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PubMed2005

AGIX-4207 [2-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic acid], a novel antioxidant and anti-inflammatory compound: cellular and biochemical characterization of antioxidant activity and inhibition of redox-sensitive inflammatory gene expression.

The pathogenesis of chronic inflammatory diseases, including rheumatoid arthritis, is regulated, at least in part, by modulation of oxidation-reduction (redox) homeostasis and the expression of redox-sensitive inflammatory genes including adhesion molecules, chemokines, and cytokines. AGIX-4207 [2-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic acid] is a novel, orally active, phenolic antioxidant and anti-inflammatory compound with antirheumatic properties. To elucidate its anti-inflammatory mechanisms, we evaluated AGIX-4207 for a variety of cellular, biochemical, and molecular properties. AGIX-4207 exhibited potent antioxidant activity toward lipid peroxides in vitro and displayed enhanced cellular uptake relative to a structurally related drug, probucol. This resulted in potent inhibition of cellular levels of reactive oxygen species in multiple cell types. AGIX-4207 selectively inhibited tumor necrosis factor (TNF)-alpha-inducible levels of the redox-sensitive genes, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, with less inhibition of E-selectin, and no effect on intracellular adhesion molecule-1 expression in endothelial cells. In addition, AGIX-4207 inhibited cytokine-induced levels of monocyte chemoattractant protein-1, interleukin (IL)-6, and IL-8 from endothelial cells and human fibroblast-like synoviocytes as well as lipopolysaccharide-induced release of TNF-alpha, IL-1beta, and IL-6 from human peripheral blood mononuclear cells. AGIX-4207 did not inhibit TNF-alpha-induced nuclear translocation of nuclear factor of the kappa-enhancer in B cells (NF-kappaB), suggesting that the mechanism of action is independent of this redox-sensitive transcription factor. Taken together, these results provide a mechanistic framework for understanding the anti-inflammatory and antirheumatic activity of AGIX-4207 and provide further support for the view that inhibition of redox-sensitive inflammatory gene expression is an attractive approach for the treatment of chronic inflammatory diseases.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1990

Experimental non-steroidal anti-inflammatory drug-induced enteropathy in the rat: similarities to inflammatory bowel disease and effect of thromboxane synthetase inhibitors.

We have validated an established animal model of acute inflammatory bowel disease in indomethacin-treated rats. Studies in both in vitro and in vivo 51chromium-labelled ethylenediamine tetra-acetate (51Cr-EDTA) permeability and tissue myeloperoxidase activity, a marker of inflammatory cell invasion, showed increased permeability and enzyme levels, respectively, in treated animals compared to controls (in vitro 51Cr-EDTA permeability: (mean (SE] control 0.10 (0.02) microliter/mg per tissue, experimental 0.17 (0.02) (p < 0.01, 2 way analysis of variance); in vivo 51Cr-EDTA permeability: control 3.9 (1.3) (% dose recovered), experimental 12.1 (1.5) (p < 0.01); tissue myeloperoxidase: control 10.8 (0.4) mU/mg, experimental 17.2 (0.5) p less than 0.01). Pretreatment or simultaneous treatment of indomethacin-treated animals with glucocorticoids, sulphasalazine, or tetracycline reduced the permeability changes and the tissue inflammatory response (in vitro 51Cr-EDTA permeability: (mean (SE] sulphasalazine + indomethacin 0.11 (0.2) microliter/mg tissue (p < 0.01), prednisolone +/- indomethacin 0.12 (0.02) (p < 0.01), tetracycline + indomethacin 0.12 (0.02) (p < 0.01]. Glucocorticoids and sulphasalazine, but not tetracycline, administered after the indomethacin also partially corrected the permeability and inflammatory changes induced by indomethacin (in vitro 51Cr-EDTA permeability: sulphasalazine 0.15 (0.02) microliter/mg, p < 0.02; prednisolone 0.12 (0.02) microliter/mg, p < 0.01). This approach was used to investigate the effects of two different thromboxane synthetase inhibitors in indomethacin-treated animals. Simultaneous treatment with thromboxane synthetase inhibitors and indomethacin prevented the 51Cr-EDTA permeability and tissue myeloperoxidase increases induced by indomethacin alone (in vitro 51Cr-EDTA permeability: thromboxane synthetase inhibitors + indomethacin 0.11 (0.01) microliter/mg (p0.01); tissue myeloperoxidase: 11 (0.4) mU/mg, (p < 0.01). Thromboxane synthetase inhibitors administered after the indomethacin also partially corrected the permeability and inflammatory changes induced by indomethacin (in vitro 51Cr-EDTA permeability: thromboxane synthetase inhibitors 0.12 (0.02) mU/mg (p < 0.01); tissue myeloperoxidase 13.8 (0.5) (p < 0.01). These studies indicate that thromboxane synthetase inhibitors partially correct the intestinal lesion non-steroidal anti-inflammatory drug enteropathy and may therefore be of use in inflammatory bowel diseases in humans.

