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Renal vascular reactivity to vasoconstrictors is preserved in sepsis in opposition to what happens in the systemic circulation. We studied whether this distinct behavior was related to α1 adrenergic receptor density, G protein-coupled receptor kinase 2 (GRK2) and the putative role of nitric oxide (NO). Sepsis was induced in female mice by cecal ligation and puncture (CLP). Wildtype mice were treated with prazosin 12 h after CLP or nitric oxide synthase 2 (NOS-2) inhibitor, 30 min before and 6 and 12 h after CLP. In vivo experiments and biochemistry assays were performed 24 h after CLP. Sepsis decreased the systemic mean arterial pressure (MAP) and the vascular reactivity to phenylephrine. Sepsis also reduced basal renal blood flow which was normalized by treatment with prazosin. Sepsis led to a substantial decrease in GRK2 level associated with an increase in α1 adrenergic receptor density in the kidney. The disappearance of renal GRK2 was prevented in NOS-2-KO mice or mice treated with 1400 W. Treatment of non-septic mice with an NO donor reduced GRK2 content in the kidney. Therefore, our results show that an NO-dependent reduction in GRK2 level in the kidney leads to the maintenance of a normal α1 adrenergic receptor density. The preservation of the density and/or functionality of this receptor in the kidney together with a higher vasoconstrictor tonus in sepsis lead to vasoconstriction. Thus, the increased concentration of vasoconstrictor mediators together with the preservation (and even increase) of the response to them may help to explain sepsis-induced acute kidney injury.

The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system with the pathogenesis of multiple sclerosis (MS). Herein, we investigate the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also examined if the treatment with pramipexole (PPX) – a dopamine D2/D3 receptor-preferring agonist – would be able to prevent the EAE-induced motor and mood dysfunction, as well as the underlying mechanisms of action. Our findings showed that D2R immunocontent upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontent was significantly increased in the lymph nodes during the chronic phase of EAE. Also, during this phase, oxidative damage in the spinal cord and striatum of EAE animals was significantly higher. During the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. In addition, PPX treatment failed to inhibit EAE progression and anhedonic-like behavior. Otherwise, PPX inhibited the depressive-like behavior. Relevantly, PPX oral treatment downregulated IL-1β levels and increased BNDF content in the spinal cord after EAE induction. Altogether, it is possible to conclude that D2R participates in crosstalk between CNS and immune system during autoimmune and neuroinflammatory response induced by EAE, mainly in the acute and chronic phase of the disease. Relevantly, a dopamine D2/D3 receptor-preferring agonist mitigated depressive-like behavior induced by EAE, which offers a new possibility for treating depressive symptoms in MS patients.

The pro-resolving mechanism is a recently described endogenous process that controls inflammation. The present study evaluated components of this mechanism, including annexin 1 (ANXA1) and the formyl peptide receptor 2/ALX (FPR2/ALX) receptor, in the antihyperalgesic effect induced by electroacupuncture (EA) in an animal model of persistent peripheral inflammation. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2-10 Hz, ST36-SP6) or subcutaneous BML-111 injection (FPR2/ALX agonist) for 5 consecutive days. In a separate set of experiments, on the first and fifth days after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or naloxone (non-selective opioid receptor antagonist) before EA or BML-111 injection. Paw protein levels of FPR2/ALX and ANXA1 were evaluated on the second day after CFA injection by western blotting technique. EA and BML-111 reduced mechanical hyperalgesia. I.pl. naloxone or WRW4 prevented the antihyperalgesic effect induced by either EA or BML-111. EA increased ANXA1 but did not alter FPR2/ALX receptor levels in the paw. Furthermore, i.pl. pretreatment with WRW4 prevented the increase of ANXA1 levels induced by EA. This work demonstrates that the EA antihyperalgesic effect on inflammatory pain involves the ANXA1/FPR2/ALX pro-resolution pathway. This effect appears to be triggered by the activation of FPR2/ALX receptors and crosstalk communication with the opioid system.

