Zinc deficiency increases organ damage and mortality in a murine model of polymicrobial sepsis.

Sepsis is a major cause of morbidity, mortality, and healthcare costs in hospitalized patients and is the tenth leading cause of death overall in the United States (1). Currently, it is expected that between 20% and 50% of patients who develop sepsis will die despite receiving the current standard of appropriate therapy. The basic cellular and molecular mechanisms accounting for sepsis-related morbidity and mortality remain poorly understood. However, a number of host factors, including immunosuppression, advanced age, chronic alcoholism, and poor nutritional status, are known to increase sepsis mortality (2, 3). Zinc is an essential dietary micronutrient with beneficial functions that facilitate cytoprotection, improved wound healing, and tissue repair (4). Humans, in response to sepsis or endotoxin administration, experience a transient decrease in plasma zinc levels without a concomitant loss of whole body zinc content (5). This phenomenon is believed to be a component of the host defense response designed to increase cellular zinc bioavailability for cytoprotective functions that involve protein synthesis, neutralization of reactive oxygen species, and prevention of microbial invasion (6). Therefore, we postulate that individuals who are zinc deficient may be disadvantaged with respect to their ability to respond to systemic acute stress. Zinc deficiency is underestimated worldwide and is predicted to affect millions (4). Recent studies conducted in the United States and Europe indicate that a significant segment of the population, particularly those with chronic illness requiring hospitalization, are at an increased risk of zinc deficiency (7–9). Furthermore, a significant subpopulation of critically ill patients are chronic alcoholics (10), a condition associated with malnutrition, including depletion of zinc stores (4, 11). Zinc deficiency can also occur after the onset of trauma (12) or burn injury (13). Body stores of zinc and other antioxidant nutrients are further influenced by diet, advanced age, smoking, and female gender (9). Thus, it is likely that a clinically significant number of intensive care unit patients are zinc deficient. Zinc deficiency is shown to increase mortality in the context of pneumococcal pneumonia, presumably related to the impaired immune response to specific bacterial antigens that are associated with bacterial invasion (14). In this context, supplementation of zinc in at-risk patients reduces the overall incidence of respiratory infections in an elderly population shown to have significant zinc depletion (15). Paradoxically, zinc deficiency causes heightened inflammatory responses and more severe organ injury in response to bacterial endotoxin (16, 17). Many experts agree that a vigorous innate immune response to infection favors rapid resolution of infection and improved outcomes during sepsis (18). Considering the plieotropic functions of zinc relating to inflammatory and antioxidant responses, we hypothesized that zinc deficiency would be associated with increased systemic and local inflammation, increased oxidant stress, more severe vital organ damage, and higher mortality in the context of severe sepsis. To test this hypothesis, young adult mice were randomly assigned to receive a zinc-depleted diet or a matching control diet for 3 weeks before the onset of sepsis induced by cecal ligation and puncture (CLP). A third group received acute dietary supplementation of zinc 3 days before the onset of sepsis. The effects of dietary zinc depletion and supplementation on sepsis mortality, systemic inflammatory cytokine release, and indices of multiple organ damage were assessed.