ABSTRACT
Cisplatin is a chemotherapy used to treat different types of cancer, such as testicular, bladder and head and neck. Physical exercise has been shown to improve cancer therapy and recently, it was demonstrated to be able to diminish side effects such as acute kidney injury (AKI), a common side effect in cisplatin treatment. In both cases, the modulation of inflammatory cytokines seems to be one of the mechanisms, but little is known about the immune cells in this process. Here, we investigated the role of CD4 + T cells in the AKI protection by physical exercise. We subjected C57Bl6 mice to long-term physical exercise (EX) before cisplatin treatment. Sedentary groups were used as control (CT). We confirmed that physical exercise decreased AKI by evaluating creatinine and Kim-1 levels, in the serum and kidney respectively. Analyzing the organs weight, we noticed a decrease in sedentary (CIS) and exercised (CIS-EX) cisplatin treated groups. Epididymal and brown adipose tissue weight were decreased in cisplatin treated subjects in comparison to untreated groups, as well as liver and spleen. We then investigated the profile of CD4 + T cells in the spleen and we observed increased levels of Tregs and CD4+CD25+ cells in CIS group, while CIS-EX presented similar amounts as control groups. Analyzing the kidney lymph nodes, we noticed a decrease of CD4+ cells in both CIS and CIS-EX group. However, a more activated phenotype (CD69+ and CD25+) was observed in CIS groups in comparison to CIS-EX group, as well as the presence of Tregs. We then investigated the production of cytokines by these cells and no difference among the groups was observed in cytokines production in splenic CD4 + T cells. However, a clear increase in TNF and IL-10 production was observed in CD4 + T cells from lymph nodes, while CIS-EX group presented similar levels as the control groups. We confirmed that physical exercise was able to diminish cisplatin-induced AKI with concomitant decrease in CD4 + T cell activation.
Subject(s)
Acute Kidney Injury/chemically induced , Acute Kidney Injury/immunology , CD4-Positive T-Lymphocytes/immunology , Cisplatin/adverse effects , Lymphocyte Activation/immunology , Physical Conditioning, Animal , Acute Kidney Injury/prevention & control , Animals , Cytokines/biosynthesis , Lymph Nodes/pathology , Male , Mice, Inbred C57BL , Phenotype , Spleen/pathologyABSTRACT
Cancer cachexia, of which the most notable symptom is severe and rapid weight loss, is present in the majority of patients with advanced cancer. Inflammatory mediators play an important role in the development of cachexia, envisaged as a chronic inflammatory syndrome. The white adipose tissue (WAT) is one of the first compartments affected in cancer cachexia and suffers a high rate of lipolysis. It secretes several cytokines capable of directly regulating intermediate metabolism. A common pathway in the regulation of the expression of pro-inflammatory cytokines in WAT is the activation of the nuclear transcription factor kappa-B (NF-κB). We have examined the gene expression of the subunits NF-κBp65 and NF-κBp50, as well as NF-κBp65 and NF-κBp50 binding, the gene expression of pro-inflammatory mediators under NF-κB control (IL-1ß, IL-6, INF-γ, TNF-α, MCP-1), and its inhibitory protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α). The observational study involved 35 patients (control group, n = 12 and cancer group, n = 23, further divided into cachectic and non-cachectic). NF-κBp65 and its target genes expression (TNF-α, IL-1ß, MCP-1 and IκB-α) were significantly higher in cachectic cancer patients. Moreover, NF-κBp65 gene expression correlated positively with the expression of its target genes. The results strongly suggest that the NF-κB pathway plays a role in the promotion of WAT inflammation during cachexia.
Subject(s)
Cachexia/pathology , Neoplasms/pathology , Subcutaneous Fat/metabolism , Transcription Factor RelA/metabolism , B-Lymphocytes/metabolism , Case-Control Studies , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Female , Humans , I-kappa B Proteins/genetics , I-kappa B Proteins/metabolism , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lipolysis , Male , Middle Aged , NF-KappaB Inhibitor alpha , Quality of Life , Signal Transduction , Transcription Factor RelA/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Up-RegulationABSTRACT
Nephrotoxicity is substantial side effect for 30% of patients undergoing cancer therapy with cisplatin and may force them to change or even abandon the treatment. Studies regarding aerobic exercise have shown its efficacy for the treatment of many types of diseases and its capacity to reduce tumors. However, little is known about the impact of physical exercise on cisplatin-induced acute kidney injury (AKI). In the present study, our aim was to investigate the role of physical exercise in AKI induced by cisplatin. We submitted C57Bl6 male mice to seven weeks of chronic exercise on a training treadmill and treated them with single i.p. injection of cisplatin (20 mg/kg) in the last week. Exercise efficacy was confirmed by an increased capillary-to-fiber ratio in the gastrocnemius muscle of exercised groups (EX and CIS-EX). The group submitted to exercise before cisplatin administration (CIS-EX) exhibited less weight loss and decreased serum urea levels compared to the cisplatin group (CIS). Exercise also showed a protective role against cisplatin-induced cell death in the kidney. The CIS-EX group showed a lower inflammatory response, with less TNF and IL-10 expression in the kidney and serum. In the same group, we observed an increase of IL-6 and HO-1 expression in the kidney. Taken together, our results indicate that chronic aerobic exercise is able to attenuate AKI by inducing IL-6 and HO-1 production, which results in lower inflammatory and apoptotic profiles in the kidney.