Purpose: How can progestin influence the anti-inflammatory cytokine IL-10 level in the peritoneum with endometriosis? Methods: A cross-sectional study with a laboratory analysis carried out in tertiary hospitals in southern Brazil with clinical-demographic data compilation and sample collection of peritoneal lavage and a peritoneum biopsy from 40 patients — 22 with endometriosis (11 with progestin and 11 without it) and 18 in the control group — was conducted. For the sample analysis, the ELISA was performed, and a comparison of the average IL-10 concentrations by ANOVA followed by Bonferroni was carried out. Results: There was a higher concentration of IL-10 among patients with endometriosis compared to the control group (p ≤ 0.05), and statistical significance was observed with a reduction of IL-10 in the peritoneal lavage of patients with endometriosis in the use of progestin (8.1 ± 7.4 pg/ml) compared to those with endometriosis without using progestin (17.9 ± 10.5 pg/ml). Considering the disease stage, a higher level of IL-10 (p ≤ 0.05) was observed both in the initial stages (12.1 ± 10.5 pg/ml) and in advanced stages (15.4 ± 9.7 pg/ml) compared to the control (1.7 ± 1.8 pg/ml), which was significantly higher for advanced endometriosis.

Background/Purpose: Osteoarthritis (OA) is the main orthopedic disease to cause pain and edema in humans. This study evaluated the influence of complementary medicine on the hyperalgesia and edema induced by exercise in an animal model of OA as well as possible role for interleukin (IL)-1β to these outcomes. Methods: Mice (25–35 g) were subjected to intraplantar injection of Freund’s complete adjuvant and were subjected to exercise and oral treatment with ethanolic crude extract of Casearia sylvestris (ECE-CS) or vehicle (alone or in combination) and evaluated through behavioral and biochemical tests. Results: At day 5, exercise and ECE-CS alone did not reduce hyperalgesia, while the combination of both enhanced this effect. In muscle and skin tissues from the treated paw of mice, both treatments alone or in combination reduced in similar extent the levels of IL-1β in relation to the control group. Conclusion: Association of both complementary therapies may bring benefits on pain associated with OA in humans.

Background: Myofascial Reorganization (MFR) is a physiotherapy technique that mixes myofascial pressures and slips and has been used as a simple and non-invasive method that readjusts soft tissues, as well as myofascial adhesions and contractures that may cause decreased blood supply and consequently of physical activity. Objective: To verify if the MFR alters the tissue oxygenation of the trapezius muscle (TM) in subjects without the pain symptom in the evaluation day. Methods: The sample consisted of eight subjects with a mean age of 23 (± 6) years and a body mass index of 23.2 (±15.0) kg.m-2. Changes in muscle oxygenation were measured by near infrared spectroscopy (NIRS) (Portamon, Artinis, the Netherlands) in TM before and after 15 minutes of intervention. The proposed MFR protocol lasted approximately 10 minutes and consisted of pressures, stretching and myofascial slippage of the upper, middle and lower TM fibers. Data normality was performed using the Shapiro Wilk test and due to the parametric nature of the data, the paired t-test was used for pre and post intervention comparison. Results: There was a significant increase in the tissue saturation index (TSI) in the trapezius muscle (80.7±2.7% vs. 89.4±4.6%; p= 0.002) in the pre and post intervention comparison. The pre-post variation delta of oxyhemoglobin - O2 Hb (8.1±11.2 g/dL), deoxyhemoglobin - HHb (-0.72±1.6 g/dL) and total hemoglobin - tHB (7.4±12.3 g/dL) showed no significant difference. However, there was an increase in O2 Hb, tHB levels and a decrease in HHb. Conclusion: The findings showed that the MFR applied on trapezius muscle increased the TSI, which reflects on peripheral muscle oxygenation in subjects without pain in the day of evaluation.

