Chronic inflammation inhibits GH secretion and alters the serum insulin-like growth factor system in rats

Adjuvant-induced arthritis in rats is associated with growth failure, hypermetabolism and accelerated protein breakdown. The aim of this work was to study the effects of adjuvant-induced arthritis on GH and insulin-like growth factor-I (IGF-I). Arthritis was induced by an intradermal injection of complete Freund's adjuvant and rats were killed 18 and 22 days later. IGF-I and GH levels were measured by radioimmunoassay. Pituitary GH mRNA was analyzed by northern blot and IGF binding proteins (IGFBPs) by western blot. Arthritic rats showed a decrease in both serum and hepatic concentrations of IGF-I. On the contrary, arthritis increased the circulating IGFBPs. The serum concentration of IGF-I in the arthritic rats was negatively correlated with the body weight loss observed in these animals. Arthritis decreased the serum concentration of GH and this decrease seems to be due to an inhibition of GH synthesis, since pituitary GH mRNA content was decreased in arthritic rats (p<0.01). These data suggest that the decrease in body weight gain in arthritic rats may be, at least in part, secondary to the decrease in GH and IGF-I secretion. Furthermore, the increased serum IGFBPs may also be involved in the disease process.

Obesity And Inflammation And The Effect On The Hematopoietic System.

Bone marrow is organized in specialized microenvironments known as 'marrow niches'. These are important for the maintenance of stem cells and their hematopoietic progenitors whose homeostasis also depends on other cell types present in the tissue. Extrinsic factors, such as infection and inflammatory states, may affect this system by causing cytokine dysregulation (imbalance in cytokine production) and changes in cell proliferation and self-renewal rates, and may also induce changes in the metabolism and cell cycle. Known to relate to chronic inflammation, obesity is responsible for systemic changes that are best studied in the cardiovascular system. Little is known regarding the changes in the hematopoietic system induced by the inflammatory state carried by obesity or the cell and molecular mechanisms involved. The understanding of the biological behavior of hematopoietic stem cells under obesity-induced chronic inflammation could help elucidate the pathophysiological mechanisms involved in other inflammatory processes, such as neoplastic diseases and bone marrow failure syndromes.

Hypothalamic Inflammation And The Central Nervous System Control Of Energy Homeostasis.

The control of energy homeostasis relies on robust neuronal circuits that regulate food intake and energy expenditure. Although the physiology of these circuits is well understood, the molecular and cellular response of this program to chronic diseases is still largely unclear. Hypothalamic inflammation has emerged as a major driver of energy homeostasis dysfunction in both obesity and anorexia. Importantly, this inflammation disrupts the action of metabolic signals promoting anabolism or supporting catabolism. In this review, we address the evidence that favors hypothalamic inflammation as a factor that resets energy homeostasis in pathological states.

Volumetric Capnography For The Evaluation Of Chronic Airways Diseases.

Obstructive lung diseases of different etiologies present with progressive peripheral airway involvement. The peripheral airways, known as the silent lung zone, are not adequately evaluated with conventional function tests. The principle of gas washout has been used to detect pulmonary ventilation inhomogeneity and to estimate the location of the underlying disease process. Volumetric capnography (VC) analyzes the pattern of CO2 elimination as a function of expired volume. To measure normalized phase 3 slopes with VC in patients with non-cystic fibrosis bronchiectasis (NCB) and in bronchitic patients with chronic obstructive pulmonary disease (COPD) in order to compare the slopes obtained for the groups. NCB and severe COPD were enrolled sequentially from an outpatient clinic (Hospital of the State University of Campinas). A control group was established for the NCB group, paired by sex and age. All subjects performed spirometry, VC, and the 6-Minute Walk Test (6MWT). Two comparisons were made: NCB group versus its control group, and NCB group versus COPD group. The project was approved by the ethical committee of the institution. Statistical tests used were Wilcoxon or Student's t-test; P<0.05 was considered to be a statistically significant difference. Concerning the NCB group (N=20) versus the control group (N=20), significant differences were found in body mass index and in several functional variables (spirometric, VC, 6MWT) with worse results observed in the NCB group. In the comparison between the COPD group (N=20) versus the NCB group, although patients with COPD had worse spirometric and 6MWT values, the capnographic variables mean phase 2 slope (Slp2), mean phase 3 slope normalized by the mean expiratory volume, or mean phase 3 slope normalized by the end-tidal CO2 concentration were similar. These findings may indicate that the gas elimination curves are not sensitive enough to monitor the severity of structural abnormalities. The role of normalized phase 3 slope may be worth exploring as a more sensitive index of small airway disease, even though it may not be equally sensitive in discriminating the severity of the alterations.

