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Protease-activated receptors (PARs) are partly pro-inflammatory and partly anti-inflammatory: will PAR agonists or antagonists participate in future drug therapies?

Protease-activated receptors (PARs) are characterised by a unique mechanism of activation, which enables them to act as cellular sensors for protease activity. PARs are expressed throughout the cardiovascular, gastrointestinal and pulmonary systems, where they are potential drug targets for the treatment of disease. However, there are currently very few selective PAR antagonists or potent PAR agonists available as effective research tools, and moreover, there is considerable evidence to suggest that PARs can promote both pro-inflammatory and anti-inflammatory responses in a wide range of disease models. These confounding issues have, to date, prevented us from developing a clear understanding of the role of PARs in disease. Nevertheless, this review provides an overview of the distribution and function of PARs in the cardiovascular, gastrointestinal and pulmonary systems, and attempts to evaluate whether PAR agonists or antagonists have a place in future drug therapy.

Animals↗

Immunohistochemical analysis of synovial membranes from inflammatory and non-inflammatory arthritides: scarcity of CD5 positive B cells and IL2 receptor bearing T cells.

Rheumatoid Arthritis (RA) synovial membranes were examined by single and dual immunohistological techniques with a number of monoclonal antibodies against lymphocyte and macrophage related antigens. CD4 positive T lymphocytes frequently expressed MHC Class II antigens and were found in sublining collections in close association with activated macrophages as well as B lymphocytes. CD8 positive T cells surrounded these collections as well as being scattered throughout the membrane and also frequently expressed MHC Class II antigens. IL2 receptor (IL2r) expression on T cells and CD5 expression on B cells were rarely seen in these synovial membranes. Similar immunohistological architecture was found in synovial membranes from patients with psoriatic arthritis (PA) and Reiter's Syndrome (RS). Normal synovium contained few T cells, with few cells expressing MHC Class II antigens. Synovium from osteoarthritis (OA) patients also demonstrated similar immunohistological changes to those found in inflammatory arthritides, suggesting that there are only quantitative rather than qualitative differences between the synovial membrane immunohistological architecture from patients with inflammatory and noninflammatory arthritides.

Adult↗

Fibronectin and lymphocytes in inflammatory tissue. Studies of blood and synovial fluid lymphocytes from patients with rheumatoid arthritis and other inflammatory arthritides.

Lymphocytes infiltrating tissues under chronic inflammatory conditions are often surrounded by deposits of fibronectin. We have studied the possibility that this reflects capacity of lymphocytes to synthesize fibronectin and compared lymphocytes from blood and synovial fluid with respect to fibronectin interactions. In vitro activated blood lymphocytes exhibited synthesis of a fibronectin-like molecule. Synovial fluid cells appeared to synthesize the same high molecular weight component spontaneously. Activated blood lymphocytes have cell surface fibronectin and surface components of lower molecular weight which could be immunoprecipitated with anti-fibronectin antibodies as well as by insolubilized collagen. Synovial fluid cells showed cell surface fibronectin as revealed by immunocytochemical detection but seemed to lack or have relatively small amounts of the low-molecular weight fibronectin-like surface components. Synovial fluid T cells from arthritis patients showed adhesion to fibronectin. Immunocytochemistry demonstrated presence of alpha 4 and alpha 5 beta 1 integrins at the surface of the synovial fluid T cells and RGD and LDV peptides inhibited adhesion of the cells to fibronectin. Noteworthy, a portion of synovial fluid cells with lymphocyte markers also bound to plastic. Blood lymphocytes from the same arthritis patients displayed relatively poor or negligible adhesion to fibronectin unless activated to blast transformation and did not attach to plastic. Taken together these results suggest that activated lymphocytes from blood and synovial fluid may use fibronectin of exogenous or endogenous origin when interacting with tissues during inflammatory processes. Furthermore, the presence at the lymphocyte surface of components of different molecular weight precipitated by anti-fibronectin antibodies suggests that fibronectin or its fragments can bind to the lymphocyte surface.

Arthritis↗

[Efficacy of radiation synovectomy in degenerative inflammatory and chronic inflammatory joint diseases].

