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ID PMID Title PublicationDate abstract
24497819 Effects of high-impact mechanical loading on synovial cell cultures. 2004 Mar Cartilage metabolism in response to mechanical loading is an important subject in sports science and medicine. In animal studies high-impact exercise is known to stimulate bone adaptation and increase bone mass. However, mechanical impacts potentially induce tissue swelling and occasionally degradation of connective tissues in synovium and articular cartilage. These detrimental outcomes should be properly evaluated clinically and biochemically. Using two synovial cell cultures derived from normal and rheumatic tissues, we examined the biochemical effects of impulsive mechanical loads on expression and activities of influential proteolytic enzymes in joints, matrix metalloproteinases (MMPs), and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs). The molecular analysis demonstrates that an impact factor (Im ), the ratio of the maximum force to weight, served as a good indicator for assessment of the inflammatory responses. The results showed that high impact above Im = 40 to 80 elevated not only expression but also enzymatic activities of MMPs. Key PointsHigh-impact loading elevated expression and activities of MMPs in synovial cell cultures.The impact factor was used to define in vitro intensity of high-impact loading.
15180473 Immune deviation strategies in the therapy of psoriasis. 2004 Jun The experience with biologicals in currently available animal models suggest that inflammatory autoimmune disease depend on IFN-gamma-producing T helper (Th) cells. Deletion of T cells improves most of these autoimmune diseases but bears the risks of general immunosuppression. Alternatively, selective deviation of the inflammatory, disease-inducing Th cells into an anti-inflammatory Th cell phenotype may be a promising strategy to treat inflammatory autoimmune diseases, such as psoriasis, rheumatoid arthritis, multiple sclerosis or autoimmune diabetes. The common feature of these organ-specific autoimmune diseases is the close association with IFN-gamma-producing Th1 cells, which recognize organ-specific antigens and orchestrate the cells and mediators that ultimately cause the tissue damage. Even though the autoantigens recognized in psoriasis remain enigmatic, it has been the first Th1-mediated autoimmune disease successfully treated in humans by immune deviation. The basis of such an immune intervention therapy has been established in experimental mice with model diseases of multiple sclerosis, rheumatoid arthritis or autoimmune diabetes. In all these autoimmune diseases clinical improvement was associated with the skewing of IFN-gamma producing autoantigen-specific Th1 cells into an IL-4 dominated Th2 phenotype. Such Th2 cells are still reactive to the autoantigen but provide a different cytokine pattern. The most powerful cytokines capable of inducing anti-inflammatory Th2 cells are IL-4 itself or IL-11. Interestingly, another agent that has been used for decades in the therapy of psoriasis in some European countries, fumaric acid esters (FAE), seems also to induce immune deviation. This review focuses on the potential immune deviating strategies based on the use of IL-4, IL-11 or FAE in the therapy of psoriasis, the effects of these agents on the immune system, potential risks and future perspectives for therapeutic intervention by immune deviation replacing immunosuppression.
12553721 Transcription factor Egr-1 activates collagen expression in immortalized fibroblasts or fi 2002 Dec Synovial fibroblasts from rheumatoid arthritis patients express elevated levels of the transcription factor Egr-1. The metabolic consequences of Egr-1 overexpression in fibroblasts are not known in detail. Therefore we searched for gene products that are differentially expressed in Egr-1(high) versus Egr-1(low) fibroblasts. Immortalized synovial fibroblasts were transfected with two different Egr-1 expression vectors. Expression of recombinant Egr-1 was confirmed by RT-PCR and immunoblots. Random arbitrarily primed PCR revealed that Egr-1 induces enhanced transcription levels of the alpha1 chain of type I collagen. Increased expression of the alpha2 (I) chain could also be observed. We found enhanced levels of type I collagen propeptide in supernatants and stronger signals of alpha2 (I) protein in extracts of the Egr-1(high) expressing clone versus controls. Additionally, Egr-1 was transiently expressed in fibrosarcoma cells. These cells showed a pronounced elevation of type I collagen (alpha1) transcripts as well. Moreover, we could demonstrate that Egr-1 induces transcription of other genes including type II collagen (alpha1) and plateled-derived growth factor beta1. These data suggest that upregulation of Egr-1 might contribute tofibrosis observed in rheumatoid arthritis synovium by activation of genes encoding the alpha1 and alpha2 chains of type I collagen.