Inflammation markers in healthy and periodontitis patients: a preliminary data screening

Advances in diagnostic research are moving towards methods whereby the periodontal risk can be identified and quantified by objective measures using biomarkers. Patients with periodontitis may have elevated circulating levels of specific inflammatory markers that can be correlated to the severity of the disease. The purpose of this study was to evaluate whether differences in the serum levels of inflammatory biomarkers are differentially expressed in healthy and periodontitis patients. Twenty-five patients (8 healthy patients and 17 chronic periodontitis patients) were enrolled in the study. A 15 mL blood sample was used for identification of the inflammatory markers, with a human inflammatory flow cytometry multiplex assay. Among 24 assessed cytokines, only 3 (RANTES, MIG and Eotaxin) were statistically different between groups (p<0.05). In conclusion, some of the selected markers of inflammation are differentially expressed in healthy and periodontitis patients. Cytokine profile analysis may be further explored to distinguish the periodontitis patients from the ones free of disease and also to be used as a measure of risk. The present data, however, are limited and larger sample size studies are required to validate the findings of the specific biomarkers.

Effects of prone and supine position on oxygenation and inflammatory mediator in a hydrochloric acid-induced lung dysfunction in rats

PURPOSE: To compare the effectiveness of mechanical ventilation of supine versus prone position in hydrochloric acid (HCl)-induced lung dysfunction. METHODS: Twenty, adult, male, Wistar-EPM-1 rats were anesthetized and randomly grouped (n=5 animals per group) as follows: CS-MV (mechanical ventilation in supine position); CP-MV (mechanical ventilation in prone position); bilateral instillation of HCl and mechanical ventilation in supine position (HCl+S); and bilateral instillation of HCl and mechanical ventilation in prone position (HCl+P). All groups were ventilated for 180 minutes. The blood partial pressures of oxygen and carbon dioxide were measured in the time points 0 (zero; 10 minutes before lung injury for stabilization), and at the end of times acid injury, 60, 120 and 180 minutes of mechanical ventilation. At the end of experiment the animals were euthanized, and bronchoalveolar lavages (BALs) were taken to determine the contents of total proteins, inflammatory mediators, and lungs wet-to-dry ratios. RESULTS: In the HCl+P group the partial pressure of oxygen increased when compared with HCl+S (128.0±2.9 mmHg and 111.0±6.7 mmHg, respectively) within 60 minutes. TNF-α levels in BAL do not differ significantly in the HCl+P group (516.0±5.9 pg/mL), and the HCl+S (513.0±10.6 pg/mL). CONCLUSION: The use of prone position improved oxygenation, but did not reduce TNF-α in BAL upon lung dysfunction induced by HCl.

Histological response study of chronic viral hepatitis C patients treated with interferon alone or combined with ribavirin

Chronic hepatitis C is often a progressive, fibrotic disease that can lead to cirrhosis and other complications. The recommended therapy is a combination of interferon and ribavirin. Besides its antiviral action, interferon is considered to have antifibrotic activity. We examined the outcome of hepatic fibrosis and inflammation in chronic hepatitis C patients who were non-responders to interferon. We made a case series, retrospective study, based on revision of medical records and reassessment of liver biopsies. For inclusion, patients should have been treated with interferon alone or combined with ribavirin, with no virological response (non responders and relapsers) and had a liver biopsy before and after treatment. Histological evaluation included: i-outcome of fibrosis and necroinflammation; ii-annual fibrosis progression rate evaluation, before and after treatment. Seventy-five patients were included. Fifty-seven patients (76%) did not show progression of fibrosis after treatment, compared to six (8%) before treatment (p < 0.001). The mean annual fibrosis progression rate was significantly reduced after treatment (p = 0.036). Inflammatory activity improved in 19 patients (25.3%). The results support the hypothesis of an antifibrotic effect of interferon-based therapy, in non-responder patients. There was evidence of anti-inflammatory effects of treatment in some patients.

