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Assessment of inflammation and nutrition in patients with end-stage renal disease.

Malnutrition commonly occurs in patients with end-stage renal disease (ESRD), and hypoalbuminemia is considered the best clinical marker of malnutrition and mortality in this population. Recently, it has been recognized that a substantial number of patients with ESRD have serologic evidence of an augmented inflammatory response and moreover, inflammation may be as or more important than protein intake in causing hypoalbuminemia. In addition, the presence of inflammation may be a more powerful predictor of mortality than dietary protein intake. The presence of inflammation is often subtle and is detected by increased levels of the positive acute phase proteins, most notably C-reactive protein. The causes of the stimulation of the systemic inflammatory response may include reaction to dialyzer membranes, increased production of advanced glycosylated end-products, oxidative stress of uremia and overt and occult infections, especially unrecognized arteriovenous graft infections. There is a complex relationship between inflammation and nutritional status. Inflammation can cause both anorexia with protein-calorie malnutrition as well as wasting through mechanisms mediated by cytokines. Novel therapies will need to be developed to counter this systemic inflammation since it appears to be a major cause of mortality in patients with end-stage renal disease.

Albumins↗

[Relation between clinical severity of bronchial asthma and degree of airway inflammation assessed by the eosinophilic leukocyte count in induced sputum].

Airways inflammation, involving infiltration of bronchial wall with activated eosinophils, mast cells and T lymphocytes, is an established feature of asthma. Clinical assessment of disease severity is based upon pulmonary function tests, their variability and symptom score. The relationship between the degree of airway inflammation and disease control is probably not significant. Differential cell count in induced sputum seems to be a useful parameter reflecting the degree of airway inflammation in patients with bronchial asthma. We investigated 67 patients with bronchial asthma of different severity and have shown statistically significant correlation between percentage of sputum eosinophils and clinical and physiological parameters of disease control. Eosinophil counts in induced sputum were negatively correlated with FEV1 (p = 0.006), ration of FEV1/VC (p < 0.001) and diurnal variability of PEF (p < 0.001). According to previous studies, where percentage of eosinophils was less than 4% in healthy subject, we determined sputum eosinophilia if eosinophil percentage was more than 4%. Sensitivity of clinical markers of disease control for predicting the degree of airway inflammation ranged between 0.15-0.74, ratio of FEV1/VC having the highest sensitivity. Specificity of clinical markers ranged from 0.43 to 0.94, diurnal variability of PEF having the highest specificity. Despite of good correlation of clinical markers of asthma severity with sputum eosinophils, pulmonary function test, diurnal variability of PEF and rescue salbutamol can hardly predict the degree of airway inflammation or the efficacy of antiinflammatory treatment in a particular patient. Percentage of sputum eosinophils seems to be a useful and promising marker for measuring the degree of airway inflammation in patients with bronchial asthma, especially in more severe cases.

Adult↗

Inflammation, malnutrition, and cardiac disease as predictors of mortality in hemodialysis patients.