In sepsis, greater understanding of the inflammatory mechanism involved would provide insights into the condition and into its extension to the muscular apparatus in critically ill patients. Therefore, this study evaluates the inflammatory profile of pneumosepsis induced by Klebsiella pneumoniae (K.p.) in lungs and skeletal muscles during the first 72 h. Male BALB/c mice were divided into 4 groups, submitted to intratracheal inoculation of K.p. at a concentration of 2 × 108 (PS) or PBS, and assessed after 24 (PS24), 48 (PS48) and 72 (PS72) hours. The Maximum Physical Capacity Test (MPCT) was performed before and after induction. Pulmonary inflammation was assessed by total cell number, nitric oxide levels (NOx), IL-1β and TNF-α levels in bronchoalveolar lavage fluid (BALF); inflammation and muscle trophism were evaluated by the levels of TNF-α, IL-6, TGF-β and BDNF by ELISA and NF-κB by western blotting in muscle tissue. Cells and colony forming units (CFU) were also analyzed in blood samples. The PS groups showed an increase in total cells in the BALF (p

This study evaluated the effects of continuous and interval running on a treadmill on mechanical hyperalgesia in an animal model of chronic postischemia pain and analyzed the mechanism of action of this effect. Different groups of male Swiss mice with chronic postischemia pain, induced by 3 hours of paw ischemia followed by reperfusion, ran on the treadmill in different protocols—the speed (10, 13, 16, or 19 m/min), duration (15, 30, or 60 minutes), weekly frequency (3 or 5 times), weekly increase in continuous and interval running speed—were tested. Mechanical hyperalgesia was evaluated by von Frey filament 7, 14, and 21 days after paw ischemia followed by reperfusion. On day 11 after paw ischemia followed by reperfusion and after 5 days of continuous and interval running, concentrations of cytokines, oxidative stress parameters, and extracellular signal-regulated kinase 1/2 and AKT 1/2/3 expression in the spinal cord were measured. The results showed that continuous running has an antihyperalgesic effect that depends on intensity and volume. Interval running has a longer-lasting antihyperalgesic effect than continuous running. The antihyperalgesic effect depends on intensity and volume in continuous running, and increasing speed maintains the antihyperalgesic effect in both protocols. In the spinal cord, both runs decreased tumor necrosis factor-α and interleukin-6 levels and increased interleukin-10. Both running protocols reduced oxidative damage in the spinal cord. Only interval running had lower concentrations of phosphorylated extracellular signal-regulated kinase 1/2 in the spinal cord. Interval running presented a great antihyperalgesic potential with more promising results than continuous running, which may be owing to the fact that the interval running can activate different mechanisms from those activated by continuous running. Perspective A minimum of .5-hour sessions of moderate to high intensity ≥3 times a week are essential parameters for continuous and interval running–induced analgesia. However, interval running was shown to be more effective than continuous running and can be an important adjuvant treatment to chronic pain.

Currently, photobiomodulation therapy (PBMT) is gaining space in the scientific and clinical environment. To help elucidate the importance of irradiance, this study evaluated the effect of two different PBMT irradiances (3.5 and 90 mW/cm

Background and objective Sepsis is a potentially deadly organic dysfunction, and one of the main causes of mortality in intensive care units (ICU). Aerobic exercise (AE) is a preventive intervention in the establishment of inflammatory conditions, such as chronic lung diseases, but its effects on sepsis remain unclear. Therefore, this study aimed to evaluate the effects of AE on health condition, mortality, inflammation, and oxidative damage in an experimental model of pneumosepsis induced by Klebsiella pneumoniae (K.p). Methods Animals were randomly allocated to Control; Exercise (EXE); Pneumosepsis (PS) or Exercise + Pneumosepsis (EPS) groups. Exercised animals were submitted to treadmill exercise for 2 weeks, 30 min/day, prior to pneumosepsis induced by K.p tracheal instillation. Results PS produced a striking decrease in the health condition leading to massive death (85%). AE protected mice, as evidenced by better clinical scores and increased survival (70%). AE alleviated sickness behavior in EPS mice as evaluated in the open field test, and inflammation (nitrite + nitrate, TNF-α and IL-1β levels) in broncoalveolar fluid. Catalase activity, oxidative damage to proteins and DNA was increased by sepsis and prevented by exercise. Conclusion Overall, the beneficial effects of exercise in septic animals encompassed a markedly improved clinical score and decreased mortality, along with lower inflammation markers, less DNA and protein damage, as well as preserved antioxidant enzyme activity. Neural network risk analysis revealed exercise had a considerable effect on the overall health condition of septic mice.