12402412 Anti-inflammatory and immunomodulating properties of statins. An additional tool for the t 2002 Dec Cardiovascular diseases secondary to accelerated atherosclerosis are now accepted as a cause of mortality and morbidity in patients suffering from systemic lupus erythematosus and rheumatoid arthritis. More recently, atherosclerosis is emerging as one of the most serious complications in the anti-phospholipid syndrome, although large epidemiological studies, such as those performed in lupus and rheumatoid arthritis patients, have not been performed up to now. Classical risk factors (dislipidemia, hypertension, diabetes, smoking, etc.) and steroid therapy cannot completely explain the high prevalence of cardiovascular complications in systemic autoimmune diseases. Since the modern view defines atherosclerosis as a chronic inflammatory disorder, it has been suggested that systemic inflammation and soluble immune mediators (circulating autoantibodies, immune-complexes, complement activation products) might play a role in accelerating vessel pathology. The main target appears to be the endothelium because of its ability to switch to a pro-adhesive, pro-inflammatory and pro-coagulant surface in response to these mediators. Recent advances in the knowledge of the pharmacology of statins have indicated that these drugs rather than to be simple cholesterol lowering molecules display a pleiotropic effects on several mechanisms involved in the atherosclerotic plaque formation. Their anti-inflammatory activity and particularly their ability to downregulate endothelial cell activation induced by different stimuli strongly suggest their possible use in conditions in which the systemic inflammation and the endothelial activation/damage are thought to represent key pathogenic mechanisms.
15290727 Immune reactivity to connective tissue antigens in pristane induced arthritis. 2004 Aug OBJECTIVE: Pristane induced arthritis (PIA) is a seropositive experimental murine model that closely resembles rheumatoid arthritis (RA). Immune reactivity to a broad spectrum of autoantigens has been recognized in this disease model. We investigated the specificity of the autoimmune response in PIA to determine whether reactivity to connective tissue antigens is associated with the development of arthritis. METHODS: DBA/1 mice were injected with pristane and evaluated for development of joint disease and autoimmunity. Lymph nodes, spleen, sera, and arthritic paws were investigated at 1, 2, 4, 6, 9, and 12 months postinjection. T cell responses to 16 different joint components were evaluated using proliferation assays, and sera were assayed by ELISA for antibodies to these joint antigens. Cytokine concentrations after antigenic stimulation were assessed by ELISA in cultured cell supernatants and by real-time polymerase chain reaction using mRNA from spleens and arthritic paws. RESULTS: ELISA revealed positive responses to glucose-6-phosphate isomerase, chondroitin sulfate B, collagen I, collagen II, aggrecan, and DNA between 4 and 12 months post-pristane injection. In vitro tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin 6 (IL-6) responses were detected during reactions to most antigens tested, while IL-4 responses were absent. Cytokine analysis in arthritic joints revealed consistent expression of IL-1, IL-4, IL-6, TNF-alpha, and IFN-gamma mRNA. CONCLUSION: These results indicate that PIA animals develop both T cell and antibody responses to a broad spectrum of connective tissue antigens. Biglycan, aggrecan, and decorin may be relevant antigens in the pathogenesis of PIA, but no specific reaction pattern could be associated with the occurrence of disease. The data suggest that the development of pristane arthritis is not dependent upon reactivity against a single connective tissue antigen, but is a polyspecific autoimmune response to joint components elicited in pristane injected mice.
12831346 Novel approaches in the treatment of ankylosing spondylitis and other spondyloarthritides. 2003 Jul The therapeutic options for patients suffering from severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is now accumulating evidence that anti-TNF therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published on what is now several hundred AS and PsA patients, this treatment seems to be even more effective than the same therapy in rheumatoid arthritis (RA). The anti-TNF-alpha agents currently available, infliximab (Remicade); Centocor), etanercept (Enbrel); Amgen) and adalimumab (Humira; Abbott), are approved for the treatment of RA in the US; infliximab and etanercept are approved in Europe. The situation in SpA is different to RA because there is an unmet medical need, especially in AS, since no therapies with disease-controlling antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, TNF blockers might even be considered as first-line immunosuppressive agents in patients with active AS and PsA who are not sufficiently treated by non-steroidal anti-inflammatory drugs and sulfasalazine, if peripheral arthritis is present. For infliximab, a dosage of 5 mg/kg at intervals between 6 and 12 weeks was necessary to constantly suppress disease activity; this is also a major aim of long-term treatment. No dose-finding studies have yet been performed. The standard dose of etanercept is 25 mg s.c. twice-weekly. No studies on adalimumab (standard RA dose 20 - 40 mg s.c. every 2 weeks) have yet been conducted in SpA. The efficacy of etanercept was first demonstrated in PsA and etanercept is now approved for this indication. A double-blind study has also been performed in AS, with similarly clearcut efficacy. There is preliminary evidence that both agents do also work in other SpA such as undifferentiated SpA. Infliximab has recently been approved for short-term treatment of severe uncontrolled AS; the approval for etanercept is pending. Studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis might be preventable but it remains to be shown whether patients benefit from long-term anti-TNF therapy and whether radiological progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. Tuberculosis can be mostly prevented if patients are checked for previous contact with tuberculosis. Currently, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.
