1. Introduction
TNF-α, Organ damage, immune dysfunction, inflammation, cardiac damage, Hyperinflammation, organ dysfunction, Tumor necrosis, infection, septic shock, multiorgan failure, Mitochondrial dysfunction, sepsis, tissue damage
SEPSIS, TUMOR NECROSIS, PROLIFERATION, INFLAMMATION, PATHOPHYSIOLOGY, TUMOR NECROSIS, TRANSFORMING, INFECTION, SEPTIC SHOCK, MULTIORGAN FAILURE, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, PATHOGENESIS, INFLAMMATORY RESPONSE
These authors contributed equally to this work.Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1β, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFβ), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NOSepsis and septic shock are global health problems and their prevalence generates a high economic cost; 51% of patients are admitted to intensive care units (ICUs), and 17.3% are treated in intermediate care (IC) or coronary units (UCCs) [In patients with sepsis and septic shock, dysfunction and loss of cellular and metabolic homeostasis are conditioned by the patient’s response to the infection and are associated with a high mortality [Immunoregulation by cytokines is vital; interferons mediate natural immunity, activate mononuclear phagocytes and neutrophils, and increase the molecules of the major histocompatibility complex. During septic shock, the participation of cytokines, such as IL-2 and IL-4, regulate the activation, proliferation, and differentiation of leukocytes [Similarly, IL-6 mediates natural immunity since it induces the synthesis of acute-phase proteins in the liver and is a proliferation factor for activated B cells. Its levels increase in patients with infection and are associated with mortality in patients with sepsis [The endothelium actively participates in the pathophysiology and damage associated with sepsis, leading to systemic inflammation [The deregulation of the host response and multiorgan failure due to infection is attributed to the interaction of various mechanisms, where oxidative stress (OS) participates. Mitochondrial dysfunction plays a vital role in the pathogenesis of septic shock [Some cytokines regulate inflammation, such as interleukin 10 (IL-10), which inhibits the activity and production of TNF-α, IL-1, IL-2, and chemokines [Immune cells express pattern recognition receptors (PRRs) that rapidly initiate host defense responses upon detecting tissue damage or microbial infection. Intracellular damage-associated molecular proteins (DAMPs) mediate immune recognition of damaged tissue. Toll-like receptors (TLRs), a subfamily of PRRs, have emerged as crucial receptors for DAMP recognition and initiation of the inflammatory response. During sepsis, immune response activation occurs due to the release of high levels of DAMPs originating from invading microorganisms and damaged host tissue, leading to overstimulation of immune cells. This unbalanced response is known as a cytokine storm and transforms its function from fighting excess infection into damage due to inflammation [Furthermore, the stimuli produced by the infection lead to cell apoptosis through the intracellular or extracellular pathway (intrinsic or extrinsic pathway). Intrinsically, proapoptotic members of the Bcl family regulate the exit of cytochrome c from mitochondria, such as Bid and Bax. Other Bcl members (Bcl-XL and Bcl-2) are anti-apoptotic and are critical in signaling pathways leading to apoptosis or cell survival. Endoplasmic reticulum stress is another mechanism of apoptosis triggered by intracellular stimuli and mediated by caspase 12. In the extrinsic way, activation occurs due to binding a ligand, a polypeptide of the TNF family, with its receptor. This leads to activating initiator caspases 2, 8, and 10. Once activated, the caspases are cleaved and activate other effector caspases (3, 6, and 7), which enhance the cleavage of cytoskeletal and nuclear proteins, leading to apoptosis cells. The immune system’s responsiveness is impaired during sepsis, and increased apoptosis of immune cells may explain the development of immune dysfunction. Therefore, it is necessary to eliminate a more significant number of apoptotic cells. Despite critical efforts in septic shock research, no therapy significantly modifies its outcome, and new treatments have led to several experimental studies focusing on the apoptotic process [Cytokines [Recently, antagonistic therapies anticytokine therapy targeting (tumor necrosis factor alpha [TNF-alpha], interleukin-1 [IL-1]) and anti-endotoxin strategies have been proposed as important therapeutic targets in sepsis. They use antibodies against endotoxins or endotoxin receptor/carrier molecules (anti-CD14 or anti-LPS binding proteins) [On the other hand, many experimental studies of in vitro models of sepsis using mouse hepatocytes AML12 have been published. These cells were treated with lipopolysaccharide (LPS) to induce sepsis by hepatocyte injury. In cells pretreated with melatonin, the effects on oxidative stress, inflammation, mitophagy, mitochondrial biogenesis, and adenosine triphosphate (ATP) levels were reduced, and the mitochondrial quality was improved. This finding demonstrated that the antioxidant melatonin had potential benefic therapeutic effects in sepsis induced in the liver by injury, promoting mitophagy and stimulating the biogenesis of mitochondrial activity. These findings justify research to explore the precise effects, the underlying mechanisms, and the effectiveness of melatonin in the clinical setting [In animal models of sepsis, there were significant anti-inflammatory, antioxidant, and anti-apoptotic effects with the use of Sulforaphane, which inhibits the TLR4/NF-κB signaling pathway. There was a reduction in the cardiac damage caused by sepsis [During septic shock, the cytokine storm is caused by the invasion of pathogens and a sustained high level of cytokines, which alter homeostasis and cause potentially fatal organ dysfunction [Hyperinflammation is a prooxidant state with increased expression of reactive oxygen species (ROS). [Superoxide (OClinical trials to control only inflammation in septic shock have not had overwhelming success for many years. However, new immunomodulatory therapies and cytokine blockers have shown great success in severe cases of COVID-19 [