Animals↗

PubMed1984

Relationship between the anti-inflammatory effects and intrapleural accumulations of anti-inflammatory drugs in rats carrageenin pleurisy.

We simultaneously determined the time course of the anti-exudative effects of three types of anti-inflammatory drug and their concentrations in serum and pleural exudate in carrageenin-induced pleurisy in rats. Dexamethasone (DM, steroidal anti-inflammatory drug, 0.1 mg/kg, p.o.) in spite of the gradual decline of DM concentration in the pleural exudate with time and its actual loss at 16 h after carrageenin, showed an anti-exudative effect throughout the period of testing after carrageenin which was more marked in the relatively late phase than in the relatively early phase. Mepirizole (MP, non-acidic, non-steroidal antiinflammatory drug, 100 mg/kg, p.o.) showed an anti-exudative effect only at 3 h after carrageenin and not thereafter, although MP concentration in exudate was the same between 3 and 6 h after carrageenin and then declined gradually. Ketoprofen (KP, acidic, non-steroidal anti-inflammatory drug, 1 mg/kg, p.o.) showed an anti-exudative effect for 6 h after carrageenin and not thereafter, while KP concentration in exudate reached the peak at 3 h after carrageenin and then declined with time. However, at the relatively late phase (10 h after carrageenin) the twice administration of KP resulted in an increase in its exudate concentration enough to show an anti-inflammatory effect, but did not result in any more anti-exudative effect than the single administration of KP. Therefore, these differences in the anti-exudative effects of three types of anti-inflammatory drug can not be explained by the change in their concentrations in the inflamed tissue, but may reflect the difference in their intrinsic anti-inflammatory activities. The anti-inflammatory drugs accumulated in the inflamed pleural cavity independently of their ability to bind to plasma proteins, because the ratio of concentrations of three types of drug in exudate to those in serum were similar in spite of marked differences in protein binding capacities among these drugs.

Animals↗

PubMed1992

Anti-inflammatory, analgesic, and antipyretic effects and gastrointestinal toxicity of the new anti-inflammatory drug N-(3-[3-(piperidinylmethyl)phenoxy]propyl)-carbamoylmethylthio ]ethyl 1-(p-chlorobenzoyl) 5-methoxy-2-methyl-3-indolylacetate.