15476255 Antigen-specific immunomodulation of collagen-induced arthritis with tumor necrosis factor 2004 Oct OBJECTIVE: Dendritic cells (DCs) are crucial for the initiation of T cell immunity and therefore play an important role in the initiation and regulation of immune responses in arthritis. Full mobilization of effector T cells depends on the proper maturation of DCs. Current evidence indicates that the type of T cell response induced is crucially dependent on the activation status of the DCs. In this study, we explored the immunologic effects of differentially matured DCs on the development of collagen-induced arthritis (CIA). METHODS: Bone marrow-derived DCs were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Before immunization with bovine type II collagen (CII) protein, mice were repeatedly injected with DCs that had been pulsed with CII. Immature, semimature, or fully mature DCs were injected. Mice were boosted on day 21 after CII immunization, and the disease course was monitored. RESULTS: While vaccination with immature or lipopolysaccharide-activated DCs had no significant effect on the disease course, administration of antigen-loaded, tumor necrosis factor (TNF)-modulated DCs propagated in GM-CSF with or without interleukin-4 resulted in a delayed onset of arthritis and a lower clinical score. The response was antigen-specific, since TNF-treated DCs pulsed with a control antigen did not modify the disease course. A specific decrease in the collagen-specific "Th1-associated" IgG2a response was observed, whereas IgG1 titers were unaffected. CONCLUSION: CIA can be prevented through vaccination with TNF-matured DCs in an antigen-specific manner. These findings provide a rationale for immunotherapy using DCs in rheumatoid arthritis.
12692188 TSG-6: a multifunctional protein associated with inflammation. 2003 May 15 TSG-6 expression is upregulated in many cell types in response to a variety of proinflammatory mediators and growth factors. This protein is detected in several inflammatory disease states (e.g. rheumatoid arthritis) and in the context of inflammation-like processes, such as ovulation, and is often associated with extracellular matrix remodelling. TSG-6 has anti-inflammatory and chondroprotective effects in various models of inflammation and arthritis, which suggest that it is a component of a negative feedback loop capable of downregulating the inflammatory response. Growing evidence also indicates that TSG-6 acts as a crucial factor in ovulation by influencing the expansion of the hyaluronan-rich cumulus extracellular matrix in the preovulatory follicle. TSG-6 is a member of the Link module superfamily and binds to hyaluronan (a vital component of extracellular matrix), as well as other glycosaminoglycans, via its Link module. In addition, TSG-6 forms both covalent and non-covalent complexes with inter-alpha-inhibitor (a serine protease inhibitor present at high levels in serum) and potentiates its anti-plasmin activity.
15116595 Glenoid resurfacing in shoulder arthroplasty: indications and contraindications. 2004 The indications for glenoid resurfacing are controversial. Advantages of glenoid resurfacing include decreased glenoid pain from metal-on-bone articulation, increased stability provided by the conforming glenoid component in the presence of asymmetric glenoid wear, and lateralization of the joint line providing for improved range of motion and strength. Proponents of hemiarthroplasty claim that function and pain relief are equivalent to glenoid resurfacing without the concomitant risk of glenoid loosening and loss of glenoid bone stock. In addition, hemiarthroplasty requires less surgical time and is less expensive than total shoulder arthroplasty. Total shoulder arthroplasty has been shown to be superior to hemiarthroplasty with regard to pain relief, range of motion, and function. Resurfacing of the glenoid has been indicated in older patients with primary osteoarthritis. In addition, patients with rheumatoid arthritis generally have better improvement in pain and function when treated with total shoulder arthroplasty than with hemiarthroplasty. Patients with severe rotator cuff disease, persistent instability, and lack of glenoid bone stock should be treated with hemiarthroplasty alone because glenoid resurfacing is associated with early loosening and failure. Patients with osteonecrosis isolated to the humeral head should be treated with hemiarthroplasty to preserve the native, congruent glenoid.