Pneumonia-induced sepsis is responsible for about 50% of cases in the world. Patients who develop severe sepsis and septic shock present organ dysfunction and elevated plasma cytokine levels, which may lead to death. Clinical scores are important to evaluate the framework of septic patients and are used to predict the syndrome progress, prognostics, and mortality. The objective of the present study was to verify the applicability of a murine clinical score system to experimental sepsis (pneumonia-induced sepsis in male mice) and to correlate it with mortality and bacterial dissemination in different organs. Results demonstrated that animals which present higher clinical scores (>3) are more likely to die. Animals presenting high clinical scores exhibited transient bacteremia and displayed bacterial spreading to different organs such as heart, kidney, liver, and brain. There is a correlation between clinical score and bacterial dissemination and consequently greater risk of death. In addition, animals which showed bacterial dissemination in more than three organs and high clinical scores presented high levels of cytokines (TNF-α, MCP-1, IL-6, and IL-10) in plasma, lung, heart, liver, kidney, and brain. Therefore, our study suggests that (1) severity scores have predictive power in experimental models of sepsis and (2) high concentrations of tissue cytokines may contribute to localized inflammation and be one of the factors responsible for the systemic inflammatory syndrome of sepsis.

Aerobic exercise (AE) reduces lung function decline and risk of exacerbations in asthmatic patients. However, the inflammatory lung response involved in exercise during the sensitization remains unclear. Therefore, we evaluated the effects of exercise for 2 weeks in an experimental model of sensitization and single ovalbumin-challenge. Mice were divided into 4 groups: mice non-sensitized and not submitted to exercise (Sedentary, n=10); mice non-sensitized and submitted to exercise (Exercise, n=10); mice sensitized and exposed to ovalbumin (OVA, n=10); and mice sensitized, submitted to exercise and exposed to OVA (OVA+Exercise, n=10). 24 h after the OVA/saline exposure, we counted inflammatory cells from bronchoalveolar fluid (BALF), lung levels of total IgE, IL-4, IL-5, IL-10 and IL-1ra, measurements of OVA-specific IgG1 and IgE, and VEGF and NOS-2 expression via western blotting. AE reduced cell counts from BALF in the OVA group (p

Currently, photobiomodulation therapy (PBMT) is gaining space in the scientific and clinical environment. To help elucidate the importance of irradiance, this study evaluated the effect of two different PBMT irradiances (3.5 and 90 mW/cm2), given a fixed wavelength of 630 nm and a dose of 2 J/cm2, on mechanical hyperalgesia following Complete Freund's Adjuvant (CFA) intraplantar (i.pl.) injection in mice. Additionally, we investigated the role of peripheral opioid and endothelin-B receptors (ETB-R), as well as sex differences in treatment outcome. Different groups of male or female mice were evaluated 6 and 96 h after CFA. Mechanical hyperalgesia was evaluated 30 min after treatments. Naloxone or Bq-788 administration, fifteen minutes before PBMT or Sarafotoxin S6c, helped determine the involvement of peripheral opioid and ETB-Rs on PBMT. Lastly, ETB-Rs skin immunocontent in both sexes was quantified after PBMT consecutive daily treatments. PBMT at an irradiance of 90 mW/cm2, was more effective than 3.5 mW/cm2. Bq-788 and naloxone administration prevented the effects of PBMT and SRTX S6c; however, PBMT did not influence peripheral ETB-Rs immunocontent. The results suggest that irradiance influences PMBT effect; and that activation of ETB-R play a role in peripheral PBMT opioid induced analgesia. Lastly, PMBT effects do not appear to be sex-dependent.