The anti-inflammatory, analgesic, and antipyretic effects and gastrointestinal toxicity of N-(3-[3-(piperidinylmethyl) phenoxy] propyl)- carbamoylmethylthio] ethyl 1-(p-chlorobenzoyl) 5-methoxy-2-methyl-3-indolylacetate (CP-331, CAS 127966-70-5), a new anti-inflammatory drug, were evaluated using indomethacin as a control. CP-331 exerted anti-inflammatory, analgesic and antipyretic effects on the models of carrageenin-induced paw edema, increased vascular permeability, ultraviolet light-induced erythema, granuloma proliferation, adjuvant arthritis, inflammatory pain, and yeast-induced fever. However, these effects were observed at a molar level similar to or higher than that of indomethacin. In addition, CP-331 influenced more markedly than indomethacin the delayed type hypersensitivity to sheep red blood cells. On the other hand, CP-331 did not damage the gastric mucosa even at a high dose of 1,000 mg/kg and also induced slighter damage to the intestinal mucosa than indomethacin. Thus, CP-331 exerted anti-inflammatory, analgesic, and antipyretic effects but without showing gastric toxicity, which is a common side effect of anti-inflammatory drugs. These results suggest the clinical applicability of this drug in the long-term therapy of inflammatory diseases such as rheumatoid arthritis.

Animals↗

PubMed1996

Inflammatory myofibroblastic tumor (inflammatory pseudotumor): DNA flow cytometric analysis of nine pediatric cases.

BACKGROUND: Inflammatory myofibroblastic tumor or inflammatory pseudotumor is an uncommon lesion reported in various organs and believed to be a non-neoplastic reactive inflammatory condition. The concept of benign lesion has been recently challenged from both clinical demonstration of recurrence and cytogenetic evidence of acquired clonal chromosomal abnormality. Because DNA aneuploidy can be a useful marker for neoplasia, we analyzed nuclear DNA content of these lesions using flow cytometry. METHODS: In this study, inflammatory myofibroblastic tumors from nine children were examined retrospectively by evaluating clinicopathologic features and ploidy. DNA ploidy status was analyzed by flow cytometry in nuclei isolated from paraffin-embedded tumor tissues. RESULTS: Three of the nine patients had local recurrence or distant metastases. Flow cytometric DNA analysis revealed five of the nine cases were diploid and four hyperdiploid (DNA indices 1.14, 1.16, 1.19, and 1.33). All lesions had a low S-phase fraction. Samples from the three subjects with clinical recurrence were all hyperdiploid. CONCLUSIONS: The present data indicate that flow cytometry identifies aneuploidy (hyperdiploidy) in approximately half of the cases of inflammatory myofibroblastic tumors. This feature appears to reflect a more aggressive biologic behavior. In addition to the reported cytogenetic abnormalities, our data suggest that inflammatory myofibroblastic tumor, generally considered a benign reactive inflammatory process, may evolve as a distinct, potentially malignant, lesion. Therefore, flow cytometric DNA analysis is a suitable tool to provide the clinician with both diagnostic and prognostic information and to individuate the most feasible therapeutic approach.

Child↗

PubMed2006

The inflammatory reaction pattern distinguishes primary dysferlinopathies from idiopathic inflammatory myopathies: an important role for the membrane attack complex.

Degenerative muscle changes in dysferlinopathies are often accompanied by inflammatory infiltrates and may even mimic primary idiopathic inflammatory myopathies. In the present study, the inflammatory reaction pattern with respect to the cellular composition of the infiltrates and the expression of potent cytokines was characterized in dysferlinopathies and in idiopathic inflammatory myopathies. Cellular infiltrates in dysferlinopathies mainly consisted of CD4+CD25- T cells and macrophages. We noted a prominent expression of interferon-gamma which may contribute to the marked upregulation of MHC class I antigen observed on the vast majority of muscle fibres. Furthermore, membrane attack complex positive deposits were found on intact as well as necrotic muscle fibres. Collectively, our study indicates that the inflammatory reaction pattern in dysferlinopathies is distinct from the one in idiopathic inflammatory myopathies. In particular, membrane attack complex deposits and a pro-inflammatory milieu in the absence of interleukin-10 expression may contribute to progressive muscle damage in dysferlinopathies.

Blotting, Western↗

PubMed2006

Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease--a randomized placebo-controlled study.