AIM: Effect of radiosynovectomy (RS) should be evaluated both by subjective and objective parameters in patients with osteoarthritis and in patients with inflammatory joint disorders not caused by rheumatoid arthritis. METHODS: A total of 98 joints in 61 patients were investigated. Patients were divided into two groups. The first group included 35 patients with therapy-resistant effusions caused by severe osteoarthritis (46 joints). The second group consisted of 26 patients (52 joints) with ankylosing spondylitis, reactive arthritis, undifferentiated spondylarthropathy, psoriatic arthritis, pigmented villo-nodular synovitis, and recurrent synovitis following surgery. Effect of RS was evaluated by a standardized questionnaire and quantified by T/B-ratios derived from blood pool images prior to and after RS. RESULTS: Within the first patient group suffering from osteoarthritis, 40% showed a good or excellent improvement of clinical symptoms, 51% were unchanged, and in 9% symptoms worsened. Similar results were found in the second patient group. The majority of unchanged results were small finger joints. In contrast, wrist and knee joints showed a better improvement. Good correlation between results of bone scan and patients subjective impression was found in 38% and 67% in the first and the second patient group, respectively. CONCLUSION: Radiosynovectomy might be an effective treatment in osteoarthritis and inflammatory joint disorders not caused by rheumatoid arthritis.

Adult↗

[Quantitation of mRNA in micro-samples of the brain by competitive PCR: analysis of expression of interleukin-1 beta mRNA in rat hypothalamus and hippocampus after inflammatory or non-inflammatory stress].

Changes in the expressions of interleukin-1 beta (IL-1 beta) mRNA in the rat brain were investigated during inflammatory or non-inflammatory stress. We utilized competitive reverse transcription PCR (RT-PCR) to quantitate precisely the minute amount of IL-1 beta mRNA in small tissues which were micro-punched out from discrete sites in the brain. Intraperitoneal injection of lipopolysaccharide (100 micrograms/kg) caused a widespread and high elevation of IL-1 beta mRNA in the hypothalamus, hippocampus and cerebral cortex. Immobilization stress significantly increased IL-1 beta mRNA only in the hypothalamus, when examined in the brain block samples, which reached a peak 30 minutes after the start of stress. However, examination of the small tissues punched out from discrete sites in the brain revealed a profound elevation of IL-1 beta mRNA in the CA1 region of the hippocampus and in all the hypothalamic nuclei examined 30 minutes after the start of immobilization stress, but not in the CA3 region and the dentate gyrus or cerebral cortex. The method shown in this report proved to be useful and may be applied to quantify the low amount of mRNA in the small areas in the brain.

Animals↗

Cell localization of the anti-inflammatory protein annexin 1 during experimental inflammatory response.

The localization of the glucocorticoid-inducible protein annexin 1 (ANX-1) in leukocytes during the process of experimental inflammation has been studied using immunocytochemistry. ANX- 1 immunoreactivity was detected in extravasated neutrophils and eosinophils as well as in resident tissue mast cells. Following injection of carrageenin, the mesenteric tissue was highly inflamed with large presence of leukocytes (predominantly neutrophils with a small percentage of eosinophils) adherent to post-capillary venules and extravasated in the perivascular tissue. ANX-1 immunoreactivity was detected in the cytosol of neutrophils and eosinophils mainly associated with granules and/or vesicles. A good degree of localization in the endosomes was observed in the neutrophils. In both cell types, some ANX-1 immunoreactivity in the nucleus and in the plasma membrane was also detected. Resident mast cells were also activated. Mast cells were positive for ANX-1, without apparent changes in protein content in relation to their activation status. Degranulated mast cells still presented ANX-1 associated with the granule matrix. In conclusion, this study demonstrated the presence of ANX-1 in leukocytes that play a central role in the host inflammatory response. These are the extravasating polymorphonuclear cells, or the resident mast cells. These data provide morphological support to the notion that endogenous and exogenous ANX-1 are able to modulate the reactivity of these cell types, and more generally, of the experimental inflammatory reaction.

Animals↗

Increased IL-18 in patients with systemic lupus erythematosus: relations with Th-1, Th-2, pro-inflammatory cytokines and disease activity. IL-18 is a marker of disease activity but does not correlate with pro-inflammatory cytokines.

OBJECTIVE: The aim of this study was to investigate the imbalance between Th-1 and Th-2 cytokines in systemic lupus erythematosus patients (SLE) and to asses if any of these cytokines could be related to disease activity. METHODS: Twenty SLE patients and 20 healthy individuals were investigated. Blood samples were collected to evaluate, using ELISA method, serum levels of a wide array of cytokines including: Th-1 type cytokines (Interleukin (IL)-12, Interferon (IFN)-gamma), Th-2 cytokines (IL-4, IL-10), pro-inflammatory cytokines (tumor necrosis factor (TNF)-alpha, IL-1beta and IL-18). Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Data were evaluated using the Mann-Whitney and Spearman's rank tests. RESULTS: The SLE patients group had a higher IL-4, IL-10, IL-12 and IL-18 serum concentration compared to the normal control group. IL-18 was negatively correlated with IL-4 and positively correlated with IFN-gamma. No serum cytokine level was correlated with disease activity except for IL-18, which was found strongly correlated with "active disease", defined as SLEDAI > 8 points. IL-18 showed no correlation with pro-inflammatory cytokines. CONCLUSIONS: Our results show that Th-1 as well Th-2 cytokines can be elevated in SLE patients suggesting that lupus is a complex disease that may be supported by different cytokine patterns in different time-points. Only IL-18 has been found to be disease-activity related. The role of IL-18 in the pathogenesis of SLE might be important through apoptosis-mediating properties.

