathobiological events that lead to acute injury of the lungs and other body organs. This analysis of vitamin C's role in the treatment of ARDS includes a focused systematic review of the literature relevant to the molecular physiology of vitamin C and to the past performance of clinical trials using the agent.

Keywords: ARDS; NETosis; cell-free hemoglobin (CFH); lung vascular injury; neutrophil extracellular traps (NETS); reactive oxygen species (ROS); sepsis; sodium vitamin C transporters SVCT 1 and 2; vitamin C.

Figure 1

(A) Activated neutrophils adhere to the surfaces of pulmonary capillaries following the onset of sepsis. (B) Activated neutrophils damage pulmonary capillary surfaces, which lead to the disruption of the alveolar capillary membrane and loss of lung barrier function. (C) Activated adherent neutrophils transmigrate into the alveolar space. Oxidants, proteases, proinflammatory lipids, cell-free DNA, and potent cytokines and chemokines damage constituents of the alveolar space, further promoting inflammatory injury.

Figure 1

(A) Activated neutrophils adhere to the surfaces of pulmonary capillaries following the onset of sepsis. (B) Activated neutrophils damage pulmonary capillary surfaces, which lead to the disruption of the alveolar capillary membrane and loss of lung barrier function. (C) Activated adherent neutrophils transmigrate into the alveolar space. Oxidants, proteases, proinflammatory lipids, cell-free DNA, and potent cytokines and chemokines damage constituents of the alveolar space, further promoting inflammatory injury.

Figure 2

ARDS bronchoalveolar lavage cytology showing neutrophils extruding extracellular traps (arrows).

Figure 3

Neutrophils extracellularly extrude genomic contents and active enzymes following exposure to bacteria, endotoxins, fungi, and certain cytokines and chemokines.

Figure 4

Vitamin C infusion significantly reduced plasma cell-free DNA concentrations following the onset of sepsis-induced ARDS. Asterisk indicates significant reduction.

Figure 5

Parenteral vitamin C infusion in mice with peritoneal sepsis significantly reduced lung mRNA content of the proinflammatory chemokines KC and LIX. FIP = Feces-Induced Peritonitis, AscA = Ascorbic Acid.

Figure 6

Vitamin C significantly improves alveolar fluid clearance in septic mice. FIP = Feces-induced Peritonitis, AscA = Ascorbic Acid.

Figure 7

The molecular physiology of vitamin C’s attenuation of reactive oxygen species.