Lung-Brain Crosstalk in Sepsis: Protective Effect of Prophylactic Physical Exercise Against Inflammation and Oxidative Stress in Rats.

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. The crosstalk occurs between the primary focus of infection and lung and other organ systems including the central nervous system via soluble and cellular inflammatory mediators and that this involves both the innate and adaptive immune systems. These interactions are reflected by genomic changes and abnormal rates of cellular apoptosis. The lungs and the brain are rapidly affected due to an inflammatory response and oxidative stress in sepsis. Physical exercise promotes positive responses in the inflammatory cascade and oxidative/antioxidant system. In this sense, we aimed at determining the possible protectant effects of a physical exercise program against inflammation and oxidative stress on the lungs and the brain of rats subjected to sepsis. Adult male Wistar rats were randomly assigned to the sham + sedentary (S), sham + trained (T), and cecal ligation and perforation (CLP) + S and CLP + T and subjected to a physical exercise program using a treadmill for 21 days. Forty-eight hours after the last training session, sepsis was induced by the CLP model. Twenty-four hours later, the animals were euthanized and the lungs, the hippocampus, and the prefrontal cortex were harvested to determine the levels of cytokines by enzyme-linked immunosorbent assay (ELISA) and nitrite and reactive oxygen species production, oxidative damage to proteins, and antioxidant enzymes by spectrophotometric method. Sepsis increased the lung and brain levels of TNF-α, IL-1ß, and IL-6, while diminished IL-10 levels, elevated nitrite levels and reactive oxygen species production, augmented the levels of protein carbonyls and diminished the sulfhydryl content, and decreased SOD activity and GSH levels. The exercise program diminished the levels of TNF-α, IL-1ß, IL-6, nitrite, and reactive oxygen species production, as well as the levels of protein carbonyls but augmented the sulfhydryl content, and elevated SOD activity. In conclusion, the exercise program protected the lungs and the brain of septic rats against inflammation and oxidative stress.

NLRP3 Activation Contributes to Acute Brain Damage Leading to Memory Impairment in Sepsis-Surviving Rats.

Sepsis survivors present acute and long-term cognitive impairment and the pathophysiology of neurological dysfunction in sepsis involves microglial activation. Recently, the involvement of cytosolic receptors capable of forming protein complexes called inflammasomes have been demonstrated to perpetuate neuroinflammation. Thus, we investigated the involvement of the NLRP3 inflammasome activation on early and late brain changes in experimental sepsis. Two-month-old male Wistar rats were submitted to the sepsis model by cecal ligation and perforation (CLP group) or laparotomy only (sham group). Immediately after surgery, the animals received saline or NLRP3 inflammasome formation inhibitor (MCC950, 140 ng/kg) intracerebroventricularly. Prefrontal cortex and hippocampus were isolated for cytokine analysis, microglial and astrocyte activation, oxidative stress measurements, nitric oxide formation, and mitochondrial respiratory chain activity at 24 h after CLP. A subset of animals was followed for 10 days for survival assessment, and then behavioral tests were performed. The administration of MCC950 restored the elevation of IL-1ß, TNF-α, IL-6, and IL-10 cytokine levels in the hippocampus. NLRP3 receptor levels increased in the prefrontal cortex and hippocampus at 24 h after sepsis, associated with microglial, but not astrocyte, activation. MCC950 reduced oxidative damage to lipids and proteins as well as preserved the activity of the enzyme SOD in the hippocampus. Mitochondrial respiratory chain activity presented variations in both structures studied. MCC950 reduced microglial activation, decreased acute neurochemical and behavioral alteration, and increased survival after experimental sepsis.

Lipoic Acid and Fish Oil Combination Potentiates Neuroinflammation and Oxidative Stress Regulation and Prevents Cognitive Decline of Rats After Sepsis.

Sepsis causes organ dysfunction due to an infection, and it may impact the central nervous system. Neuroinflammation and oxidative stress are related to brain dysfunction after sepsis. Both processes affect microglia activation, neurotrophin production, and long-term cognition. Fish oil (FO) is an anti-inflammatory compound, and lipoic acid (LA) is a universal antioxidant substance. They exert neuroprotective roles when administered alone. We aimed at determining the effect of FO+LA combination on microglia activation and brain dysfunction after sepsis. Microglia cells from neonatal pups were co-treated with lipopolysaccharide (LPS) and FO or LA, alone or combined, for 24 h. Cytokine levels were measured. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) and treated orally with FO, LA, or FO+LA. At 24 h after surgery, the hippocampus, prefrontal cortex, and total cortex were obtained and assayed for levels of cytokines, myeloperoxidase (MPO) activity, protein carbonyls, superoxide dismutase (SOD), and catalase (CAT) activity. At 10 days after surgery, brain-derived neurotrophic factor (BDNF) levels were determined and behavioral tests were performed. The combination diminished in vitro levels of pro-inflammatory cytokines. The combination reduced TNF-α in the cortex, IL-1ß in the prefrontal cortex, as well as MPO activity, and decreased protein carbonyls formation in all structures. The combination enhanced catalase activity in the prefrontal cortex and hippocampus, elevated BDNF levels in all structures, and prevented behavioral impairment. In summary, the combination was effective in preventing cognitive damage by reducing neuroinflammation and oxidative stress and increasing BDNF levels.

Effects of the use of bioceramic wraps in patients with lower limb venous ulcers: A randomized double-blind placebo-controlled trial.

BACKGROUND: Venous ulcer represents the most advanced stage of chronic venous insufficiency. It is an important public health problem and has a significant impact on patients' quality of life due to chronic pain, inability to work, need for hospitalization and frequent outpatient follow-up. OBJECTIVE: We investigated the treatment benefits of far-infrared ceramic (cFIR), in a 90-day study of lower limb venous ulcers and looked at ulcer healing scores, quality of life, serum bio-markers of oxidative stress and antioxidant defense enzymes. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This is a randomized double-blind placebo-controlled study conducted in the Vascular Surgery Service of a hospital located in the northwest region of the State of Rio Grande do Sul, Brazil. We included patients with lower limb venous ulcers who were randomized to use either a bioceramics wrap or a placebo wrap for 90 days. MAIN OUTCOME MEASURES: The following evaluations were conducted at baseline and after 15, 30, 60 and 90 days: ulcer healing score, quality of life, and serum markers of oxidative stress and antioxidant enzyme activity. RESULTS: Patients (n = 24) with lower limb venous ulcers were randomized into two treatment groups. cFIR decreased the ulcer size on day 30 (P = 0.042) and 90 (P = 0.034) and the total ulcer healing scale scores on day 30 (P = 0.049) and 90 (P = 0.02) of the treatment, when compared to baseline. Additionally, cFIR improved tissue type (epithelial tissue) on day 60 (P = 0.022) when compared to baseline evaluation. CONCLUSION: cFIR clinically improved ulcer healing in patients with lower limb venous ulcers. TRIAL REGISTRATION: RBR-8c7xzn on ReBEC.