Adult↗

[The hemodiafiltration with infusion of acetate-free dialysis fluid can modify the inflammatory response in patients "high responders" to inflammatory stimuli?].

PURPOSE: This study aimed to verify the effects of paired hemodiafiltration on-line (PHF-AF) on inflammation in patients who were "high responders" to inflammatory stimuli: elevated C-reactive protein (CRP), genetic polymorphisms influencing a low transcription for interleukin-10 (IL-10) and a high transcription for IFN-gamma. METHODS: Ten patients selected as high responders for IFN-gamma and low responders for IL-10 were included in a crossover study to compare PHF-AF and standard bicarbonate hemodialysis (BHD). At study entry and before the start of each dialysis session the following examinations were performed: CRP, albumin, fibrinogen, ferritin, transferrin, prealbumin and serum levels of IL-6, IL-10, IFN-gamma, tumor necrosis factor-alpha (TNF-alpha). After the 1st and 3rd week of the study, the blood samples were also collected after the dialysis session. RESULTS: . There was a significant reduction in albumin and prealbumin in PHF-AF patients during the study; none of the other parameters were changed in both patient groups. CRP tended to be elevated after dialysis in both PHF-AF and BHD. While IL-6, IL-10 and IFN-gamma were unchanged during the dialysis session, there was a significant variation in TNF-alpha levels, which were increased in BHD (from 10.9 +/- 3.1 to 14.7 +/- 4.1 pg/mL; p=0.004) and reduced in PHF-AF (from 11.9 +/-2.8 to 6.3 +/- 2.2 pg/mL; p=0.0004). CONCLUSION: Although the cytokine levels were unchanged during the study in both BHD and PHF-AF, the modification of TNF-alpha during the dialysis session was considered as inflammatory significance.

Acetates↗

[Relationship between grade I and II inflammatory foci and certain inflammatory ophthalmic diseases].

The purpose of the study was demonstration of relations between grade I and II inflammatory foci in the oral cavity and certain inflammatory diseases of the eyes. Forty-three patients of either sex were studied. They were aged 19 to 78 years and were referred with the diagnosis of optic neuritis (intraocular and retrobulbar), iritis, retinitis and keratitis. Apart from routine clinical and radiological investigations the electrocutaneous test, the test for pulp viability with faradic current, and Schüller's iodine test were done. In 31 patients the electrocutaneous test was positive.

Adult↗

[In vitro differentiation of inflammatory and non-inflammatory states of the synovial fluid by magnetic protonic relaxation].

The differentiation between inflammatory and non inflammatory states has been performed using Nuclear Magnetic Resonance (NMR) in vitro by measuring relaxation times T1 and T2 in 84 synovials fluids obtained from various rheumatologic diseases. The results show that the T1/T2 ratio is more sensitive to distinguish these two situations rather than the isolated T1 or T2 values. In particular, high values of T1/T2 ratio are found in septic arthritis.

Arthritis↗

Elevated granulocyte strontium in inflammatory arthritides is related to the inflammatory activity.

Total cellular strontium and calcium were measured by the nuclear microprobe technique. Increased mass fraction of both elements was found in granulocytes isolated from patients with active rheumatoid arthritis and other kinds of inflammatory arthritides. Increased granulocyte calcium but only marginally elevated granulocyte strontium was demonstrated in patients with scleroderma. The granulocyte accumulation of strontium and calcium seems to be linked to the degree of inflammatory activity, because the granulocyte content of both elements was positively correlated to the plasma concentration of acute-phase proteins. Corticosteroid therapy induced a marked reduction of granulocyte strontium but a more modest decrease of granulocyte calcium. The serum levels of strontium and calcium were within the normal ranges in all patients and were not significantly altered by corticosteroids.

Adolescent↗

Mechanisms of anti-inflammatory action of dexamethasone: blockade by hydrocortisone mesylate and actinomycin D of the inhibitory effect of dexamethasone on leukocyte infiltration in inflammatory sites.

