Pathogenesis Of Chronic Inflammation Research Articles

Use of Nurse Practitioners and Physician Extenders in Rheumatology: A Western North Carolina Perspective

### Objective Cyclooxygenase-2 (COX-2) expression is associated with the pathogenesis of chronic inflammation and pain in osteoarthritis (OA). A study was undertaken to determine whether interleukin-1β (IL-1β)-mediated induction of COX-2 can be regulated by microRNAs (miRNAs) in OA. ### Methods Human chondrocytes were stimulated with IL-1β in vitro. Total RNA was prepared using Trizol reagent. Gene expression was quantified using TaqMan Assays and miRNA targets were identified using bioinformatics. Transfection with reporter construct and premiRNA and antimiRNA was employed to verify suppression of target mRNA. Expression of COX-2 proteins was determined by immunoblotting. The role of activated p38-MAPKs was evaluated using specific inhibitor. ### Results The 3′UTR of COX-2 mRNA contained the 'seed-matched' sequences for miR-199a\* and miR-101_3. Increased expression of COX-2 correlated with the downregulation of miR-199a\* and miR-101_3 in IL-1β-stimulated normal and OA chondrocytes. miR-199a\* directly suppressed the luciferase activity of a COX-2 3′UTR reporter construct and inhibited the IL-1β-induced expression of COX-2 protein in OA chondrocytes. Modulation of miR-199a\* expression also caused significant inhibition of IL-1β-induced upregulation of mPGES1 and prostaglandin E~2~ production in OA chondrocytes. Activation of p38-MAPK downregulated the expression of miR-199a\* and induced COX-2 expression. Treatment with antimiR-101_3 increased COX-2 expression in IL-1β-stimulated chondrocytes, but overexpression of miR-101_3 had no significant effect on COX-2 protein expression. ### Conclusions miR-199a\* is a direct regulator of COX-2 expression in OA chondrocytes. IL-1β-induced activation of p38-MAPK correlates inversely with miR199a\* expression levels. miR-199a\* may be an important regulator of human cartilage homeostasis and a new target for OA therapy.

Helicobacter exploits integrin for type IV secretion and kinase activation

Integrins are important mammalian receptors involved in normal cellular functions as well as pathogenesis of chronic inflammation and cancer. We propose that integrins are exploited by the gastric pathogen and type-1 carcinogen Helicobacter pylori for injection of the bacterial oncoprotein cytotoxin-associated gene A (CagA) into gastric epithelial cells. Virulent H. pylori express a type-IV secretion pilus that injects CagA into the host cell; CagA then becomes tyrosine-phosphorylated by Src family kinases. However, the identity of the host cell receptor involved in this process has remained unknown. Here we show that the H. pylori CagL protein is a specialized adhesin that is targeted to the pilus surface, where it binds to and activates integrin alpha5beta1 receptor on gastric epithelial cells through an arginine-glycine-aspartate motif. This interaction triggers CagA delivery into target cells as well as activation of focal adhesion kinase and Src. Our findings provide insights into the role of integrins in H.-pylori-induced pathogenesis. CagL may be exploited as a new molecular tool for our further understanding of integrin signalling.

Regression of serum C‐reactive protein concentrations by dietary flavonoid intake in U.S. adults

C-reactive protein (CRP) is a chronic inflammation biomarker and identified recently as a risk factor for cardiovascular disease (CVD). Flavonoids have high antioxidant capacities which may be involved in the pathogenesis of chronic inflammation. However, the benefit of flavonoid intake for reducing inflammation process among a general, free-living population large-scale randomized trials has not been proved nor still contradictory. We hypothesized that dietary flavonoid intake are inversely associated with serum CRP concentrations after adjustment for sociodemographic, lifestyle factors in US adults. Data from the National Health and Nutrition Examination Survey (NHANES 1999–2002) were used for a cross-sectional study. Subjects were of 19+y men and women (n=8,335), after excluding pregnant and/or lactating women. Flavonoid intake was estimated by combining the USDA flavonoid batabases and 24-hr dietary recall data of the NHANES. CRP concentration was higher in women, older adults, Black, those with high BMI, alcohol consumers, cigarette smoker, those with low physical activity level (p < 0.01). Intakes of fruits and fruit juices, vegetables, breads and grain foods were significantly correlated with lower serum CRP concentrations, and also with specific flavonoid intakes (p < 0.05). The Intakes of total flavonoid, in addition to individual flavonols, flavones, anthocyanidins, isoflavones, significantly correlated with lower serum CRP concentration after adjusting for covariates (p < 0.05). Dietary flavonoid intakes have anti-inflammatory potential and thus reduce CVD risks.