Various studies suggest a strong association between nutrition and clinical outcome in hemodialysis (HD) patients. Several morbidity factors that per se increase the risk of a poor outcome, such as cardiovascular disease (CVD) and inflammation, may also cause malnutrition. Among laboratory parameters used to assess nutritional status, serum albumin appears to be a particularly strong predictor of morbidity and mortality. This study assessed the importance of nutritional status and inflammation and other comorbidity factors as predictors of mortality in HD patients. Nutritional status was evaluated in 128 HD patients by subjective global nutritional assessment (SGNA) and by measuring several anthropometric markers (actual body weight, percentage of actual body weight to desirable body weight, midarm muscle circumferences, triceps skinfold thickness), and serum albumin, plasma insulin such as insulin growth factor-1 and as a marker of inflammation, serum C-reactive protein (s-CRP) levels. The mortality during the next 36 mo was analyzed in relation to age, gender, CVD, SGNA, serum albumin, CRP, and several other factors by Kaplan-Meier analysis multivariate. Cox proportional hazard analysis was used to identify independent predictors of mortality. After 36 mo, 58 patients were still on HD treatment, 57 patients (45%) had died while receiving treatment, and 13 had received a kidney transplant. The main cause of death was CVD (58%), followed by infection (18%); malnutrition/cachexia was a rare direct cause of death (5%). Kaplan-Meier analysis showed that age, female gender, CVD, diabetes, SGNA, all anthropometric parameters, serum albumin, plasma insulinlike growth factor-1, and s-CRP were significant predictors of mortality. Analysis by the Cox model showed that age, gender, CVD, nutritional status (SGNA), and CRP were independent predictors of mortality at 36 mo. A low albumin level was not an independent predictor, although it was strongly associated with a reduced survival rate in the Kaplan-Meier analysis. Inflammation, malnutrition, and CVD appeared to contribute to increased mortality in a stepwise manner. The mortality at 36 mo was 0% when none of these complications was present, whereas the mortality was 75% in those patients with all three risk factors present at baseline. It is concluded that in addition to malnutrition and comorbidities (CVD, diabetes mellitus), inflammation (elevated s-CRP) is a significant independent risk factor for mortality in HD patients. Inflammation, malnutrition, and CVD appear to be interrelated, each additionally contributing to the high mortality in these patients.

Adult↗

[The role of infection and inflammation in the pathogenesis of atherosclerosis].

Pathogenesis of the atherosclerotic process is deemed as multifactorial. To the most important risk factors, besides certain family predisposition, there belongs hypercholesterolemia, arterial hypertension, obesity, diabetes mellitus, smoking and others. In the last years there are more and more data about the role of inflammation and infection in the whole development of atherosclerosis. The witness for this hypothesis is the findings of high parameters of inflammation in involved vessels as well as in the blood of atherosclerosis suffering persons. Opinions about the inflammation theory appear from the 90th. Local sterile inflammation in the subendotelium of the middle and big arteries has been proved to consist of specific immune reaction (activation of the T-lymphocytes) as well as nonspecific characteristic by elevated monocytes in the artery wall during the whole process of atherogenesis. Inflammation in the plaque can trigger and hold several factors engaged in the atherosclerotic process, such as oxidized LDL cholesterol, elevated production of various superoxides, activated macrophages, activated T-lymphocytes, cytokines (IL-1, IL-6, interferon gamma) and lipoprotein Lp (a). In this inflammation process levels of CRP (acute phase protein), fibrinogen and erythrocyte sedimentation are elevated as a reaction of the organism to nonspecific chronic infections. Because of this it is thought that elevated fibrinogen and erythrocyte sedimentation are markers of the cardiovascular risk. Some papers deal with antiinflammatory effects of statins, because these lower CRP levels so they also lower atherosclerotic risk through not only lowering of cholesterol levels. Also asprine, as an antiinflammation agent, changing the CRP levels, would be of benefit for patients with vascular disease because its antiaggregation and antiinflammatory effects. ACE inhibitors are also antiinflamatory through blocking of tissue production of angiotensin II (artery wall and atherosclerotic plaque). Enzymatic inhibitors changing angiotensin can also have a partial antiinflammatory effect. The infection theory is supported also by tracing of some microorganisms in the atherosclerotic plaque or in the blood, as e.g. Helicobacter pylori or Chlamydia pneumoniae; to the autoimmune origin is indicated the presence of the specific immunity reaction against heat shock proteins (HSP) or oxidized LDL. This infection theory offers new therapy possibilities. Therefore eradication for example by antibiotics can lead to stabilization of the atherosclerotic plaque with positive consequences, as it was discovered by many studies.

Animals↗

[Current views of tuberculosis inflammation].