The present study was designed to clarify molecular mechanisms underlying inhibitory effect of dexamethasone on leukocyte infiltration in the inflammatory site. For the assay of leukocyte infiltration, two or four blebs were made s.c. on the back of rats by injecting with 2% carboxymethyl cellulose solution containing a chemoattractant, casein. Leukocyte accumulation in the bleb was inhibited considerably by local application of dexamethasone at a concentration of 0.6 X 10(-6) M. Hydrocortisone mesylate, which was reported in the study with hepatoma tissue culture cells to be a long-acting antagonist against glucocorticoid in binding to the corticoid receptor, blocked the above leukocyte inhibitory effect of dexamethasone when applied simultaneously with dexamethasone. The leukocyte infiltration was unaffected by the application of hydrocortisone mesylate alone. Treatment with androstenedione, which was reported to be inactive in the hepatoma tissue culture cells, did not interfere with the inhibitory effect of dexamethasone at all. Actinomycin D, when applied simultaneously with dexamethasone, significantly suppressed the leukocyte-inhibitory effect of dexamethasone. In contrast with those observations, the inhibitory effect of dexamethasone was not affected at all in cases that actinomycin D and hydrocortisone mesylate, respectively, were applied after the administration of dexamethasone. These results indicate essential roles of glucocorticoid receptor and gene expression for the manifestation of the inhibitory effect of dexamethasone on leukocyte infiltration in the inflammatory site.

Androstenedione↗

Anemia of inflammatory disease in the dog: availability of storage iron in inflammatory disease.

The iron-chelating agent deferoxamine (DF) was administered as a single dose and also daily over a prolonged period to evaluate availability of storage iron in dogs with induced anemia of inflammatory disease. In a 6-hour period, total urinary ferrioxamine (measured as urinary iron) excretion in controls was 251.22 +/- 119.68 microgram (mean +/- 1 SD), a 5.32 +/- 2.64-fold increase over prechelation values. In anemia of inflammatory disease-affected dogs, excretion was diminished to 115.67 +/- 34.86 microgram, a 2.87 +/- 1.10-fold increase, indicating a restricted iron excretion and sequestration of iron in a less soluble, less chelatable form. During prolonged DF administration, a pattern of increasing total urinary iron excretion was observed. This pattern is consistent with iron being stored as an insoluble polynuclear hydroxide in protein of ferritin and hemosiderin. The increase in hemoglobin and serum iron concentrations during prolonged DF administration indicates that increased iron stores are present, but in a less labile form. During the process of chelation, iron is converted to a more readily utilized state, and the increased availability of iron promotes hemoglobin synthesis. Thus, storage iron in the form of hemosiderin and ferritin is released to the metabolizable pool.

Anemia↗

Inflammatory cloacogenic polyp. A unique inflammatory lesion of the anal transitional zone.

This report describes the clinical and pathologic features of eight cases of an unusual inflammatory polyp arising from the transitional zone of the anus. This lesion has been designated as the inflammatory cloacogenic polyp. Rectal bleeding is the most common presenting clinical symptom. The polyp is usually located on the anterior wall of the anal canal. Morphologically, it is characterized by a tubulovillous pattern of growth, superficial ulceration, displaced groups of crypts into submucosa, and extension of chronically inflamed fibromuscular stroma into the lamina propria. Clinical and morphologic similarities with the solitary rectal ulcer syndrome suggests that prolapse of transitional zone mucosa may be important in its pathogenesis. Simple surgical resection appears to be the treatment of choice.

Adult↗

The Short Inflammatory Bowel Disease Questionnaire: a quality of life instrument for community physicians managing inflammatory bowel disease. CCRPT Investigators. Canadian Crohn's Relapse Prevention Trial.