The balance between different immunological stimuli is essential in the progression and stabilization of atherosclerotic plaques. Immune regulation has been suggested as potential target for the treatment of atherosclerotic disease. We sought to determine whether treatment with pentoxifylline, a phosphodiesterase inhibitor with immunomodulating properties, could reduce the pro-inflammatory response observed in patients with acute coronary syndromes (ACS) and increase anti-inflammatory activity. In a double-blind, prospective, placebo-controlled study, 64 patients with ACS were randomized to receive pentoxifylline 400mg TID or placebo for 6 months. Analysis of the pro-inflammatory markers, C-reactive protein (CRP), interleukin (IL)-6, IL-12, interferon-gamma and tumor necrosis factor (TNF)-alpha and the anti-inflammatory cytokines, transforming growth factor (TGF)-beta1 and IL-10 were done at baseline, 1 and 6 months. Pentoxifylline treatment significantly reduced the adjusted levels of CRP and TNF-alpha compared to placebo after 6 months (P=0.04 and P<0.01, respectively). IL-12 increase was significantly less pronounced with pentoxifylline (P=0.04). The levels of the anti-inflammatory cytokine, IL-10, also declined significantly less in the pentoxifylline group compared to placebo (P<0.01) with a trend towards a higher increase of TGF-beta1 in the former group (P=0.16). Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory response in patients with ACS and may have beneficial clinical effects on cardiovascular events.

Acute Coronary Syndrome↗

PubMed2004

Role of single nucleotide polymorphisms of pro-inflammatory cytokine genes in the relationship between serum lipids and inflammatory parameters, and the lipid-lowering effect of fish oil in healthy males.

BACKGROUND AND AIMS: Lipid metabolism, obesity and inflammation are intimately related. Plasma triglycerides increase during the inflammatory response to pathogens and obesity increases inflammatory stress. Pro-inflammatory cytokines are secreted by adipocytes in uninfected obese subjects. Polymorphisms (SNPs) in cytokine genes influence the intensity of cytokine production and inflammatory stress. Fish oil has lipid-lowering and anti-inflammatory properties. The influence of cytokine gene polymorphisms on the interaction between adiposity, inflammation and the properties of fish oil is unknown. METHODS: Fasting plasma triglycerides, acute phase proteins and BMI were studied in 159 healthy men and the effect of 6 g/d fish oil for 12 weeks on the former two parameters studied. Subjects were genotyped for SNPs at positions -511, -174, +252 and -308 in the IL-1beta, IL-6, LT-alpha (TNF-beta) and TNF-alpha genes, respectively. Data were divided into three sub-groups of BMI, 16.7-22.8, 22.9-24.9 and 25.1-33.7 kg/m2, respectively. RESULTS: Correlations were apparent between CRP and triglycerides in the highest tertile r = 0.324, P < 0.05 and between CRP and serum amyloid in all tertiles. Mean concentrations of all three molecules were higher in the middle and highest tertile than in the lowest. Irrespective of BMI, CRP and triglycerides were positively correlated in subjects with a TNF-alpha-308GG, LT-alpha AG, IL-1beta-511TT and IL-6-174GG genotype. The latter three genotypes are associated with enhanced inflammation. Genotype and BMI interacted. Concentrations of triglyceride rose significantly with increasing tertile only in subjects with a LT-alpha AA genotype. CRP concentrations rose in subjects with a LT-alpha AG genotype. Triglycerides were lowered by fish oil. Pre-supplementation concentrations were correlated with the decrease, r = -0.494 P < 0.0001. Genotype influenced the effects of fish oil. A fall occurred in triglycerides, across tertiles of BMI, only in individuals possessing a LT-alpha+252 AA genotype. Irrespective of BMI, possession of an A allele of this SNP was necessary for the correlation to occur. CONCLUSIONS: Possession of genotypes associated with raised inflammatory stress strengthen the association between fasting plasma triglycerides and CRP. The ability of fish oil to exert a lipid-lowering, anti-inflammatory influence in healthy men is influenced by BMI and possession of the LT-alpha+252 A allele.