Lung hyperinflation stimulates the release of inflammatory mediators in spontaneously breathing subjects

Lung hyperinflation up to vital capacity is used to re-expand collapsed lung areas and to improve gas exchange during general anesthesia. However, it may induce inflammation in normal lungs. The objective of this study was to evaluate the effects of a lung hyperinflation maneuver (LHM) on plasma cytokine release in 10 healthy subjects (age: 26.1 ± 1.2 years, BMI: 23.8 ± 3.6 kg/m²). LHM was performed applying continuous positive airway pressure (CPAP) with a face mask, increased by 3-cmH2O steps up to 20 cmH2O every 5 breaths. At CPAP 20 cmH2O, an inspiratory pressure of 20 cmH2O above CPAP was applied, reaching an airway pressure of 40 cmH2O for 10 breaths. CPAP was then decreased stepwise. Blood samples were collected before and 2 and 12 h after LHM. TNF-α, IL-1β, IL-6, IL-8, IL-10, and IL-12 were measured by flow cytometry. Lung hyperinflation significantly increased (P < 0.05) all measured cytokines (TNF-α: 1.2 ± 3.8 vs 6.4 ± 8.6 pg/mL; IL-1β: 4.9 ± 15.6 vs 22.4 ± 28.4 pg/mL; IL-6: 1.4 ± 3.3 vs 6.5 ± 5.6 pg/mL; IL-8: 13.2 ± 8.8 vs 33.4 ± 26.4 pg/mL; IL-10: 3.3 ± 3.3 vs 7.7 ± 6.5 pg/mL, and IL-12: 3.1 ± 7.9 vs 9 ± 11.4 pg/mL), which returned to basal levels 12 h later. A significant correlation was found between changes in pro- (IL-6) and anti-inflammatory (IL-10) cytokines (r = 0.89, P = 0.004). LHM-induced lung stretching was associated with an early inflammatory response in healthy spontaneously breathing subjects.

PDIA3, HSPA5 and viementin, proteins identified by 2-DE in the valvular tissue, are the target antigens of peripheral and heart infiltrating T cells from chronic rheumatic heart disease patients

Rheumatic fever (RF) is a post-infectious autoimmune disease due to sequel of group A streptococcus (GAS) pharyngitis. Rheumatic heart disease (RHD), the major manifestation of RF, is characterized by inflammation of heart valves and myocardium. Molecular mimicry between GAS antigens and host proteins has been shown at B and T cell level. However the identification of the autoantigens recognized by B and T cells within the inflammatory microenvironment of heart tissue in patients with RHD is still incompletely elucidated. In the present study, we used two-dimensional gel electrophoresis (2-DE) and mass spectrometry to identify valvular tissue proteins target of T cells from chronic RHD patients. We could identify three proteins recognized by heart infiltrating and peripheral T cells as protein disulfide isomerase ER-60 precursor (PDIA3), 78 kD glucose-regulated protein precursor (HSPA5) and vimentin, with coverage of 45%, 43 and 34%, respectively. These proteins were recognized in a proliferation assay by peripheral and heart infiltrating T cells from RHD patients suggesting that they may be involved in the autoimmune reactions that leads to valve damage. We also observed that several other proteins isolated by 2-DE but not identified by mass spectrometry were also recognized by T cells. The identified cardiac proteins are likely relevant antigens involved in T cell-mediated autoimmune responses in RF/RHD that may contribute to the development of RHD

Prognostic factors for progression of liver structural lesions in chronic hepatitis C patients