The value of histological and histochemical studies in the diagnosis of a phase of tuberculosis progression or healing is shown. Electron microscopic study of tuberculous inflammation in different phases of its evolution evaluated the functional status of cellular elements of the lung and granuloma. The body's antituberculous resistance due to molecular genetic mechanisms is realized through intercellular interactions and macrophageal functions. Immune macrophages are characterized by a higher metabolic activity, they suppress the intracellular multiplication of Mycobacterium tuberculosis (MBT) and are more protected from their toxic action. The pathogenetic mechanisms responsible for caseous pneumonia were studied. Three stages of evolution of the process: Stage 1 is the breakdown of defense and adaptive mechanisms: disorganization of connective tissue and alveolar parenchyma; enhanced permeability of blood and lymphatic microvascular walls with developed interstitial and intraalveolar edema, plasma and fibrin exudation, fibrinoid swelling of collagenous fibers, and their lysis; occurrence of lung parenchymal microinfarcts and infarction-pneumonia; type 2 alveolocytic dysfunction with surfactant destruction; Stage 2 is the breakdown of local immunity; exudative and alterative tuberculous inflammation with involvement of immunocompetent organs; suppressed T-cellular immunity, a shift of a T helper/T suppressor ratio to the latter, lymphopenia; impaired intercellular interactions, cellular apoptosis in blood and inflammation areas, and suppressed granulomatous reaction; inhibited L transformation of Mycobacteria tuberculosis, intensive MBT multiplication in the foci of tuberculous inflammation, particularly those which are resistant to many antibiotic drugs, a larger number of associations of the nonspecific microflora and fungi. Stage 3 is caseous pneumonia and generalization of a tuberculous process: a predominance of an alterative reaction of inflammation; the presence of allergic and caseous and necrotic vasculitis, bronchiolitis, and endo-panbronchitis; depressed granulomatous reaction; the development of acute alterative sequestrating pneumoniogenic caverns. Histological, histochemical, and electron microscopic studies of tuberculous inflammation may specify the mechanisms of the pathogenesis of tuberculosis and may serve as the basis for early diagnosis of the disease and for timely correction of performed treatment in order to enhance its efficiency.

Giant Cells↗

Acute exacerbations of COPD: is inflammation central to prevention and treatment strategies?

Acute exacerbations (AE) represent one of the hallmarks of Chronic Obstructive Pulmonary Disease (COPD). They are characterised by increased from baseline dyspnoea, cough and sputum production and/or purulence, variably associated with fever and systemic symptoms. As in stable COPD, airway inflammation is an important part of the disease underlying the clinical manifestations. Studies on airway inflammation in AE by means of invasive methodologies (e.g. fiberoptic bronchoscopy with bronchial biopsy and/or bronchoalveolar lavage) are difficult due to clinical, practical and ethical issues. New and less- (sputum) or non-invasive methodologies (exhaled markers) are becoming increasingly applied also to the study of AE in COPD. The overall data on airway inflammation during AE seems to indicate an "acute on chronic" picture of inflammation, with increased proportions of inflammatory cells in tissue and lavage/sputum samples and with the change in the proportions of some of the cell types, such as a substantial increase in the numbers of eosinophils. Cytokines and inflammatory mediators involved in AE seem to be those related to PMN chemotaxis (IL-8 and LT) and those related to eosinophilic inflammation. A more precise categorisation of the event causing AE (e.g. viral vs. bacterial), and of the baseline patients' characteristics (e.g. severe vs. mild-moderate stage) associated with a wider application of well-standardised non-invasive methodologies could bring us in the future better clues on the pattern of airway inflammation during AE.

Bronchi↗

Sex influence on chronic intestinal inflammation in Helicobacter hepaticus-infected A/JCr mice.