Acute-Phase Proteins↗

PubMed1997

NF-kappa B as a target for anti-inflammatory gene therapy: suppression of inflammatory responses in monocytic and stromal cells by stable gene transfer of I kappa B alpha cDNA.

One of the most challenging issues of anti-inflammatory gene therapy is the complexity of inflammatory pathways. Transcription factor NF-kappa B plays a pivotal role in activation of multiple inflammatory molecules, and therefore represents the logical target for intervention. We evaluated the feasibility of suppressing the inflammatory responses in different cell lines through specific inhibition of NF-kappa B by gene transfer of I kappa B alpha, the naturally occurring intracellular inhibitor of NF-kappa B. The I kappa B alpha overexpressing cells were established using retroviral gene transfer or stable transfection with the wild-type (wt) I kappa B alpha cDNA. In all cell types, overexpression of wt I kappa B alpha resulted in a profound (> 100-fold) increase of the I kappa B alpha message and a moderate (two- to three-fold) increase of the I kappa B alpha protein. The effects of the I kappa B alpha overexpression on the NF-kappa B activation and the inflammatory responses varied significantly in different cell lines. In conditionally immortalized human endometrial stromal cells, overexpression of I kappa B alpha prevented both interleukin-1 (IL-1)-inducible degradation of endogenous I kappa B alpha protein and activation of NF-kappa B. Accordingly, induction of cytokines interleukin-8 (IL-8) and Gro gamma was markedly suppressed. In monocytic THP-1 cells, both lipopolysaccharide (LPS)-inducible degradation of I kappa B alpha and NF-kappa B activation were only partially inhibited by overexpression of exogenous I kappa B alpha cDNA. None the less, the LPS-induced transcription of IL-1 beta and secretion of cytokines interleukin-6 (IL-6) and IL-8 were virtually abolished. In epithelial HT-29 cells, no inflammatory responses were inhibited. These results demonstrate the range of responses in various cell lines to gene transfer of I kappa B alpha and indicate the feasibility of suppression of inflammatory responses in appropriate target cells and their progeny by suppression of NF-kappa B.

Cell Line↗

PubMedDate not supplied

Inflammatory responses to carrageenan injection in LEW/N and F344/N rats: LEW/N rats show sex- and age-dependent changes in inflammatory reactions.

We studied the inflammatory responses of LEW/N and F344/N inbred rat strains after peripheral injection of carrageenan. The inflammatory responses were assessed in terms of volume, relative and total white blood cell counts of the exudates. Moreover, in both strains, blood CD4, CD8, CD25, naive CD4 (CD4/CD45RC) cell and B (CD45R) cell counts and plasma corticosterone levels, constituents of systemic inflammatory responses to carrageenan were evaluated. In general, LEW/N rats are highly responsive to challenge with carrageenan, whereas F344 rats are not. The strong local inflammatory responses to carrageenan are primarily exhibited by female LEW/N rats. The intensity of local inflammatory responses of LEW/N rats changes with the rat age, the highest exhibited by LEW/N rats up to 3 months of age, thereafter the carrageenan-induced inflammatory responses decline. Our results indicate that peripheral injection of carrageenan induces strong systemic immune component. After carrageenan injection, increases in CD8 and naive CD4 blood lymphocytes are seen. Although the carrageenan challenge does not change CD4 blood lymphocytes in both LEW/N and F344/N rat strains, LEW/N rats exhibit higher levels of CD4 cells than F344/N rats. Additionally, LEW/N rats demonstrated lower levels of B cells and higher naive CD4 lymphocytes. Carrageenan challenges induce significant increases in plasma corticosterone response in F344/N rats, as well as increases in LEW/N rats 1 h after injection. Our data stress the importance of rat age and gender in experiments studying inflammatory responses.

Age Factors↗

PubMed2003

The phenotype of inflammatory macrophages is stimulus dependent: implications for the nature of the inflammatory response.