Potent inhibition of the inductions of inducible nitric oxide synthase and cyclooxygenase-2 by taiwaniaflavone

The improper productions of nitric oxide and prostaglandins following the inductions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are involved in the pathogenesis of chronic inflammation. Selaginella tamariscina is used as an oriental medicine for its anti-inflammatory effects. Here, we isolated taiwaniaflavone from S. tamariscina and investigated whether taiwaniaflavone affects the induction of iNOS and COX-2 in RAW264.7 macrophages stimulated with lipopolysaccharide. We found that taiwaniaflavone blocks the transactivations of iNOS and COX-2 genes by blocking the nuclear translocation of p65 and subsequent nuclear factor-kappaB inactivation. It is known that NF-kappaB activation is controlled by the phosphorylation and subsequent degradation of I-kappaBalpha, and in the present study, we found that the phosphorylation and degradation of I-kappaBalpha were also inhibited by taiwaniaflavone. Our findings indicate that taiwaniaflavone may provide a developmental basis for an agent against inflammatory diseases.

Interleukin-10, Interleukin- 16 and Interferon-γ in serum of patients with rheumatoid arthritis and correlation with disease activity

Rheumatoid arthritis (RA) is a systemic inflammatory disease of unknown etiology. The rheumatoid synovium is characterized by infiltration of T cells, macrophage, B cells, and proliferating fibroblasts which aggressively invade cartilage and bone, thus destroying joints' ability to function. In rheumatoid arthritis (RA) both an imbalance between excessive production of the proinflamatory and ant-inflammatory cytokines and skewing of the T cell to a T helper like response. Cytokines have been shown to play a modulatory role in the pathogenesis of RA. The imunoregulatory cytokine IL-10 increases autoantibody production by B cell stimulates its survival, proliferation and differentiation. Moreover IL-10 inhibits the generation of proinflamatory cytokines and proliferation of T helper lymphocyte. Interleukin 16 might play a role in the pathogenesis of chronic inflammation in RA. It has a proinflammatory properties by promoting recruitment of T cells into the rheumatoid synovium. Also IFN-γ is of interest because of the role it plays in the initiation and perpetuation of T helper cell . Serum level of IL-10, IL-16, and IFN-γ were determined in patients with rheumatoid arthritis in relation to disease activity. All patients with RA (n=30) showed highly significant increase in ESR, CRP, IL-10, IL- 16, IFNγ compared to control group (p<0.01). Positive correlation were found between IL-10 and each IL-16 and IFN-γ (p<0.001) (r=0.63, 0.55) respectively, and highly significant correlation between IL-16 and IFNγ (p<0.001) (r=0.89)were determined. Results showed positive correlation between ESR and each IL-10, IL-16, IFNγ (p<0.001) (r=0.67, 0.87, 0.75) respectively. And highly significant correlation between CRP and each IL- 10, IL-16, IFNγ (p<0.001) (r=0.0.71, 0.83, 0.73) which indicate relation between increase level of cytokine with disease activity. These data suggest that there is increased production of IL-10, IL-16, and IFN-γ in patients with rheumatoid arthritis, and that it is correlated with the disease activity. These cytokines are interesting for further research inflammatory disease.