Helicobacter hepaticus is a bacterial pathogen of mice that has been reported to cause chronic intestinal inflammation in A/JCr, germfree Swiss Webster, and immunodeficient mice. To the authors' knowledge, the influence of sex on development of chronic intestinal inflammation in H. hepaticus-infected mice has not been investigated. The purposes of the study reported here were to determine whether severity of intestinal inflammation differs between male and female A/JCr mice chronically infected with H. hepaticus and to characterize the mucosal immune response in these mice. The cecum of male and female A/JCr mice infected with H. hepaticus for 1 month and 3 months was objectively evaluated histologically for intestinal disease. Also, semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was done to measure interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin 4 (IL-4), IL-10, macrophage inflammatory protein-1alpha (MIP-1alpha), interferon-inducible protein of 10 kDa (IP-10), and monokine induced by gamma interferon (MIG) mRNA values in the cecal tissue of these mice. Significant differences in cecal lesion scores were not present at 1 month after infection. However, infected female mice had significantly up-regulated expression of cecal IL-10, MIP-1alpha, IP-10, and MIG mRNA compared with that in uninfected females, and expression of IL-10 and MIP-1alpha was significantly greater than that detected in infected male mice (P < or = 0.05). At 3 months after infection, cecal lesion scores were significantly (P < or = 0.05) increased in female and male mice compared with uninfected controls, and infected female mice had significantly (P < or = 0.05) higher cecal lesion scores than did infected male mice. In addition, infected females had significant (P < or = 0.05) increases in cecal IFN-gamma, TNF-alpha, IL-10, MIP-1alpha, IP-10, and MIG mRNA values compared with values in uninfected females and infected males, and male mice had significant (P < or = 0.05) increases in cecal TNF-alpha and IL-10 mRNA values compared with those for male control mice. These data indicate that, in H. hepaticus-infected A/JCr mice, females develop more severe intestinal inflammation than do males, and the chronic mucosal inflammation is polarized toward a Th1 response that is not down-regulated by increased activity of IL-10. We propose that H. hepaticus-infected A/JCr mice will serve as a good animal model with which to study the influence of sex on bacterial-induced mucosal inflammation.

Animals↗

[Inflammation focal spots in uncontrolled diabetes].

UNLABELLED: During last few years we could observe systematic growth of diabetes sick rate. The purpose to be achieved in treating diabetes is to keep the glycemy on the level near to the glycemy of the healthy system. Sometimes we can not succeed in keeping target level of glycemy. Among many reasons leading to such conditions are infection and inflammation processes. OBJECTIVES: Assess the rate of infection and inflammation processes among patients suffering from uncontrolled diabetes and its most frequent locations. MATERIAL AND METHODS: 68 patients suffering from uncontrolled diabetes treated in the Internal Disease Clinic in 2001-2002. RESULTS: Among 68 cases examined, in 54 (79.4%) infection and inflammation process was found, where in half of the cases infection and inflammation process was found in more than one location. The most common locations were: pharyngeal and nasal cavity; larynx (51.5%) nasal sinus (32.4%), jaws (20.6%), urinary system (19.1%). CONCLUSIONS: In most cases of uncontrolled diabetes inflammation focal spots could be found, half of them in more than one location. In case of patients suffering from uncontrolled diabetes it is fully justified to conduct obligatory tests aimed at identifying infection and inflammation processes in most common locations.

Diabetes Mellitus↗

Malnutrition inflammation complex syndrome in maintenance haemodialysis patients.

Malnutrition inflammation complex syndrome (MICS) occurs in maintenance haemodialysis (MHD) patients and is a strong predictor of morbidity and mortality in these patients. The aim of our study was to evaluate the influence of inflammation on the biochemical and anthropometrical parameters of the nutritional status in MHD patients. Our study was made on 154 patients (93 men and 61 women, mean age=54.7 yrs. and mean time on dialysis 84 months) over a period of 6 months. The indicator of inflammation, C-reactive protein (CRP), was measured monthly at the central laboratory by nephelometry. The assessment tools used to evaluate the influence of inflammation on the nutritional status in MHD patients were: serum albumin and cholesterol level, midarm circumference (MAC), midarm muscle circumference (MAMC), triceps skin fold thickness (TSF) and body mass index (BMI). Student's t-test was used for group mean comparison between men and women. Person's correlation r was used to determine the significance and the strength of associations. The CRP level was significantly greater in men than in women (12.9 vs. 7.97, p < 0.04). The CRP level showed a strong correlation only with the serum concentration of cholesterol (r=0.49, p < 0.000), and did not correlate with the serum albumin of the MHD patients. There was no correlation between the CRP level and the anthropometrical parameters of the MHD patients in our study. Two separate processes, inflammation and reduced protein intake, each separately contributed to causing a decrease in serum albumin concentration and anthropometrical measurements. The levels of acute phase proteins vary widely as opposed to the serum albumin level; for that reason, changes in the albumin catabolic rate or synthesis require a considerable time to become visible. The average value of the protein catabolic rate of the patients in our study was 1.01 g/kg/d, a value that showed adequate protein intake. These findings would suggest that clinical attention to the maintenance of adequate nutrition could blunt the effects of inflammation on both somatic and visceral protein stores.