Many diseases are characterized by inflammatory reactions involving both the innate and adaptive arms of the immune system. Thioglycolate medium (TM) injection into the peritoneal cavity has long been used as a stimulus for eliciting inflammatory macrophages for study and for determining the importance of a particular mediator in inflammation. However, the response to this irritant may not be relevant to many inflammatory diseases. Therefore, we have developed an Ag-specific peritonitis model using methylated BSA (mBSA) as the stimulus. Priming mice intradermally with mBSA in adjuvant and boosting 14 days later, followed by an i.p. challenge with mBSA after an additional 7 days, led to an inflammatory reaction equivalent in magnitude to that induced with TM as judged by the number of exudate cells. The inflammatory macrophages elicited by the mBSA protocol differed, being smaller and less vacuolated than TM-elicited macrophages. Also, macrophages from 4-day mBSA-induced exudates expressed more MHC class II than TM-induced exudates, were able to stimulate allogeneic T lymphocytes, and upon in vitro stimulation with LPS secreted greater levels of IL-6 and IL-1beta. Macrophages from 4-day TM-induced exudates, on the other hand, expressed Ly6C and ER-MP58, immature myeloid markers. The inflammatory response elicited using the Ag mBSA may be more relevant for studying the inflammatory responses in many diseases, such as those of autoimmune origin and those involving an acquired immune response.

Animals↗

PubMed2005

Cancer cell immune escape and tumor progression by exploitation of anti-inflammatory and pro-inflammatory responses.

Apoptotic cells can be eliminated by phagocytosis, which is mediated by antigen-presenting cells (APCs), such as macrophages and dendritic cells (DCs), through phosphatidylserine (PS) on apoptotic cells and phosphatidylserine receptor (PSR) on APCs. The phagocytosis of apoptotic cells by macrophages is strictly regulated by not only the inflammatory reaction, but also by an increase in anti-inflammatory factors such as IL-10, TGF-beta, and prostaglandin E2 (PGE2), leading to an anti-inflammatory situation, whereby apoptosis contributes to a noninflammatory response. However, because PS and PSR are expressed in cancer cells, shed soluble phosphatidylserine (sPS) can interact with the PS receptor on macrophages, which promotes an anti-inflammatory response to macrophages that may lead to immune escape. The sPS derived from cancer cells also reacts with the PSR on the cancer cells to produce IL-10, TGF-beta, and PGE2, which can cause suppression of anti-tumor immunity through the anti-inflammatory response to macrophages, which produces tumor-associated macrophages. Furthermore, sPS and TGF-beta inhibit the maturation of immature DCs, resulting in a functional inhibition of DCs. The potential roles of PS and PSR in cancer cells and macrophages in immune escape mediated by sPS and anti-inflammatory factors are discussed, which may explain their dual regulation of anti- and pro-inflammatory responses during tumor progression.

Apoptosis↗

PubMed2000

Inflammatory myofibroblastic tumor (inflammatory fibrosarcoma) of the bone.

Although inflammatory myofibroblastic tumors, originally described in the lung, have recently been recognized to occur in various sites, their origin in bone is exceptional. We present a case of inflammatory myofibroblastic tumor, so-called inflammatory fibrosarcoma, of the bone. The tumor occurred in the iliac bone of a 70-year-old woman. Standard radiographs and magnetic resonance imaging revealed a destructive bone tumor that expanded into the soft tissue. Although the patient underwent excision of the hemi-iliac bone, multiple pulmonary metastases were noted 1 year after the operation. On histologic examination, the tumor was found to be composed of a sarcoma-like cellular area and a hypocellular fibrous area. Inflammatory cell infiltration into the tumor was a distinctive feature and is analogous with that of conventional inflammatory myofibroblastic tumor or inflammatory fibrosarcoma of the soft tissue. This is the first report to our knowledge of an inflammatory myofibroblastic tumor of the bone with distant metastasis.