Altered Epithelial Cell Lineage Allocation and Global Expansion of the Crypt Epithelial Stem Cell Population Are Associated with Ileitis in SAMP1/YitFc Mice

Crohn's disease is characterized by cycles of mucosal injury and ulceration followed by epithelial regeneration and restoration of normal epithelial function. In this study, we examined whether ileitis in SAMP1/YitFc mice, a recombinant-inbred line that spontaneously develops ileitis resembling human Crohn's disease, was associated with alterations in normal patterns of epithelial differentiation or changes in epithelial regeneration after experimental injury. Increased numbers of Paneth, goblet, and intermediate cells were present focally in the ileum of SAMP1/YitFc mice by 4 weeks of age, before any histological evidence of acute or chronic inflammation. This increase in secretory cells became more pronounced at sites of ileitis with increasing age and inflammation. Additionally, there was mispositioning of Paneth and intermediate cells along the crypt-to-villus unit. A concomitant reduction in the number of absorptive enterocytes was observed. In contrast to the ileal-specific changes in lineage allocation, crypt stem cell numbers began to increase in both the ileum and proximal jejunum at the onset of inflammation in SAMP1/YitFc mice. These data suggest that the alterations in epithelial cell differentiation and increases in the size of the crypt stem cell population observed in SAMP1/YitFc mice are regulated by distinct mechanisms. We speculate that these epithelial alterations may play a role in the pathogenesis of ileitis in this murine model of Crohn's disease.

Effects of iron manipulation on trace elements level in a model of colitis in rats

Trace elements (TE) metabolism is altered in inflammatory bowel diseases. TE (zinc and copper) are constituents of antioxidant enzymes. Iron is involved in the pathogenesis of chronic inflammation. The aim was to evaluate zinc and copper status and the effects of iron manipulation in experimental colitis. Twenty-four male Sprague-Dawley rats were divided into four groups: standard diet, iron-deprived diet, iron-supplemented diet, and sham-treated controls. Macroscopic damage was scored. DNA adducts were measured in the colon. Liver and colonic concentration of TE were measured. Macroscopic damage was reduced in iron-deprived groups and increased in iron-supplemented rats. Damage to the DNA was reduced in iron-deprived groups and increased in iron-supplemented groups. Liver and colonic iron concentrations were reduced in iron-deprived and increased in iron-supplemented rats. Liver zinc concentration was reduced after supplementation whereas colonic levels were similar in controls and treated rats. Liver copper concentration was reduced in all the colitic groups except in the iron-supplemented group whereas colonic concentration was increased in iron-deprived rats. Iron deprivation diminishes the severity of DNBS colitis while supplementation worsens colitis. Zinc and copper status are modified by iron manipulation.

The Relationship between Inflammatory Markers, Leptin and Adiponectin in Chronic Hemodialysis Patients

Chronic inflammation is prevalent in dialysis patients. We investigated the relationship between inflammation and newly identified adipokines: leptin and adiponectin in this population. A total of 129 chronic hemodialysis patients were collected. Serum high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), leptin and adiponectin levels were determined as well as other metabolic variables. Correlation studies and multiple regression analysis were performed among variables. Our results showed that hemodialysis patients had elevated levels of inflammatory markers, leptin and adiponectin. Diabetic subjects had higher serum CRP and lower albumin levels than non-diabetics. Serum CRP levels were positively correlated with IL-6 levels and negatively correlated with albumin levels. Serum leptin levels were directly related to CRP levels while adiponectin levels were inversely related to CRP levels. A significant negative correlation was observed between serum leptin and adiponectin levels. Serum IL-6 levels were the single independent factor affecting CRP levels. Body mass index can predict both serum leptin and adiponectin levels. We conclude that hemodialysis patients are at an increased risk of chronic inflammation and diabetes patients are even more susceptible to this status. Both serum leptin and adiponectin levels are associated with inflammatory markers. As adipose tissue is the major secreting site of these adipokines, our results suggest that adipose tissue plays an important role in the pathogenesis of chronic inflammation in dialysis patients.

Oxysterols from human bile induce apoptosis of canine gallbladder epithelial cells in monolayer culture.