C-Reactive Protein↗

[Study of the role of insulin and insulin receptor in allergic airway inflammation of rats].

OBJECTIVE: To reveal the possible mechanism underlying the inverse relationship between IDDM and asthma and the role of insulin and insulin receptor in allergic airway inflammation. METHODS: Diabetes mellitus was induced in rats by intraperitoneal injection of streptozotocin. Rats were sensitized by subcutaneous injection of ovalbumin (OVA) and challenged with an aerosolized solution of 1% OVA for 20 min 14 days after sensitization to provoke allergic airway inflammation. Sixty-four male Sprague-Dawley rats were divided into 8 groups: group A (asthma), group D (diabetes), group I (insulin treated), group AD (asthma + diabetes), group AI (asthma + insulin treated), group DI (diabetes + insulin treated), group ADI (asthma + diabetes + insulin treated), and group C (control). Blood glucose measurements, total and differential leukocyte counts and serum insulin measurements were carried out. Bronchoalveolar lavage (BAL) were performed, total and differential cell counts were determined. Hematoxylin-eosin stained paraffin section of lung tissue was examined to observe the histological changes. Immunohistochemistry method was used to describe the distribution of insulin receptor, and the expression of insulin receptor mRNA were measured by RT-PCR. RESULTS: All groups of diabetes had higher blood glucose levels than non-diabetes groups. After antigen challenge, the rats of group A, AI, ADI exhibited airway inflammation characterized by significantly elevated eosinophils and neutrophils, group AD only exhibited mild airway inflammation. The serum insulin levels were higher in groups ADI, AI and A (27 mIU/L +/- 8 mIU/L, 83 mIU/L +/- 12 mIU/L, 71 mIU/L +/- 12 mIU/L respectively) compared with their respective control group (group DI, I, C, 15 mIU/L +/- 4 mIU/L, 64 mIU/L +/- 9 mIU/L; 49 mIU/L +/- 14 mIU/L respectively). Immunohistochemistry staining for insulin receptor revealed a diffused distribution pattern of the receptor in the lung tissue. Positive cells infiltrating in the alveolar spaces, submucosa of bronchus, blood vessels, and bronchial mucosa were increased significantly in groups A, AI and ADI. In groups with induced diabetes the expression of insulin receptor mRNA was elevated compared with that in the non-diabetes groups (0.2588 +/- 0.0809 vs 0.0896 +/- 0.0308, P = 0.00). CONCLUSION: Administration of low dose insulin aggravated airway inflammation to antigen provocation in rats. Insulin secretion is increased in the presence of inflammation. In the lung of antigen-challenged rats, insulin receptors on the surface of the infiltrating inflammatory cells and bronchial secretory cells are increased.

Animals↗

Nasal polyposis: role of allergy on therapeutic response of eosinophil- and noneosinophil-dominated inflammation.

BACKGROUND: It is considered that allergy, at least in some cases, is associated with nasal polyps and affects recurrence rate. Our purpose was to determine the effects of aeroallergen hypersensitization on therapeutic response of eosinophil- and noneosinophil-dominated inflammation. METHODS: Sixty-eight patients were enrolled. Histopathological investigation and a skin-prick test were done and categorized as eosinophil-dominated inflammation with positive (ESPT+) or negative skin test (ESPT-) and nonesoinophil-dominated inflammation with positive (NESPT+) or negative skin test (NESPT-). Patients were treated over 6 weeks with budesonide nasal spray, 400 microg/day. At 0, 3, and 6 weeks after treatment, nasal symptoms, polyp size, nasal and oral peak expiratory flow (PEF) index and overall assessment within and between groups were evaluated and compared. RESULTS: At 3 and 6 weeks after treatment, the ESPT- group showed the most, and the NESPT+ group showed the least therapeutic improvement. In comparing between the positive and negative skin tests in each histopathology, the positive skin tests tended to have less improvement than the negative skin tests in all variables. The differences increased over time and reached statistical significance at 6 weeks in the PEF index and overall assessment of eosinophil-dominated inflammation (p = 0.004 and 0.033, respectively) and in sneezing score, postnasal drip score, and overall assessment of noneosinophil-dominated inflammation (p = 0.019, 0.035, and 0.013, respectively). CONCLUSION: Nonallergic eosinophilic polyps had the best and allergic noneosinophilic polyps had the worst therapeutic response. Within each histopathology, allergic nasal polyps had less therapeutic response than nonallergic nasal polyps. This augmented effect could be caused by concomitant allergic inflammation.

