Power of Place: Intravascular Superoxide Dismutase for Prevention of Acute Respiratory Distress Syndrome.

The Earth formed z4.5 billion years ago, but its atmosphere was largely devoid of oxygen until 2 billion years later, when concentrations increased dramatically (1). This increase in oxygen was followed by an explosion in biodiversity and included the evolution of multicellular organisms that depended on oxygen for energy production and survival (2). At virtually the same time, adaptations to deal with superoxide and other reactive oxygen species (ROS) also evolved. Many of these adaptations remain highly conserved among today’s species, including the superoxide dismutase (SOD) enzymes (3) that catalyze the breakdown of superoxide into hydrogen peroxide. Accordingly, their function is absolutely essential for normal development, maintenance of homeostasis, and prevention of disease. Because oxidant damage is a well-recognized contributor to acute respiratory distress syndrome (ARDS) and septic shock, strategies that enhance SOD function pose a seemingly attractive therapeutic strategy. In this issue of the Journal, Tanaka and colleagues (pp. 179–190) test the efficacy of lecithinized SOD for preventing organ damage in mouse models of sepsis and ARDS (4). The lecithinized SOD used by Tanaka and colleagues contains a human Cu/Zn-SOD complexed with phosphatidylcholine (PC) derivatives to form PC-SOD, a compound that exhibits enhanced stability in plasma and improved tissue affinity (5). Using the murine cecal ligation and puncture (CLP) model of sepsis, the authors convincingly demonstrate that administration of intravenous PC-SOD before surgery improved survival, diminished systemic inflammation, attenuated kidney injury, and reduced vascular permeability in the kidneys and liver. Notably, these beneficial effects were not seen when the PC-SOD was administered intratracheally. Salutary effects of intravenous PC-SOD were also demonstrated in ventilator-induced lung injury and intratracheal LPS models of ARDS. In both models, pretreatment with PC-SOD attenuated pulmonary capillary leak and histologically assessed injury. Moreover, in the LPS model, mice treated with intravenous PC-SOD had reduced inflammatory cytokine and leukocyte levels in alveolar lavage fluid and attenuated capillary leak in the liver. Intratracheal dosing of PC-SOD was not tested. Finally, to demonstrate that the beneficial effects of PC-SOD were mediated by ROS, the authors used in vivo imaging with the luminol-based chemiluminescent probe L-012. Treatment with PC-SOD reduced uptake of the probe in the abdomens of mice after CLP and in the lungs after intratracheal LPS. Taken as a whole, the results of this study support a role for targeted administration of PC-SOD in the treatment of sepsis and ARDS. However, several critical questions remain unanswered, including ones regarding the optimal timing of therapy, potential differences between direct and indirect causes of lung injury, the cellular compartments targeted by PC-SOD, and the precise mechanisms by which redox balance is altered. In the context of clinical therapeutics, the timing of administration is perhaps the most critical. At the heart of the matter is whether PC-SOD is only effective as a preventative agent or whether it may provide benefit after the onset of illness. This issue is clearly highlighted by the group’s mortality studies in the CLP model, in which pretreatment with PC-SOD led to striking improvements in survival, but delay of treatment by a mere hour provided no statistically significant benefit. Because many patients arrive in the emergency room or intensive care unit after the onset of sepsis and/or lung injury, the therapeutic window must be more clearly defined. In addition to understanding when PC-SOD might be administered in relationship to the onset of disease, it is also essential to determine which patient populations might derive the greatest benefit. One potential group might be chronic alcoholics, in whom impaired glutathione synthesis leads to enhanced oxidative stress. Such individuals are at increased risk for the development of ARDS and suffer increased mortality (6, 7). Tobacco smoke also induces oxidative stress in the lungs, and smokers are also increased risk of developing ARDS (8–10). Individuals with genetic polymorphisms that affect redox balance make up a third group, in which case both gain and loss of function need to be considered. For example, in one study, patients with ARDS with polymorphisms in glutathione-S-transferase appeared to derive significant benefits from N-acetylcysteine infusion, whereas control subjects did not (11). Conversely, in another study, a block of single-nucleotide polymorphisms in extracellular superoxide dismutase (EC-SOD) was associated with improved outcomes in individuals with infection-related ARDS (12). One could speculate that the first group would benefit from PC-SOD and the second group would not because of baseline high vascular SOD levels. These observations support the need to define at-risk populations and provide a rationale for new therapeutic approaches. The authors note that a nebulized form of PC-SOD has been developed for treatment of idiopathic pulmonary fibrosis and that this may decrease systemic toxicity. This raises interesting questions about the optimal route of administration for patients with direct versus indirect causes of lung injury. In this context, it must be noted that although intratracheally administered PC-SOD did not appear to be beneficial in the CLP model of sepsis, the intravenous route was. Unfortunately, intratracheal dosing of PC-SOD was not tested in the ventilator-induced lung injury and LPS models. However, the authors have previously demonstrated efficacy of both inhaled and intravenous PC-SOD for reducing bleomycin-induced fibrosis (13, 14) and elastase-induced emphysema (15, 16), models in which disease is largely lung-limited. Accordingly, it is possible that intravenous administration of PC-SOD may be optimal for indirect forms of lung injury, whereas inhaled dosing may be preferable for direct forms. Three isoforms of SOD exist in mammals: cytosolic Cu/Zn-SOD (SOD1), mitochondrial Mn SOD (SOD2), and