Oxysterols have been detected in various mammalian organs and blood. Biliary epithelium is exposed to high concentrations of cholesterol, and we have identified three keto-oxysterols (cholest-4-en-3-one, cholesta-4,6-dien-3-one, cholesta-3,5-dien-7-one) in human bile and gallstones. Because the effects of oxysterols on biliary physiology are not well defined, we investigated their biological effects on dog gallbladder epithelial cells. Enriched medium (culture medium containing taurocholate and lecithin and cholesterol +/- various oxysterols) was applied to confluent monolayers of dog gallbladder epithelial cells in culture. Cytotoxicity and apoptosis were studied by morphological analysis and flow cytometry. Oxysterols in the mitochondrial fraction were identified by gas chromatography/mass spectrometry, whereas release of cytochrome c from mitochondria was assayed by spectrophotometry and Western blot analysis. Compared with cells treated with culture medium or with enriched medium containing cholesterol, oxysterol-treated cells showed significantly increased apoptosis (P < 0.05). Exogenously applied oxysterols were recovered from the mitochondrial fraction. Cytochrome c release from mitochondria was increased significantly by cholest-4-en-3-one, cholesta-4,6-dien-3-one, and 5beta-cholestan-3-one (all P < 0.05). Thus oxysterols recovered from human bile and gallstones induce apoptosis of biliary epithelium via a mitochondrial-dependent pathway and may play a role in the pathogenesis of chronic inflammation and carcinogenesis in the gallbladder.

Inhibitory effects of interferon-gamma on the heterologous desensitization of beta-adrenoceptors by transforming growth factor-beta 1 in tracheal smooth muscle.

Transforming growth factor-beta1 (TGF-beta 1) is generally considered to play an important role in the pathogenesis of chronic inflammation and fibrosis. This study was designed to determine mechanisms of reduced responsiveness of guinea-pig tracheal smooth muscle to beta-adrenoceptor agonists by TGF-beta 1, using isometric tension records and tissue cAMP measurement. Moreover, we examined the involvement of the signal transduction processes of TGF-beta superfamily in the desensitization of beta-adrenoceptors. After exposure to 0.2-2000 pm TGF-beta 1 for 4-8 h, the inhibitory effects of 1 microm isoprenaline (ISO) and 10 microm forskolin on 1 microm MCh-induced contraction were markedly reduced in a concentration-dependent fashion. The desensitization by TGF-beta 1 was greater against ISO than for forskolin. The values of EC75 for the curves for ISO after exposure to the normal bathing solution and TGF-beta 1 were 0.039 +/- 0.02 and 0.38 +/- 0.28 microm, respectively. The values of EC50 for the curves for forskolin under these conditions were 0.50 +/- 0.12 and 0.89 +/- 0.21 microm, respectively. On the other hand, the inhibitory effects of phosphodiesterase inhibitors such as theophylline and rolipram were not attenuated after exposure to TGF-beta 1. Concentration-inhibition curve for ISO was shifted to the right after exposure to 2000 pm TGF-beta 1 for 8 h more than that curve for forskolin. In contrast, the curve for theophylline was not shifted to the right by TGF-beta 1. When the tissues were incubated with TGF-beta 1 in the presence of IFN-gamma, an intracellular antagonist of TGF-beta signalling, IFN-gamma inhibited the reduced response to ISO and forskolin after exposure to TGF-beta 1 in a concentration-dependent fashion. After exposure to TGF-beta 1, the effects of cAMP accumulation of ISO was significantly reduced, however, neither forskolin-nor theophylline-induced cAMP accumulation was affected. IFN-gamma had no significant effect on cAMP accumulation either to ISO or forskolin. Impairment of the beta-adrenoceptors/adenylyl cyclase pathway are involved in heterologous desensitization of beta-adrenoceptors induced by TGF-beta 1 in airway smooth muscle. IFN-gamma functionally suppresses this phenomenon via cAMP-independent processes. Phosphodiesterase is still intact under this condition.