OBJECTIVE: Health-related quality of life (HRQOL) affects outcome in chronic diseases such as inflammatory bowel disease (IBD). The inflammatory bowel disease questionnaire (IBDQ), a disease-specific HRQOL questionnaire, can define changes in health status in IBD, but simple instruments are needed for daily application. The present study proposed to develop a short version of the IBDQ, the SIBDQ, for community physicians. METHODS: Using data from a clinical trial in 149 patients with Crohn's disease, 10 items were selected (by forward stepwise regression) that best explained the variance of the IBDQ or dimensional scores (bowel, systemic, social, emotional). The validity, reliability, and responsiveness of the SIBDQ were then assessed in 150 different patients with Crohn's disease and 45 with ulcerative colitis. All scores were reported with a 7-point scale (1 = poor HRQOL, 7 = optimum HRQOL). RESULTS: Mean SIBDQ scores were similar (p = 0.22) in Crohn's patients among 14 participating centers at study entry. Mean scores were lower in active Crohn's disease (range 4.00-4.92) than inactive disease (range 4.67-5.83; p = 0.0015). In active ulcerative colitis, the mean SIBDQ was 4.79 +/- 1.17 compared to 5.90 +/- 0.80 (p = 0.0006) in inactive disease. The SIBDQ explained 92% and 90% of the IBDQ variance in Crohn's disease and ulcerative colitis, respectively. In patients with stable Crohn's disease, the test-retest reliability coefficient was 0.65 and Crohnbach's alpha was 0.78, indicating good reliability. In patients with Crohn's disease who relapsed during follow-up, the mean SIBDQ decreased by -0.93 + 0.55 (p = 0.001). CONCLUSION: The SIBDQ is valid, reliable, and able to detect meaningful clinical changes in HRQOL that might occur in the office setting.

Adult↗

[Aminosalicylates and steroids in the treatment ot chronic inflammatory bowel diseases--consensus paper of the Working Group for Chronic Inflammatory Bowel Diseases of the OGGH].

5-aminosalicylates (5-ASA) and steroids constitute a cornerstone of medical therapy in patients with inflammatory bowel diseases (IBD). Whereas the efficacy of 5-ASA in Crohn's disease (CD) is equivocal, ulcerative colitis (UC) is the main indication for this drug. In UC, 5-ASA is effective in the treatment of mild to moderate acute disease and in maintenance of remission. Furthermore, 5-ASA topical therapy is an important treatment option in patients with mild to moderate proctitis and/or left-sided UC and shows additive efficacy to oral therapy. From retrospective data a chemo-preventative activity of long-term 5-ASA therapy in UC is delineated. Steroids are treatment of first choice for moderate to severe cases of CD and UC. Budesonide, a modified steroid with less side effects, plays a major role in the treatment of ileocolonic CD +/- involvement of the right colon and is used as treatment of choice in mild-to-moderate cases. In case of acute, severe disease conventional steroids are superior compared to budesonide and therefore budesonide should only be used after considerable improvement of disease activity. The necessity to apply steroids in a given patient represents a negative prognostic indicator for the course of disease and should incite the early introduction of immunosuppressive therapy in this case. Steroids are only effective as short term therapy of IBD and are to be avoided for maintenance treatment. In all cases of steroid therapy an osteoporosis prophylaxis with calcium and vitamin D is recommended. Topical steroid treatment is less effective in left-sided UC compared to 5-ASA.

Aminosalicylic Acids↗

Condom use and the risk of recurrent pelvic inflammatory disease, chronic pelvic pain, or infertility following an episode of pelvic inflammatory disease.

Among 684 sexually active women with pelvic inflammatory disease (PID) followed up for a mean of 35 months, we related contraceptive use to self-reported PID recurrence, chronic pelvic pain, and infertility. Persistent use of condoms during the study reduced the risk of recurrent PID, chronic pelvic pain, and infertility. Consistent condom use (about 60% of encounters) at baseline also reduced these risks, after adjustment for confounders, by 30% to 60%. Self-reported persistent and consistent condom use was associated with lower rates of PID sequelae.

Adolescent↗

Mechanism of the uricosuric action of the anti-inflammatory drug E3040 used to treat inflammatory bowel disease I: study using a rat model of hyperuricemia.

E3040, a new class of anti-inflammatory drug, was found to reduce the plasma uric acid level in the first phase of clinical studies. In the present study, the mechanism of the uricosuric action of E3040 was investigated using the hyperuricemia model rat. The fractional excretion of uric acid (FEurate), an indicator of the excretion of uric acid in the renal tubules, at 30, 60 and 90 min after administration of E3040 (50 mg kg(-1)) was significantly elevated as compared with that in the control. This elevation of the FEurate by E3040 was dose-dependent. Although the FEurate was elevated spontaneously 30 min after administration of E3040-sulfate (E-Sul) and glucuronide (E-Glu) (100 mg kg(-1), respectively), the value was not significantly different from the control. Based on these results, it was suggested that E3040 has a uricosuric action, probably in the proximal tubules, and the uricosuric action after administration of E3040 may be mainly due to the parent drug. Concerning the tissue distribution, the kidney concentration of E-Sul after i.v. administration of the E3040 (50 mg kg(-1)) was higher than that of the parent drug (kidney/plasma ratio approximately 2).

Animals↗