Adolescent↗

[The anti-inflammation effects of Smilax china ethylacetate extract in rats and mice].

OBJECTIVE: To study the anti-inflammations of the ethyl acetate extract of S. china on acute and chronic inflammations. METHOD: The rat paw edema induced by egg-albumin, the ear edema and the foot edema of mice induced by xylene and formaldehyde, the increased vascular permeability of capillary induced by intraperitoneal injection of 0.7% acetic acid in mice were used to study on the acute, early inflammations and chronic inflammation for the ethyl acetate extract of S. china. RESULT: The extract (50-100 g x kg(-1)) could significantly decrease the rat paw edema, and inhibit the ear edema, the increased vascular permeability and the foot edema of mice. CONCLUSION: The ethyl acetate extract of S. china possesses remarkable anti-inflammatory effects on acute inflammation, and also displays anti-inflammatory effects on the chronic inflammation at a certain extent.

Animals↗

Inflammation and extracellular volume expansion are related to sodium and water removal in patients on peritoneal dialysis.

BACKGROUND: Inflammation is an important risk for mortality in dialysis patients. Extracellular fluid volume (ECFv) expansion, a condition commonly seen in peritoneal dialysis (PD) patients, may be associated with inflammation. However, published support for this relationship is scarce. OBJECTIVES: To quantify the proportion of patients on PD with inflammation and to analyze the role of ECFv expansion and the factors related to these conditions. DESIGN: A prospective, multicenter cross-sectional study in six hospitals with a PD program. PATIENTS AND METHODS: Adult patients on PD were studied. Clinical data, body composition, and sodium and fluid intake were recorded. Biochemical analysis, C-reactive protein (CRP), and peritoneal and urinary fluid and sodium removal were also measured. RESULTS: CRP values positive (>or=3.0 mg/L) for inflammation were found in 147 (80.3%) and negative in 36 patients. Patients with positive CRP had higher ECFv/total body water (TBW) ratio (women 47.69 +/- 0.69 vs 47.36 +/- 0.65, men 43.15 +/- 1.14 vs 42.84 +/- 0.65; p < 0.05), higher serum glucose (125.09 +/- 81.90 vs 103.28 +/- 43.30 mg/dL, p < 0.03), and lower serum albumin (2.86 +/- 0.54 vs 3.17 +/- 0.38 g/dL, p < 0.001) levels. They also had lower ultrafiltration (1003 +/- 645 vs 1323 +/- 413 mL/day, p < 0.005) and total fluid removal (1260 +/- 648 vs 1648 +/- 496 mL/day, p < 0.001), and less peritoneal (15.59 +/- 162.14 vs 78.11 +/- 110.70 mEq/day, p < 0.01) and total sodium removal (42.06 +/- 142.49 vs 118.60 +/- 69.73 mEq/day, p < 0.001). In the multivariate analysis, only ECFv/TBW was significantly (p < 0.04) and independently associated with inflammation. ECFv/TBW was correlated with fluid removal (r = 0.16, p < 0.03) and renal sodium removal (r = 0.2, p < 0.01). CONCLUSION: The data suggest that ECFv expansion may have a significant role as an inflammatory stimulus. The results disclose a relationship between the two variables, ECFv expansion and inflammation, identified as independent risk factors for mortality in PD patients.