14661569 [Airway obstruction in a patient using a cuff button-like silicone cannula for tracheal st 2003 Nov We described a case of postoperative airway obstruction in a patient using a cuff button-like silicone cannula for tracheal stoma. A 59-year-old woman with rheumatoid arthritis, was admitted to the hospital for total knee arthroplasty. She had been managed by a long-term tracheostomy for rheumatic cricoarytenoid arthritis. Preoperative examination revealed no cardiopulmonary compromise. The surgery was performed under combined spinal-epidural anesthesia without any respiratory problems. Fifteen hours after surgery, she complained of dyspnea. Her oxygen saturation by pulse oximeter was 22-28%. We immediately removed the silicone cannula and inserted a tracheostomy tube. Her condition was dramatically improved next few minutes after the insertion. There were no dyskinesia and neurological disorders. We considered that airway obstruction occurred with the inadequate position of the cuff button-like silicone cannula, attached to the posterior wall of the trachea, sputum augmenting the obstruction.
24383896 Exploring the signalling pathways promoting T cell effector responses in chronic inflammat 2002 Jun Abstract  Over the last decade, it has become clear that T helper cell differentiation is determined by a programme of gene transcription, which is in turn dictated by signalling pathways emanating from both T cell antigen receptors and cytokine receptors. This model has provided an experimental framework for exploring the molecular mechanisms through which T cell effector responses initiate autoimmunity, chronic inflammatory disease, and allergy. Much less clear are the processes that regulate T helper cell differentiation and effector responses in established chronic inflammatory diseases such as rheumatoid arthritis. This review describes recent experimental data which suggest that the inflammatory process profoundly influences T cell receptor and cytokine signal transduction pathways in such a way as to attenuate both immunoregulatory and host defence mechanisms on the one hand, while promoting cell survival and effector responses on the other. These findings are consistent with a model in which the inflammatory response is initiated primarily by antigen-driven T cell effector responses, while the chronic phase of the disease process is sustained by cytokine-driven effector responses.
11890208 Clinical significance of cytokine determination in synovial fluid. 2002 Feb Cytokines are a complex family of small regulatory proteins able to mediate intercellular communication and play a crucial role in immunologic and inflammatory reactions. Many reports have demonstrated that some cytokines, in particular tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-1beta, IL-6, and IL-8, so-called proinflammatory, may have a major role in the pathogenesis of joint diseases. Thus, high levels of these substances have been found in inflammatory arthropathies, in particular in those characterized by a more aggressive and destructive outcome, such as rheumatoid arthritis, gout, and infectious arthritis. In keeping with their role, the determination of cytokines in synovial fluid may be proposed for clinical purposes, including diagnostic and prognostic assessments. Furthermore, as some of these cytokines may reflect disease activity, their determination may also be useful in the evaluation of therapy.
17041387 Molecular biology and immunology for clinicians 20: Angiogenesis and vascular growth facto 2002 Oct If we accept the perfectly reasonable premise that the mass of inflammatory tissue in rheumatoid arthritis (and psoriatic arthritis or any other inflammatory joint disease) requires oxygen and nutrition to survive and grow, we are confronted with a novel concept for therapy: if we can block the nutritional supply of the pannus, we can suppress or prevent its growth and the subsequent destruction of the joint. Thus, an understanding of how new blood vessels nourish the inflammatory mass could be pivotal in successfully treating our patients. Angiogenesis is the process whereby new blood vessels enter the site of inflammation or growing malignancy to supply the invading tissue. Many growth factors and local tissue conditions help to determine blood vessel growth, there being pro- and anti-angiogenetic influences. Thus, this is fertile ground for therapeutic molecular manipulations.
