Potential Antioxidant Multitherapy against Complications Occurring in Sepsis

Abstract

Septic shock currently represents one of the main causes of mortality in critical patient units with an increase in its incidence in recent years, and it is also associated with a high burden of morbidity in surviving patients. Within the pathogenesis of sepsis, oxidative stress plays an important role. The excessive formation of reactive oxygen species (ROS) leads to mitochondrial damage and vasomotor dysfunction that characterizes those patients who fall into septic shock. Currently, despite numerous studies carried out in patients with septic shock of different causes, effective therapies have not yet been developed to reduce the morbidity and mortality associated with this pathology. Despite the contribution of ROS in the pathophysiology of sepsis and septic shock, most studies performed in humans, with antioxidant monotherapies, have not resulted in promising data. Nevertheless, some interventions with compounds such as ascorbate, N-acetylcysteine, and selenium would have a positive effect in reducing the morbidity and mortality associated with this pathology. However, more studies are required to demonstrate the efficacy of these therapies. Taking into account the multifactorial features of the pathophysiology of sepsis, we put forward the hypothesis that a supplementation based on the association of more than one antioxidant compound should result in a synergistic or additive effect, thus improving the beneficial effects of each of them alone, potentially serving as a pharmacological adjunct resource to standard therapy to reduce sepsis complications. Therefore, in this review, it is proposed that the use of combined antioxidant therapies could lead to a better clinical outcome of patients with sepsis or septic shock, given the relevance of oxidative stress in the pathogenesis of this multi-organ dysfunction.

Exploring the role of antioxidants in sepsis-associated oxidative stress: a comprehensive review

“…As a life-threatening complication caused by OS and inflammatory reactions, it represents a leading contributor to mortality in critically ill individuals. Several molecular mechanisms underlying the progression of sepsis are associated with the dysregulation between the generation of ROS and its elimination through cellular antioxidant pathways ( Abelli et al., 2022 ). In sepsis, excessive generation of oxygen free radicals contributes to the development of multiple organ failure and mortality ( Cowley et al., 1996 ).…”

“…Consequently, it is plausible that interventions aimed at bolstering host immunity could potentially augment survival rates ( Puertollano et al., 2011 ). Moreover, during OS occurring in sepsis, three primary mechanisms play a pivotal role: vasomotor impairment, mitochondrial dysfunction, and necrosis in various tissues ( Abelli et al., 2022 ). Hence, an overabundance of ROS gives rise to a disturbance in the physiological endothelial function, resulting in vasoplegia, an excessive procoagulant state induced by the inhibition of the ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) enzyme, and impairment of mitochondrial integrity, thereby disturbing the signaling cascades governing thrombosis and inflammation ( Dolmatova et al., 2021 ).…”

“…In instances where sepsis remains unregulated, a series of subsequent occurrences may transpire, ultimately leading to the development of septic shock and multi-organ failure ( Chiu and Legrand, 2021 ). Many pathophysiological pathways, including sepsis, inflammation, and organ disorders, have been linked to OS ( Abelli et al., 2022 ). The current review article aims to present a comprehensive overview of the cellular metabolism of reactive oxygen species (ROS) and its involvement in pathophysiological processes, particularly in sepsis.…”

Dose-Dependent Effects of Lipopolysaccharide on the Endothelium—Sepsis versus Metabolic Endotoxemia-Induced Cellular Senescence

“…Septic patients also exhibit overwhelming oxidative stress, which results from the uncontrolled production of reactive oxygen and nitrogen species from activated immune cells. This explains why antioxidant therapies, using vitamin C, selenium, or N-acetylcysteine, were investigated in sepsis models [61]. However, they did not show any positive effects in humans [11].…”

Chemical, Biological and Biomedical Aspects of Bioantioxidants

“…They demonstrate the synergistic therapeutic efficacy of AT1R antagonist drugs with other cardiovascular therapeutics for ischemia. Abelli et al [25] discussed the use of combined antioxidant multitherapy in sepsis, where it has been suggested that oxidative stress and inflammation play a crucial role. The authors reviewed the role of potent antioxidants such as Vitamin C and E, N-acetylcysteine, and selenium for sepsis therapies.…”