Proinflammatory cytokines are critical mediators that control Mycobacterium tuberculosis (Mtb) growth during active tuberculosis (ATB). To further inhibit bacterial proliferation in diseased individuals, drug inhibitors of cell wall synthesis such as isoniazid (INH) are employed. However, whether INH presents an indirect effect on bacterial growth by regulating host cytokines during ATB is not well known. To examine this hypothesis, we used an in vitro human granuloma system generated with primary leukocytes from healthy donors adapted to model ATB. Intense Mtb proliferation in cell cultures was associated with monocyte/macrophage activation and secretion of IL-1β and TNF. Treatment with INH significantly reduced Mtb survival, but altered neither T-cell-mediated Mtb killing, nor production of IL-1β and TNF. However, blockade of both IL-1R1 and TNF signaling rescued INH-induced killing, suggesting synergistic roles of these cytokines in mediating control of Mtb proliferation. Additionally, mycobacterial killing by INH was highly dependent upon drug activation by the pathogen catalase-peroxidase KatG and involved a host PI3K-dependent pathway. Finally, experiments using coinfected (KatG-mutated and H37Rv strains) cells suggested that active INH does not directly enhance host-mediated killing of Mtb. Our results thus indicate that Mtb-stimulated host IL-1 and TNF have potential roles in TB chemotherapy.

In the last decades, balneotherapy or thermalism has been used for health promotion and in the treatment of inflammatory and chronic processes. We found that balneotherapy reduced mechanical hyperalgesia, as well the increase of BDNF and NOS2 levels in the spinal cord, while increased BDNF and NOS1 in the paw. The data presented herein demonstrated for the first time in a murine model of neuropathic pain, the analgesic effect of balneotherapy with the water from the natural springs of Santo Amaro da Imperatriz-Brazil. Nevertheless, future clinical trials should be conducted to test the effectiveness of balneotherapy in neuropathic pain patients.

To characterize Annexin A1 (ANXA1), FPR2/ALX and cytokines expression in peritoneal endometriosis and to clarify their role in its etiology, a cross-sectional study was performed with forty women in reproductive age (22 patients with endometriosis and 18 control women) that had undergone laparoscopic surgery. Peritoneal biopsy and fluid aspirations from endometriosis and control samples were analyzed for the expression of ANXA1, FPR2/ALX and cytokines. ANXA1 and FPR2 / ALX levels were measured by Western blotting and interleukin 1s (IL-1β), interleukin 4 (IL-4), interleukin 6 (IL-6), and interleukin 10 (IL-10) levels were quantified by enzyme-linked immunosorbent assay (ELISA). The present study identified the presence in human peritoneal tissue of ANXA1 and FPR2 / ALX both in healthy condition and in women with peritoneal endometriosis, however, was lower in endometriosis samples than in control samples. By quantifying the IL-6 and IL-1β cytokines in the peritoneal fluid by ELISA, this study identified a higher IL-6 concentration in endometriosis group, but no significative difference in IL-1s levels. The IL-4 and IL-10 levels could not be detected. These results indicate that the reduction of the inflammatory resolution mediators could be responsible for the inflammatory process perpetuation, maintenance and worsening of endometriosis.

