Sepsis and Oxidative Stress in the Newborn: From Pathogenesis to Novel Therapeutic Targets

Abstract

Sepsis is at present one of the leading causes of morbidity and mortality in the neonatal population. Together with inflammation, oxidative stress is involved in detrimental pathways activated during neonatal sepsis, eventually leading to organ dysfunction and death. The redox cascade during sepsis is mainly initiated by IL-6 and IL-8 stimulation in newborns and includes multiple noxious processes, as direct cell damage induced by reactive oxygen species, activation of gene expression leading to amplification of inflammation and oxidative stress, and impairment of mitochondrial function. Once proinflammatory and prooxidant pathways are established as stimulated by causing pathogens, self-maintaining unfavorable redox cycles ensue, leading to oxidative stress-related cellular damage, independently from the activating pathogens themselves. Despite antioxidant systems are induced during neonatal sepsis, as an adaptive response to an increased oxidative burden, a condition of redox imbalance favoring oxidative pathways occurs, resulting in increased markers of oxidative stress damage. Therefore, antioxidant treatment would exert beneficial effects during neonatal sepsis, potentially interrupting prooxidant pathways and preventing the maintenance of detrimental redox cycles that cannot be directly affected by antibiotic treatment. Among others, antioxidant agents investigated in clinical settings as adjunct treatment for neonatal sepsis include melatonin and pentoxifylline, both showing promising results, while novel antioxidant molecules, as edaravone and endothelin receptor antagonists, are at present under investigation in animal models. Finally, mitochondria-targeted antioxidant treatments could represent an interesting line of research in the treatment of neonatal sepsis.

Mycoplasma gallisepticum Infection Impaired the Structural Integrity and Immune Function of Bursa of Fabricius in Chicken: Implication of Oxidative Stress and Apoptosis

“…In the present study, the effects of MG-infection on structural integrity and immune function of chicken BOF were scrutinized. Oxidative stress is increased during many pathogenic infections (34). Similarly, our data also showed that MG-infection induced oxidative stress and significantly reduced antioxidant activities at day 3 and day 7 post-infection.…”

Association between DNA Damage and Serum Levels of Copper, Zinc, and Selenium in Full-Term Neonates with Late-Onset Sepsis

“…ROS and RNS are originated from mitochondria as a consequence of aerobic metabolism and are normally removed from cells by antioxidant enzymes. 6,7 The imbalance between production and clearance of radicals causes oxidative stress. 7 In neonatal sepsis, causative organisms establish pro-oxidant and proinflammatory pathways.…”

“…Toxins released by the causative organisms cause sequential events including the release of inflammatory mediators and production of reactive oxygen species (ROS) as well as reactive nitrogen species (RNS). 6 The failure of removing ROS and RNS due to the imbalance between their production and antioxidant defense agents is called oxidative stress. 7 Oxidative stress is a redox cascade associated with the damage of DNA and dysfunction of different organs.…”

“…7 Oxidative stress is a redox cascade associated with the damage of DNA and dysfunction of different organs. 6 Trace elements such as copper (Cu), zinc (Zn), and selenium (Se) are essential cofactors known to play crucial roles in neonatal development and growth, immune regulation, and maintenance of redox homeostasis. 8,9 Although the alteration in the status of these micronutrients is usually associated with impaired immune function and higher oxidative stress, their role in LOS is still under evaluation.…”

Targeting the eCIRP/TREM-1 Interaction with a Small Molecule Inhibitor Improves Cardiac Dysfunction in Neonatal Sepsis

“…[37] Oxidative stress as a cause of mitochondrial dysfunction appears to be particularly prominent in neonates. [69] In this study, we have demonstrated that eCIRP is su cient to increase cardiomyocyte ROS and mitochondrial superoxide, increase calcium in ux into mitochondria, and promote depolarization of the mitochondria. Furthermore, we have shown that inhibition of the eCIRP/TREM-1 interaction with the M3 peptide ameliorated these effects.…”