Aged↗

PubMed2000

[Evaluation of time course and inter-relationship of inflammatory mediators in experimental inflammatory reaction].

Inflammatory signs, such as heat, redness, swelling and pain, have been described from the Greek era. In these phenomena various endogenous active substances, i.e., inflammatory mediators, could cause and manifest vascular dilatation, a vascular permeability increase and sensitization of pain receptors, etc. In order to evaluate the roles of inflammatory mediators, we have studied the time courses of inflammatory reaction along with detection of various active substances directly or indirectly in the experimental animal model of pleurisy, such as rat carrageenin-induced, and zymosan-induced pleurisy. These pleurisies showed almost similar time courses of pleural exudate accumulation and neutrophil migration. However, mediators detected in the exudates of such pleurisies were different; in carrageenin-induced pleurisy bradykinin and prostacyclin (PGI2) caused exudate formation, while zymosan-induced pleurisy showed early degradation of mast cells and activation of complements, followed by an increase in platelet activating factor (PAF). In both pleurisies TNF alpha, IL-1, IL-6 and CINC (cytokine-induced neutrophil chemoattractant) appeared similarly in the exudates to cause chemoattractant for neutrophils. TNF alpha and IL-1 could stimulate to produce IL-6 and IL-8. While prostaglandins may regulate cytokine production via a cellular cAMP-dependent mechanism. Thus one should consider the time for application of anti-inflammatory drugs, such as cyclooxygenase inhibitor, indomethacin, since it causes increases in TNF alpha and IL-1 production by reducing PGI2 and prostaglandin E2 (PGE2) levels. In conclusion, inflammatory reaction has its own automatic regulation mechanism through complex cross talks between inflammatory mediators.

Animals↗

PubMed1988

Pharmacological modulation of localized inflammatory reactions: the nonsteroidal anti-inflammatory drug as an adjunct to therapy.

An experimental model was utilized to examine the physiological effects of nonsteroidal anti-inflammatory compounds on locally induced inflammatory lesions in laboratory rabbits. The modulation of specific parameters associated with the inflammatory response, was monitored in vivo using radiolabeled cells and proteins, following the local administration of either indomethacin (INDO), acetylsalicylic acid (ASA) or sterile saline (as control) in the dermis. In one half of the dorsal aspect of each animal, Arthus-type dermal lesions were induced in triplicate, while similar sites were prepared at identical time periods (1-4, and 6 h) on the contralateral halves. In these latter sites, either INDO or ASA was administered (100 micrograms/site). The non-drug-treated lesions served as intrinsic controls when the inflammatory parameters of vascular permeability, neutrophil (polymorphonuclear) leukocyte infiltration and hemorrhage were investigated. Also, sterile saline or drug-injected, noninflamed sites prepared in each half served as further controls. Statistical analysis indicated a significant suppression of the above-named inflammatory parameters when either INDO or ASA was applied to localized inflammatory sites, as compared to non-drug-treated lesions. This study may serve to illustrate the value of deploying nonsteroidal anti-inflammatory preparations, topically, when conservatively managing the acute patient in clinical practice.

Animals↗

PubMed1985

Studies on fibronectin in inflammatory vs non-inflammatory polymorphonuclear leucocytes of patients with rheumatoid arthritis. I. Immunofluorescent and flow cytometric analysis.

Using indirect immunofluorescence and flow cytometry, we studied the reactivity of an antibody to human fibronectin with human polymorphonuclear leucocytes (PMNL). Our main objective was to compare the intensity of reaction of this antibody with inflammatory vs non-inflammatory PMNL. We used peripheral blood PMNL as a source of non-inflammatory cells and PMNL isolated from the synovial fluid of patients with rheumatoid arthritis as a source of inflammatory cells. Our findings revealed considerably brighter staining of the inflammatory PMNL. Using flow cytometry as a method of measurement, a difference in fluorescence intensity of at least 40 channels (log scale) was observed in all 12 patients studied when comparing peripheral blood with synovial fluid PMNL. In inflammatory PMNL, fibronectin was found both at the intracellular and membrane levels of the cell whereas fibronectin could be detected only intracellularly in non-inflammatory PMNL.

