Aging influences in the blood-brain barrier permeability and cerebral oxidative stress in sepsis
Introduction
Sepsis is a set of serious manifestations throughout the body produced by an infection. Its clinical manifestations include those associated with the infectious focus in question (Singer et al., 2016). In terms of epidemiological characteristics, the high rates of sepsis incidence and mortality have not changed in recent decades, leading the World Health Organization (WHO) to include sepsis in global health priorities (WHO, 2018). In the United States, the incidence of sepsis is 300 cases per 100,000 inhabitants, where ¼ of the patients who are hospitalized end up dying (Dellinger et al., 2013). Importantly, in patients who progress to septic shock, a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality, leads to approximately 50% the mortality. Sepsis incidence has increased in recent years due to the development of associated chronic diseases, the use of immunosuppressants, transplants, chemotherapies, invasive procedures and the aging of the population (Mayr et al., 2014).
Older patients are much more likely to develop sepsis. A North American study reported that patients aged 65 or more represented 12% of the population while accounting for almost 65% of sepsis cases (relative risk 13.1), and were 2.3 times more likely to die (Gotts and Matthay, 2016). Moreover, infections that affect respiratory, bloodstream, and genitourinary systems are the most common underlying causes of sepsis in the elderly (Liang, 2017).
The exacerbation of the inflammatory response leads to changes in the systemic circulation, causing vasodilation and hypotension, alterations in the microcirculation and disturbances in the coagulation cascade. These events compromise cellular homeostasis and can result in Central Nervous System (CNS) dysfunction through mechanisms that can be interconnected and have their effects enhanced (Huet et al., 2011; Coletta et al., 2014).
Under the influence of inflammatory mediators and oxidizing agents released in the periphery due to the infectious stimulus, it is possible to observe changes in the BBB permeability of rats at 24 h after sepsis induction (Biff et al., 2013). From this rupture, the infiltration of cells from the peripheral immune system occurs, such as neutrophils, as well as the passage of toxic compounds and activation of the microglia, which results in the potentiation of the neuroimmune response and the stimulus of oxidative stress and a local inflammatory response (Danielski et al., 2018).
The progression of neural damage in sepsis is related to a higher intensity of oxidative stress due to damage to biomolecules such as lipids, proteins and DNA, especially because the brain has lower concentrations of antioxidant defenses and a high metabolic rate (Cobley et al., 2018, Danielski et al., 2018). Also, neutrophil infiltration, by the action of the myeloperoxidase (MPO) enzyme, favours the synthesis of reactive species and the progress of neuronal damage and neuroinflammation (Macdonald et al., 2003).
The hippocampus is highly vulnerable to the effects caused by inflammation and oxidative stress (Bartsch and Wulff, 2015). It is known that lipopolysaccharide (LPS) stimulates the increase in the number of macrophages and perivascular microglial cells, which are related to a higher production of pro-inflammatory cytokines and nitric oxide and, consequently, neuronal damage, inhibition of neurogenesis and reduced hippocampal function (Annane, 2009; Banks et al., 2015; Wolff et al., 2009). Nevertheless, the cortical tissue is also greatly susceptible to harmful effects promoted by inflammatory processes, and oxidative stress resulted from infectious processes (Nolan et al., 2003).
Thus, we hypothesized that oxidative stress due to sepsis provokes a greater injury in old rats compared to young ones due to the effects of aging on brain function, such as an increase in BBB vulnerability, decreased production of antioxidant enzymes and perpetuation of the inflammatory response by neurodegeneration processes. Thus, this study aims to compare the BBB permeability and the development of oxidative stress in the brain regions of young and old rats submitted a model of polymicrobial sepsis.
Section snippets
Animals
Adult male Wistar rats (02 months, 220-310 g) and old ones (07 months, 360–465 g) (Netto et al., 2018) were evaluated. The animals were obtained from the Federal University of Santa Catarina and were housed at the University of South Santa Catarina facilities, in polypropylene boxes of adequate dimensions with wood shavings, in a climate-controlled environment (22 °C ± 2 °C), with 12 hour light/dark cycle controlled by timer, receiving water and standard diet ad libitum throughout the
Results
Fig. 1 shows the results of BBB permeability at 24 h after CLP in the hippocampus (Fig. 1A) and prefrontal cortex (Fig. 2B). There was an increase in the BBB permeability of CLP groups in both brain region, compared to sham animals. Besides, the older rats (CLP 210d group) presented enhanced BBB permeability than younger rats (CLP 60d group).
Concerning MPO activity, as indicative of neutrophil infiltration, there was a significant increase in the hippocampus (Fig. 2A) of both CLP groups
Discussion
The present study shows that sepsis triggered an increase in brain oxidative stress and neuroinflammation, which was enhanced with aging. This potentiation is reflected by the progression of BBB permeability, increased MPO activity, oxidative damage to lipids, and decreased CAT activity.
Possible mechanisms of sepsis-related brain dysfunction include neuroinflammation, impaired brain microcirculation, excitotoxicity, oxidative stress and BBB dysfunction (Zhang et al., 2017). The BBB is an active
CRediT authorship contribution statement
Term: Petronilho F and Barichello T.
Conceptualization: Petronilho F and Margotti W.
Methodology: Goldim MPS, Hubner M, Cidreira T, Denicol TL, Joaquim L, De Carli RJ, Danielski LG, Metzker KLL and Bonfante S.
Resources: Petronilho F.
Writing - Original Draft: Petronilho F, Margotti W, Barichello T and Giustina AD.
Writing - Review & Editing: Petronilho F, Margotti W, Barichello T and Giustina AD.
Supervision: Petronilho F.
Project administration: Petronilho F.
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