Alterations in the cytoskeleton of enterocytes in Crohn's disease and ulcerative colitis

Introduction : Actin filaments are an important component of the cytoskeleton of enterocytes. Regulation of actin polymerization allows cells to control their shape, secrete and phagocytosis. The aim of this study was to analyse the distribution of actin in normal enterocytes (NE) and atypical enterocytes characterized by rapid antigen uptake into the cytosol (RACE) and ultrastructural alterations which have been previously described by our group in Crohn's disease (CD) and ulcerative colitis (UC). Methods: The labeling density (LD) of immunogold binding to antibodies against actin was determined in the terminal web and at the basolateral membrane by immunoelectron microscopy in NE and RACE of CD (n = 5), UC (n = 5) and healthy controls (HC: ileum (ll) n = 5 , colon (Co) n=5) . Statistics: Wilcoxon U-test; P < 0.05 was considered significant. Results: In RACE cells actin filaments seemed to be disassembled and labeling densitiy of actin was sigmficantly reduced relative to NE of CD and UC in the terminal web and at the basolatera[ membrane (P<0.05). Actin labeling of NE in CD and UC did not show any significant difference to HC with the exception of actin labeling at the basolateral membrane of CD, that was sigmficantly reduced relative to HC (P<0.04). Discussion: Alterations in the distribution of actin, that is an important factor for cell stability and transcellular transport processes could be responsible for the increased absorption of antigens in RACE. Due to this RACE may play a key role in the pathogenesis of chronic inflammation in CD and UC.

Carditis is associated with Helicobacter pylori-induced gastritis and not reflux esophagitis.

Pathogenesis of chronic inflammation at the gastric cardia is not yet clear. It is controversial whether cardiac-type mucosa is normal structure at the cardiac region. Therefore, we studied the existence of correlations between carditis, infection, and gastroesophageal reflux disease, and determined the prevalence of cardiac mucosa at the endoscopically defined cardiac region. Gastric biopsy specimens were analyzed from 27 patients with reflux esophagitis and 30 subjects without reflux esophagitis. Carditis was not associated with reflux esophagitis, but with infection. Moreover, the degree of gastritis and atrophy at the cardia were closely related to those of the antrum and body. Cardiac mucosa was not always present in the endoscopically defined cardiac region, and its prevalence was positively correlated with gastritis and atrophy grade of the cardia and age. In conclusion, -induced pangastritis may lead to the development of carditis, which is associated with occurrence of cardiac-type mucosa at the cardiac region.

Inflammation in the cardia.

The detection of chronic inflammation and intestinal metaplasia at the gastric side of a normal-appearing esophagogastric junction started active research on gastric cardia pathology. The main causes for this interest have been the increasing incidence of gastroesophageal reflux disease (GERD) and cardia adenocarcinoma. Many controversies still exist. It is even controversial whether noninflamed gastric cardia epithelium is a normal structure present at birth or an acquired lesion as a consequence of GERD. Similarly, the pathogenesis of chronic inflammation and intestinal metaplasia of gastric cardia are a matter of debate. Some researchers consider these lesions to be a consequence of Helicobacter pylori infection, whereas others think that chronic cardia inflammation and intestinal metaplasia are consequences of GERD. In this paper we review recent published studies in this field.

Selective Inhibition of Inducible Nitric Oxide Synthase Exacerbates Erosive Joint Disease

NO is an essential cytotoxic agent in host defense, yet can be autotoxic if overproduced, as evidenced in inflammatory lesions and tissue destruction in experimental arthritis models. Treatment of streptococcal cell wal1-induced arthritis in rats with N:(G)-monomethyl-L-arginine (L-NMMA), a competitive nonspecific inhibitor of both constitutive and inducible isoforms of NO synthase (NOS), prevents intraarticular accumulation of leukocytes, joint swelling, and bone erosion. Because increased inducible NOS (iNOS) expression and NO generation are associated with pathogenesis of chronic inflammation, we investigated whether a selective inhibitor of iNOS, N:-iminoethyl-L-lysine (L-NIL), would have more directed anti-arthritic properties. Whereas both L-NMMA and L-NIL inhibited nitrite production by streptococcal cell wall-stimulated rat mononuclear cells in vitro and systemic treatment of arthritic rats with L-NMMA ablated synovitis, surprisingly L-NIL did not mediate resolution of inflammatory joint lesions. On the contrary, daily administration of L-NIL failed to reduce the acute response and exacerbated the chronic inflammatory response, as reflected by profound tissue destruction and loss of bone and cartilage. Although the number of iNOS-positive cells within the synovium decreased after treatment with L-NIL, immunohistochemical analyses revealed a distinct pattern of endothelial and neuronal NOS expression in the arthritic synovium that was unaffected by the isoform-specific L-NIL treatment. These studies uncover a contribution of the constitutive isoforms of NOS to the evolution of acute and chronic inflammation pathology which may be important in the design of therapeutic agents.

