A challenging medical problem often observed in critically ill patients is that in response to severe injury or illness, even those organs not directly affected by the original problem become dysfunctional. For example, patients with severe infection will often develop respiratory failure requiring mechanical ventilation, renal failure requiring dialysis, hepatic dysfunction, coagulation abnormalities, and hypotension requiring vasopressors. This condition, known as the multiple organ dysfunction syndrome (MODS), or by, some of its more prominent manifestations such as acute respiratory distress syndrome (ARDS), can be reversible, but the only treatment is supportive care as there is no therapy to directly prevent or reverse MODS. The incidence of MODS in intensive care unit (ICU) patients is 10-40% and the incidence of death in MODS is 40-50%. Even with survival, organ recovery can take months with significant associated morbidity and cost.
The annual incidence of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) approximates 200,000 cases in the United States, with mortality approaching 40%. Despite extensive research into the pathogenesis of ALI and clinical trials testing new therapeutics, the improvement in outcomes following ARDS over the past decade are due to improved strategies of mechanical ventilation and advanced support of other failing organs, as there remains no effective pharmacotherapy to treat patients with this syndrome. Furthermore, patients who survive frequently have significant psychological and physical morbidity, residual physical limitations and poor quality of life. The development of ALI/ARDS occurs as a consequence of critical illness of diverse etiologies; however, many of these are highly relevant to the military. For example, despite surviving an initial major trauma (e.g., blast and/or explosive), there is a high mortality associated with the subsequent development of multiple organ dysfunction syndrome (MODS). Postmortem findings show the lungs to be more frequently affected than any other organ in patients who die after trauma. In addition to trauma, other combat and military related causes of ALI/ARDS include toxic inhalation, burns, near-drowning, radiation, sepsis, and blood transfusion. The underlying pathological changes include neutrophil infiltration, pulmonary edema, hemorrhage, and microvascular thrombosis. There are no current methods to prevent the onset of MODS, only treatment of its effects. Thus, there is an on-going need for effective treatments to prevent the development of these syndromes.