AIM: To evaluate the epidemiological, clinical, laboratory and histological variables capable of predicting the progression of hepatic structural disturbances in chronic hepatitis C patients during the time interval between two liver biopsies. METHODS: Clinical charts of 112 chronic hepatitis C patients were retrospectively analyzed, whereas liver biopsies were revised. Immunohistochemical detection of interferon receptor was based on the Envision-Peroxidase System. RESULTS: In the multivariate analysis, the variables in the age at first biopsy, ALT levels, presence of lymphoid aggregates and siderosis were the determinants of the best model for predicting the severity of the disease. The direct progression rate of hepatic structural lesions was significantly higher in untreated patients, intermediate in treated non-responders and lower in treated responders to antiviral therapy (non-treated vs responders, 0.22 +/- 0.50 vs -0.15 +/- 0.46, P = 0.0053). Immuno-expression of interferon receptor is not a relevant factor. CONCLUSION: The best predictors of the progression of fibrosis are age at the first liver biopsy, extent of ALT elevation, inflammation at liver histology and hepatic siderosis. Antiviral treatment is effective in preventing the progression of liver structural lesions in chronic hepatitis C patients. (C) 2008 WJG. All rights reserved.

Acute and chronic effects of exercise on inflammatory markers and B-type natriuretic peptide in patients with coronary artery disease

Few studies have prospectively addressed the effects of exercise in the inflammatory activity of patients with coronary artery disease (CAD). We sought to evaluate the consequences of an acute bout of exercise on inflammatory markers and BNP in untrained CAD patients before and after randomization to a training program. 34 CAD patients underwent a 50-min acute exercise session on a cycle-ergometer at 65% peak oxygen uptake before and after blood sampling. They were then randomized to a 4-month chronic exercise program (15 patients) or general lifestyle recommendations (19 patients), undergoing a new acute session of exercise after that. In the overall population, acute exercise caused a significant increase in C-reactive protein [CRP; 1.79 (4.49) vs. 1.94 (4.89) mg/L, P < 0.001], monokine induced by interferon-gamma [Mig; 351 (324) vs. 373 (330) pg/mL, P = 0.027] and vascular adhesion molecule-1 [VCAM-1; 226 (82) vs. 252 (110) pg/mL, P = 0.02]. After 4-months, in exercise-trained patients, there was a significant decrease in the inflammatory response provoked by the acute exercise compared to patients in the control group reflected by a significant decrease in the differences between rest and post-exercise levels of CRP [-0.29 (0.84) mg/L vs. -0.11 (0.21) mg/L, P = 0.05]. Resting BNP was also significantly lower in exercise-trained patients when compared to untrained controls [15.6 (16.2) vs. 9.7 (11.4) pg/mL, P = 0.04 and 19.2 (27.8) vs. 23.2 (27.5) pg/mL, P = 0.76; respectively]. Chronic exercise training might partially reverse the inflammatory response caused by acute exercise in CAD patients. These results suggest that regular exercise is an important nonpharmacological strategy to the improvement in inflammation in CAD patients.

Experimental chronic low-frequency resistance training produces skeletal muscle hypertrophy in the absence of muscle damage and metabolic stress markers

Volitional animal resistance training constitutes an important approach to modeling human resistance training. However, the lack of standardization protocol poses a frequent impediment to the production of skeletal muscle hypertrophy and the study of related physiological variables (i.e., cellular damage/inflammation or metabolic stress). Therefore, the purposes of the present study were: (1) to test whether a long-term and low frequency experimental resistance training program is capable of producing absolute increases in muscle mass; (2) to examine whether cellular damage/inflammation or metabolic stress is involved in the process of hypertrophy. In order to test this hypothesis, animals were assigned to a sedentary control (C, n = 8) or a resistance trained group (RT, n = 7). Trained rats performed 2 exercise sessions per week (16 repetitions per day) during 12 weeks. Our results demonstrated that the resistance training strategy employed was capable of producing absolute mass gain in both soleus and plantaris muscles (12%, p<0.05). Furthermore, muscle tumor necrosis factor (TNF-alpha) protein expression (soleus muscle) was reduced by 24% (p<0.01) in trained group when compared to sedentary one. Finally, serum creatine kinase (CK) activity and serum lactate concentrations were not affected in either group. Such information may have practical applications if reproduced in situations where skeletal muscle hypertrophy is desired but high mechanical stimuli of skeletal muscle and inflammation are not. Copyright (C) 2010 John Wiley & Sons, Ltd.