Downregulation of TGF-beta1 mRNA and protein in the muscles of patients with inflammatory myopathies after treatment with high-dose intravenous immunoglobulin.

We used reverse transcription-polymerase chain reaction to study the level of TGF-beta1 mRNA expression and immunocytochemistry to examine the immunoreactive TGF-beta1 in muscle biopsy specimens from five patients with dermatomyositis (DM) and five patients with inclusion body myositis (IBM) obtained before and after 3 months treatment with intravenous immunoglobulin (IVIg). At baseline, the mRNA expression of TGF-beta1 was increased up to fivefold in the muscles of DM patients compared to that of IBM patients. After IVIg, TGF-beta1 was downregulated and the TGF-beta1 mRNA decreased twofold in the muscles of patients with DM who had successfully responded to therapy, but remained unchanged in the muscles of patients with IBM who did not respond. The downregulation of TGF-beta1 in DM was associated with improvement of the muscle cytoarchitecture and reduction of the endomysial inflammation and connective tissue, suggesting that in DM the excess of TGF-beta1 may be involved in the pathogenesis of chronic inflammation, fibrosis, and accumulation of extracellular matrix proteins.

Ｈａｌｌｅｒ’ｓ ｃｅｌｌと慢性副鼻腔炎 ＣＴによる検討

To study the role of Haller's cell in the pathogenesis of chronic sinusitis, CT findings examined prior to endoscopic sinus surgery of patients with chronic sinusitis were investigated. Of 51 cases, Hailer's cell was present in 19 unilaterally or bilaterally. No significant correlation was found between the presence of Hailer's cell and the severity of a pathological shadow in the maxillary, anterior ethmoid, or frontal sinuses. However, in 13 cases of unilateral Hailer's cell, the pathological findings were significantly more severe in maxillary sinuses with Hailer's cell than in the oposite side without Hailer's cell (p<0.01). These findings suggest that Hailer's cell might be one of the important factors associated with the pathology of ostiomeatal complex as well as the pathogenesis of chronic inflammation in maxillary sinuses.

Interleukin-1 receptor antagonist protein inhibits the synthesis of IgE and proinflammatory cytokines by allergen-stimulated mononuclear cells.

The ability of interleukin-1 (IL-1) to activate diverse cell populations supports its role as a preeminent cytokine in the pathogenesis of chronic inflammation. In this study, we investigated the role of Il-1 and IL-1 receptor antagonist protein (IRAP) in the regulation of allergen-induced synthesis of IgE and proinflammatory cytokines. The temporal expression of IL-1 beta and IRAP during 5-day allergen-activated peripheral mononuclear cell (PMNC) cultures suggested differential production of the two cytokines. To determine the influence of IRAP on IL-1-mediated cellular responses, we cultured PMNC from allergic donors with specific allergens in the presence or absence of IRAP pretreatment. Culture supernatants were assayed for IgE and cytokines using specific enzyme-linked immunosorbent assay. IRAP at concentrations 0.01, 0.1, and 1 microgram/ml decreased the allergen-stimulated IgE synthesis by 33 +/- 7%, 50 +/- 7%, and 66 +/- 5%, respectively (P < 0.05). Increasing the concentration of allergen did not affect the reduction in IgE synthesis observed in the presence of IRAP. Lipopolysaccharide-stimulated IgE synthesis was also significantly inhibited by IRAP (P < 0.05). In parallel experiments, anti-IL-1 beta monoclonal antibody showed a comparable inhibitory pattern on IgE synthesis (P < 0.05). IRAP inhibited the synthesis of interleukin-6, tumor necrosis factor-alpha, and granulocyte/macrophage colony-stimulating factor in a dose-dependent manner (P < 0.05); the mean inhibition was 31 +/- 4%, 75 +/- 5%, and 88 +/- 2%, respectively, at 1 microgram/ml of IRAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Eosinophils in chronically inflamed human upper airway tissues express transforming growth factor beta 1 gene (TGF beta 1).