Adult↗

[Malnutrition, inflammation and atherosclerosis (MIA-syndrome) in dialysis patients].

Malnutrition and chronic inflammation are frequently-occurring complications in dialysis patients. These conditions are associated with cardiovascular diseases and predict hospitalisation and mortality. There is assumed to be a pathophysiologic association between malnutrition, inflammation and atherosclerosis in this patient population. Indeed, chronic inflammation can induce an atherogenic and catabolic state, while a low food intake can lead to malnutrition and inflammation, but can also result from it. These complex associations constitute the basis for 'malnutrition, inflammation and atherosclerosis (MIA syndrome)'. Inflammation and malnutrition associated atherosclerosis may explain a large part of the high mortality in dialysis patients. An integrated approach is needed to treat this multifactorial complication. Randomised clinical trials on this subject are lacking as yet.

Arteriosclerosis↗

Relationship between angiogenesis and inflammation in experimental arthritis.

Background. Angiogenesis is involved in rheumatoid arthritis (RA) leading to leucocyte recruitment and inflammation in the synovium. Furthermore, synovial inflammation itself further potentiates endothelial proliferation and angiogenesis. In this study, we aimed at evaluating the reciprocical relationship between synovial inflammation and angiogenesis in a RA model, namely collagen-induced arthritis (CIA). Methods. CIA was induced by immunization of DBA/1 mice with collagen type II in adjuvant. Endothelial cells were detected using a GSL-1 lectin-specific immunohistochemical staining on knee joint sections. Angiogenesis, clinical scores and histological signs of arthritis were evaluated from the induction of CIA until the end of the experiment. Angiogenesis was quantified by counting both the isolated endothelial cells and vessels stained on each section. To evaluate the effect of increased angiogenesis on CIA, VEGF gene transfer was performed using an adeno-associated virus encoding VEGF (AAV-VEGF), by intra-muscular or intra-articular injection in mice with CIA. Results. We showed an increase in synovial angiogenesis from day 6 to day 55 after CIA induction, and, moreover, joint vascularization and clinical scores of arthritis were correlated (p < 0.0001, r = 0.61). Vascularization and histological scores were also correlated (p = 0.0006, r = 0.51). Systemic VEGF overexpression in mice with CIA was followed by an aggravation of arthritis as compared to AAV-lacZ control group (p < 0.0001). In contrast, there was no difference in clinical scores between control mice and mice injected within the knee with AAV-VEGF, even if joint vascularization was higher in this group than in all other groups (p = 0,05 versus non-injected group). Intra-articular AAV-VEGF injections induced more severe signs of histological inflammation and bone destruction than AAV-Lac Z or no injection. Conclusion. Angiogenesis and joint inflammation evolve in parallel during collagen-induced arthritis. Furthermore, this work shows that exogenous VEGF can aggravate CIA. It is direct evidence that the increase in joint vascularization leads to an exacerbation of arthritis. Taken together, these results emphasize the role of angiogenesis in inflammatory arthritis. It also suggests an early involvement of angiogenesis in joint inflammation.

Animals↗

[The effect of calcium channel blocker lercanidipine on lowgrade inflammation parameters in essential hypertension patients].

INTRODUCTION: Oxidative stress (OS), inflammation and insulin resistance are among the mechanisms that have been recently implicated in pathogenesis of essential hypertension (EH). Peripheral polymorphonuclear leukocytes (PMNLs) are primed in EH patients, releasing uncontrolled superoxide anion contributing to OS and chronic low-grade inflammation in these patients. PMNL priming correlates with insulin resistance and with PMNL intracellular calcium ([Ca2+]i). Recent studies have attributed additional anti-oxidative characteristics to the anti-hypertensive drug Lercanidipine (Vasodip), a third generation calcium-channel blocker. AIM: To evaluate possible novel effects of two months of Lercanidipine treatment on systemic and PMNL-related inflammation and on insulin resistance in EH patients. METHODS: Fifteen non-smoking EH patients with untreated mild to moderate high blood pressure (BP) and age- and gender-matched healthy controls (HC) were included in the study. Low-grade inflammation was expressed by PMNL counts and apoptosis, by plasma fibrinogen, CRP and albumin (as a negative acute phase reactant) levels. Fasting serum insulin levels served as a marker of insulin resistance. RESULTS: Inflammation parameters and insulin levels were higher in EH compared to HC. PMNL counts, fibrinogen and insulin levels positively correlated with mean arterial blood pressure values. Two months of Lercanidipine treatment showed a significant decrease in BP, PMNL counts and apoptosis, CRP and serum insulin levels and a significant increase in serum albumin levels. CONCLUSION: The authors imply that the low-grade systemic inflammation and insulin resistance detected in EH patients may be attenuated by the use of Lercanidipine, adding new unknown anti-inflammatory properties to this calcium channel blocker.

