Bench-to-bedside review: Sepsis - from the redox point of view

Sepsis is a leading cause of death in critically ill patients; the mortality in patients admitted to intensive care units and given both antibiotics and supportive care varies from 20% up to more than 60% [1,2]. The problem is becoming even more prominent because the frequency of sepsis is increasing due to the prevalence of antibiotic-resistant pathogens [3]. Historically the widely accepted hypothesis was that sepsis was in fact an uncontrolled inflammatory response. Accordingly, the organism is killing itself while the pathogens are considered as by-standers [4,5]. However, this theory was based on animal studies that do not reflect the clinical picture in humans [6]. Studies on animal models usually involve the application of large doses of endotoxin or pathogens, leading to much higher levels of circulating cytokines in comparison to humans with sepsis and ending in death by 'cytokine storm' [6]. Recent data indicate that the immune system during sepsis actually shows two phases: an initial hyper-inflammatory stage followed by a prolonged hypo-inflammatory phase [7]. In addition, numerous studies and trials have shown that the application of anti-inflammatory agents is futile, or can even worsen chances of survival [7,8]. There are some exceptions, however. For example, Annane and co-workers [9] have shown that the application of selected corticosteroids at moderate doses may decrease the mortality of sepsis. In contrast to prevalently disappointing results for anti-inflammatory therapies, a pro-inflammatory approach seems to be more promising. For example, interferon-γ, a potent macrophage activator, improved survival of patients with sepsis [10]. IL-12, an immune stimulant, reduced mortality from subsequent sepsis when administered after burn injury [11]. Pertinent to these data, Hotchkiss and Karl [7] have recently proposed a coherent immunological approach in sepsis treatment, consisting of moderate suppression of the immune system during the hyper-inflamma