Restoration of Pattern Recognition Receptor Costimulation to Treat Chromoblastomycosis, a Chronic Fungal Infection of the Skin

Chromoblastomycosis is a chronic skin infection caused by the fungus Fonsecaea pedrosoi. Exploring the reasons underlying the chronic nature of F. pedrosoi infection in a murine model of chromoblastomycosis, we find that chronicity develops due to a lack of pattern recognition receptor (PRR) costimulation. F. pedrosoi was recognized primarily by C-type lectin receptors (CLRs), but not by Toll-like receptors (TLRs), which resulted in the defective induction of proinflammatory cytokines. Inflammatory responses to F. pedrosoi could be reinstated by TLR costimulation, but also required the CLR Mincle and signaling via the Syk/CARD9 pathway. Importantly, exogenously administering TLR ligands helped clear F. pedrosoi infection in vivo. These results demonstrate how a failure in innate recognition can result in chronic infection, highlight the importance of coordinated PRR signaling, and provide proof of the principle that exogenously applied PRR agonists can be used therapeutically.

Antinociceptive and anti-inflammatory properties of 7-hydroxycoumarin in experimental animal models: potential therapeutic for the control of inflammatory chronic pain

Objectives In the present study we investigated the anti nociceptive, anti-inflammatory and antipyretic effects of 7-hydroxycoumarin (7-HC) in animal models. Methods The effects of oral 7-HC were tested against acetic acid-induced writhing, formalin test, tail flick test, complete Freund`s adjuvant (CFA)-induced hypemociception, carrageenan-induced paw oedema, lipopolysaccharide-induced fever and the rota rod test. Key findings 7-HC (3-60 mg/kg) produced a dose-related antinociception against acetic acid-induced writhing in mice and in the formalin test. In contrast, treatment with 7-HC did not prevent thermal nociception in the tail flick test. A single treatment with 7-HC, 60 mg/kg, produced a long-lasting antinociceptive effect against CFA-induced hypernociception, a chronic inflammatory pain stimulus. Notably, at 60 mg/kg per day over 4 days the administration of 7-HC produced a continuous antinociceptive effect against CFA-induced hypernociception. 7-HC (30-120 mg/kg) produced anti-inflammatory and antipyretic effects against carrageenan-induced inflammation and lipopolysaccharide-induced fever, respectively. Moreover, 7-HC was found to be safe with respect to ulcer induction. In the rota rod test, 7-HC-treated mice did not show any motor performance alterations. Conclusions The prolonged antinociceptive and anti-inflammatory effects of 7-HC, in association with its low ulcerogenic activity, indicate that this molecule might be a good candidate for development of new drugs for the control of chronic inflammatory pain and fever.

Circulating matrix metalloproteinase-8 (MMP-8) and MMP-9 are increased in chronic periodontal disease and decrease after non-surgical periodontal therapy

Background: Periodontal disease shares risk factors with cardiovascular diseases and other systemic inflammatory diseases. The present study was designed to assess the circulating matrix metalloproteinases (MMPs) from chronic periodontal disease patients and, subsequently, after periodontal therapy. Methods: We compared the plasma concentrations of MMP-2. MMP-3, MMP-8, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, and total gelatinolytic activity in patients with periodontal disease (n =28) with those of control subjects (n = 22) before and 3 months after non-surgical periodontal therapy. Results: Higher plasma MMP-3, MMP-8, and MMP-9 concentrations were found in periodontal disease patients compared with healthy controls (all P<0.05), whereas MMP-2, TIMP-1, and TIMP-2 levels were not different. Treatment decreased plasma MMP-8 and MMP-9 concentrations by 35% and 39%, respectively (both P<0.02), while no changes were found in controls. MMP-2, MMP-3, TIMP-1, and TIMP-2 remained unaltered in both groups. Plasma gelatinolytic activity was higher in periodontal disease patients compared with controls (P<0.001) and decreased after periodontal therapy (P<0.05). Conclusions: This study showed increased circulating MMP-8 and MMP-9 levels and proteolytic activity in periodontal disease patients that decrease after periodontal therapy. The effects of periodontal therapy suggest that it may attenuate inflammatory chronic diseases. (C) 2009 Published by Elsevier B.V.