Complex regional pain syndrome (CRPS) is a disorder that involves abnormal inflammation and nerve dysfunction frequently resistant to a broad range of treatments. Peripheral nerve stimulation with electroacupuncture (EA) has been widely used in different clinical conditions to control pain and inflammation; however, the use of EA in the treatment of CRPS is under investigation. In this study, we explore the effects of EA on hyperalgesia and edema induced in an animal model of chronic post-ischemia pain (CPIP model) and the possible involvement of endothelin receptor type B (ET

The original version of this article contains an error. The Author Francisco José Cidral-Filho incorrectly listed as Francisco José Cidra-Filho. The correct spelling is presented above. The original article has been corrected.

The formylpeptide receptor 2 (FPR2/ALX) is a very promiscuous receptor, utilized by lipid and protein ligands that trigger pro- or anti-inflammatory responses. FPR2/ALX expression is increased in lung tissues of septic animals and its activation has a beneficial therapeutic effect by controlling exacerbated inflammation. Although FPR2/ALX expression was observed in vascular smooth muscle cells, its role in vascular reactivity in inflammatory conditions has not been studied. In this study, we report that LPS increases FPR2/ALX expression in vascular smooth muscle cells (A7r5 cells) and aorta tissue, and that the selective agonist WKYMVm reverses LPS-induced vascular hyporeactivity in mouse aorta rings. Mice bearing pneumosepsis by Klebsiella pneumoniae and treated with WKYMVm recovered the reactivity to vasoconstrictors and the survival improved by 40%. As for the mechanisms involved, FPR2/ALX activation decreases NO production in LPS-stimulated cells and aorta, but it does not seem involve the regulation of NOS-2 expression. The molecular mechanism by which the peptide inhibits NO production still needs to be elucidated, but our data suggests an important role for NO in the WKYMVm beneficial effect observed in LPS injury and sepsis. In conclusion, our data suggest, for the first time, that a receptor, primarily described as a mediator of immune responses, may have an important role in the vascular dysfunctions observed in sepsis and may be a possible target for new therapeutic interventions.

PURPOSE The host response to infection differs between peri-implantitis and periodontitis, but the mechanisms underlying these differences are not understood. In this study, the distribution of dendritic cell subpopulations in healthy peri-implant mucosa (HPIM) was compared to that of healthy gingiva (HG). MATERIALS AND METHODS HPIM and HG specimens were obtained from nonsmoking, systemically healthy subjects. Immunohistochemistry was used to quantify the number of Langerhans cells (LCs) (CD1a+) and interstitial dendritic cells (IDCs) (factor XIIIa+) in the oral epithelium, sulcular/junctional epithelia, and lamina propria without inflammatory infiltration and with inflammatory infiltration. RESULTS Fourteen HPIM and 13 HG specimens were obtained from subjects aged 29 to 55 years. The lamina propria of the HPIM had fewer LCs than that of the HG (HPIM: 7.99 ± 10.76, HG: 25.68 ± 16.98; P = .003). There was no significant difference in the number of CD1a+ cells in the oral epithelium or the sulcular/junctional epithelia between the HPIM and the HG (P ≥ .23). A greater number of IDCs was observed in the lamina propria with inflammatory infiltration of the HPIM compared to the HG (HPIM: 57.02 ± 35.70, HG: 33.89 ± 26.98; P = .06). CONCLUSIONS In the lamina propria of HPIM, fewer LCs and more IDCs were observed. These differences may be associated with reduced stimulation of the innate and acquired immune responses initiated by LCs and the greater matrix remodeling of peri-implant tissue associated with IDCs.

Pneumonia is the major cause of sepsis, responsible for almost one-half of all sources of infection [1]. Sepsis and septic shock lead to organ failure and death. Spreading of microorganisms and their toxins through the blood could contribute to the organ dysfunction. The heart, liver and kidney are examples of organs damaged during the systemic infection and organ failure predicts poor prognosis in patients with sepsis [2]. However the correlation, if any, between bacterial spreading and organ injury is unclear. Thus, the aim of this study was to study the bacterial systemic spreading from a localized infection along with time and the target organ inflammatory profile using proinflammatory cytokines as surrogate markers.