Adult↗

Central modulation of croton oil induced subacute inflammation in rats.

Earlier studies from this laboratory have indicated that CNS exerts a modulatory influence over acute inflammation in rats. The present study examines the existence of a similar modulatory effect of CNS on a subacute inflammatory paradigm, the croton oil-induced granuloma pouch in rats. The inflammatory exudate, collected on 6th day after croton oil administration, was found to be substantially less in intracerebroventricular (icv) cannulated and artificial cerebrospinal fluid administered rats as compared to their uncannulated saline (ip) administered counterparts. This effect may be due to stress induced by cannulation. Centrally administered pharmacological agents which attenuate central monoaminergic, cholinergic or prostaglandin systems had insignificant effects on the inflammatory exudate. However, induced increase in central noradrenergic activity was found to attenuate the inflammation when the treatment was done before, but not 48 hr after, the induction of the inflammation. In contrast, induced increase in central serotonergic activity had no effect on the volume of the inflammatory exudate at either time period. Steady state levels of rat brain noradrenaline and serotonin, but not dopamine, were enhanced by the inflammatory procedure. However, these effects may be attributed to the stress induced by croton oil inflammation. The investigation indicates that the modulatory influence of CNS remains limited to the acute phase of inflammation, being exerted mainly by the central noradrenergic system. Once the inflammation has progressed, this modulatory influence of CNS is no longer apparent.

Animals↗

gamma-Glutamyl transpeptidase: a novel biochemical marker in inflammation.

gamma-Glutamyl transpeptidase (gamma-GT) plays an important role in the turnover of glutathione and protein biosynthesis. Because in inflammation both catabolic and anabolic steps are activated together with migration of cells, an alteration in gamma-GT activity was postulated to occur at the site of inflammation with the development of the inflammatory process. We discovered that gamma-GT activity was increased markedly at sites of inflammation produced in several ways in rats. A significant increase in enzyme activity appeared soon after the induction of inflammation. In carrageenin-induced acute inflammation, the paw tissue attained a 3- to 4-fold increase in enzyme activity within 4 hr; in established adjuvant arthritis, a 20- to 24-fold increase over its basal activity occurred in the rat paw tissue. The specific enzyme activity was 20-22 nmoles/min/mg protein in the cellular sediment of carrageenin-induced pleural exudate. In cotton granulomatous tissue it was 5- to 6-fold higher compared to the enzyme activity of the skeletal muscles. The in vivo increase in gamma-GT activity was prevented from occurring in proportion to the anti-inflammatory potencies of the test drugs given orally. The prevention of enzyme activity was observed with indomethacin in carrageenin-induced edematous paw tissue and with phenylbutazone in both adjuvant arthritis and carrageenin-induced pleural exudate. Prednisolone was observed to be the most potent drug against cotton granuloma. Nonsteroidal anti-inflammatory drugs (NSAIDs) were not found to affect enzyme activity in vitro when incubated with cellular infiltrate from a cotton pellet granuloma. Differences in certain physico-chemical characteristics, viz. stability at 50 degrees, pH dependency and effects of solvents, were not discernible in between the enzyme activities of the untreated and edematous paw tissues. The studies thus suggest that measurement of gamma-GT in inflammation may prove to be a valuable biochemical marker for the assessment of anti-inflammatory activity of drugs in vivo.

Animals↗