Antibodies, Anti-Idiotypic↗

PubMed1990

Does primary sclerosing cholangitis occurring in association with inflammatory bowel disease differ from that occurring in the absence of inflammatory bowel disease? A study of sixty-six subjects.

Primary sclerosing cholangitis often occurs in association with inflammatory bowel disease, particularly ulcerative colitis but also Crohn's disease of the colon either with or without terminal ileal disease. Little data exist as to the effect of inflammatory bowel disease on the presenting symptoms, radiological features, response to liver transplantation, and potential risk of bile duct carcinoma in individuals with primary sclerosing cholangitis. In an effort to answer these questions, 66 patients with primary sclerosing cholangitis were studied. The definitive diagnosis of primary sclerosing cholangitis in each was accomplished using cholangiography, which in each case demonstrated characteristic beading, ectasia and stricturing of the intrahepatic and extrahepatic bile ducts. Inflammatory bowel disease was present in 47 (71.2%) patients. Thirty nine (59.1%) had ulcerative colitis; their mean age was 42.5 +/- 11.6 yr (mean +/- SD), and the male/female ratio was 2.9:1. In addition, eight patients (12.1%) had Crohn's colitis; their mean age was 40.5 +/- 6.5 yr, and the male/female ratio of this group was 1:1. Nineteen patients (28.8%) had primary sclerosing cholangitis without any inflammatory bowel disease; their mean age was 42.0 +/- 12.1 yr, and the male/female ratio in this group was 0.72:1. Seventy-two percent of the patients without inflammatory bowel disease had either jaundice, pruritus or fatigue at presentation compared with 41% of the patients with inflammatory bowel disease (p less than 0.05). In contrast, abnormal liver function tests were more common as the first manifestation of liver disease in the latter group (38% vs. 11%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1996

Assessment of the antiexudative and antiproliferative activities of non-steroidal anti-inflammatory drugs in inflammatory models developed in rats by subcutaneous implantation of bacterial cell walls from the dental plaque.

A purified bacterial cell walls suspension from human dental plaque were biochemically prepared to serve as flogogenous agent in producing experimental inflammatory models in rats. In the vascular permeability inhibition assay (edemogenic test), the subcutaneous implantation of the flogogenous agent elicited an acute inflammatory reaction highly susceptible to the effects of the non-steroidal anti-inflammatory drugs (NSAIDs). The intradermal injection of the flogogenous agent in the dorsum of rats developed experimental granulomas also susceptible to the anti-inflammatory effects of the NSAIDs. Otherwise, the antimitotic effect of drugs was carried out in the model of cellular proliferation of duodenal mucosa of rats by incorporation of tritiated thymidine (3H TdR) in the DNA. These models of acute and chronic inflammation, and the antimitotic model permitted us to evaluate the anti-inflammatory and antimitotic effects of sulindac, ibuprofen, naproxen and glucametacin. In the antiexudative activity, evaluated by the edemogenic test, naproxen was the more effective drug followed by sulindac, ibuprofen and glucametacin (in a decreasing order of potency) to inhibit the exudative response induced by the bacterial cell walls suspension, in all experimental periods. In the chronic anti-inflammatory activity, evaluated by the granuloma inhibition assay, all drugs were capable to demonstrate effectiveness against the development of the experimental granulomas induced by an intradermal injection of the flogogenous agent. In the model of cellular proliferation, all tested drugs demonstrated antimitotic activity in all experimental periods (4, 6 and 8 days), also. Sulindac induced the higher antimitotic effect, in all experimental periods, followed by ibuprofen, naproxen and glucametacin in a decreasing order of efficacy. There was a positive correlation between the antiexudative, anti-proliferative, and antimitotic effects.

Animals↗