Transforming growth factor beta (TGF beta) is a multifunctional protein which has been suggested to play a central role in the pathogenesis of chronic inflammation and fibrosis. Nasal polyposis is a condition affecting the upper airways characterized by the presence of chronic inflammation and varying degrees of fibrosis. To examine the potential role of TGF beta in the pathogenesis of this condition, we investigated gene expression and cytokine production in nasal polyp tissues as well as in the normal nasal mucosa. By Northern blot analysis using a porcine TGF beta 1 cDNA probe, we detected TGF beta 1-specific mRNA in nasal polyp tissues, as well as in the tissue from a patient with allergic rhinitis, but not in the normal nasal mucosa. By the combination of tissue section staining with chromotrope 2R with in situ hybridization using the same TGF beta 1 probe, we found that approximately 50% of the eosinophils infiltrating the polyp tissue express the TGF beta 1 gene. In addition, immunohistochemical localization of TGF beta 1 was detected associated with extracellular matrix as well as in cells in the stroma. These results suggest that in nasal polyposis where eosinophils are the most prevalent inflammatory cell, TGF beta 1 synthesized by these cells may contribute to the structural abnormalities such as stromal fibrosis and basement membrane thickening which characterize this disease.

The VLA-4/VCAM-1 pathway is involved in lymphocyte adhesion to endothelium in rheumatoid synovium.

Lymphocyte migration to inflammatory sites is an essential factor in the pathogenesis of chronic inflammation. An ensemble of adhesion receptors mediating lymphocyte-endothelial cell recognition and binding are thought to play a crucial role in this process. In the present study, we have explored the molecular basis of lymphocyte adhesion to endothelium in the synovial membrane of patients with rheumatoid arthritis. We established that the very late antigen-4 [VLA-4 (CD49d)] and the vascular cell adhesion molecule-1 (VCAM-1) are important mediators of binding to synovial endothelium of resting and, to a greater extent, of activated T lymphocytes, whereas the leukocyte-function associated antigen-1 [LFA-1 (CD11a/18)]/intercellular adhesion molecule-1 [ICAM-1 (CD54)] pathway is less important in this interaction. In contrast to its prominent role in lymphocyte interaction with endothelium in rheumatoid synovium, the VLA-4/VCAM-1 pathway does not significantly contribute to lymphocyte adhesion to peripheral lymph node high endothelial venule. Thus, the VLA-4/VCAM-1 pathway may be of primary importance in mediating lymphocyte adhesion to inflamed endothelium and in lymphocyte homing to rheumatoid synovium.

The kallikrein-kininogen-kinin system in chronic inflammation.

We examined bradykinin's effects on macrophages and fibroblasts, two cell types important in the pathogenesis of chronic inflammation. Bradykinin stimulated release of proteins of 18 kDa from macrophages. These proteins caused increased thymocyte proliferation (interleukin 1, IL-1) and completely inhibited lipoprotein lipase (tumor necrosis factor, TNF). When fibroblasts were incubated with bradykinin, PGE2 synthesis was stimulated. Pretreatment with IL-1 or TNF dramatically amplified bradykinin-stimulated PGE2 synthesis. Thus, bradykinin is involved in a positive feedback loop in which bradykinin activates macrophages to release potent inflammatory cytokines; these in turn amplify responsiveness of bradykinin target tissues.