12097413 Prevention and induction of autoimmune exocrinopathy is dependent on pathogenic autoantige 2002 Jul 15 The in vivo role of autoantigen cleavage during apoptosis in autoimmune diseases remains unclear. Previously, we found a cleavage product of 120-kDa alpha-fodrin as an important autoantigen in the pathogenesis of primary Sjögren's syndrome (SS). In the murine primary SS model, tissue-infiltrating CD4(+) T cells purified from the salivary glands bear a large proportion of Fas ligand, and the salivary gland duct cells constitutively possess Fas. Infiltrating CD4(+) T cells, but not CD8(+) T cells, identified significant (51)Cr release against mouse salivary gland cells. In vitro studies demonstrated that apoptotic mouse salivary gland cells result in a specific alpha-fodrin cleavage into 120 kDa and that preincubation with caspase inhibitor peptides blocked alpha-fodrin cleavage. In vivo treatment with caspase inhibitors N-benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone and N-acetyl-Asp-Glu-Val-Asp-al-CHO into the murine model results in dramatic inhibitory effects on the development of autoimmune lesions and in restoration of sicca syndrome. Furthermore, we found that immunization with recombinant alpha-fodrin protein identical with an autoantigen into normal recipients induced autoimmune lesions similar to SS. These data indicate that prevention and induction of autoimmune exocrinopathy is dependent on autoantigen cleavage via caspase cascade and that caspase inhibitors might provide a new therapeutic option directed at reducing tissue damage in the murine model for SS.
11781351 Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's 2002 Jan BAFF (BLyS, TALL-1, THANK, zTNF4) is a member of the TNF superfamily that specifically regulates B lymphocyte proliferation and survival. Mice transgenic (Tg) for BAFF develop an autoimmune condition similar to systemic lupus erythematosus. We now demonstrate that BAFF Tg mice, as they age, develop a secondary pathology reminiscent of Sjögren's syndrome (SS), which is manifested by severe sialadenitis, decreased saliva production, and destruction of submaxillary glands. In humans, SS also correlates with elevated levels of circulating BAFF, as well as a dramatic upregulation of BAFF expression in inflamed salivary glands. A likely explanation for disease in BAFF Tg mice is excessive survival signals to autoreactive B cells, possibly as they pass through a critical tolerance checkpoint while maturing in the spleen. The marginal zone (MZ) B cell compartment, one of the enlarged B cell subsets in the spleen of BAFF Tg mice, is a potential reservoir of autoreactive B cells. Interestingly, B cells with an MZ-like phenotype infiltrate the salivary glands of BAFF Tg mice, suggesting that cells of this compartment potentially participate in tissue damage in SS and possibly other autoimmune diseases. We conclude that altered B cell differentiation and tolerance induced by excess BAFF may be central to SS pathogenesis.
14730629 Suppression of collagen-induced arthritis by natural killer T cell activation with OCH, a 2004 Jan OBJECTIVE: OCH, a synthetic analog of alpha-galactosylceramide with a truncated sphingosine chain, stimulates natural killer T (NKT) cells to produce predominantly Th2 cytokines. Thus, OCH may be a potential agent for the treatment of Th1-mediated autoimmune diseases. This study was designed to evaluate the protective effects of OCH on collagen-induced arthritis (CIA) in mice. METHODS: Mice were immunized with type II collagen (CII) and injected intraperitoneally twice per week with OCH, before or after the onset of CIA. They were monitored to assess the effect of OCH treatment on the severity of disease. Anti-CII antibodies and cytokine production were measured by enzyme-linked immunosorbent assay. Expression of cytokine genes was determined by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: OCH inhibited CIA in wild-type C57BL/6 (B6) mice but not in NKT-deficient mice. OCH suppressed CIA in SJL mice, which are prone to autoimmune diseases and have a deficiency in the number and function of NKT cells which is similar to that in patients with autoimmune diseases, even after disease has already developed. Disease protection conferred by OCH correlated with its ability to selectively induce Th2 cytokine production mediated by NKT cells and to promote collagen-specific Th2 responses. Neutralization of interleukin-4 (IL-4) or IL-10 with monoclonal antibodies abolished disease protection by OCH, indicating a critical role for these cytokines. CONCLUSION: Taken together, our findings suggest that OCH holds possibilities as a therapeutic agent for autoimmune diseases such as rheumatoid arthritis.
15257256 Arthropathies and thyroid diseases. 2004 Jun AIM: Improvement of articular symptoms following thyroidectomy has often been observed in patients with an association of thyroid and joint diseases. An assessment has therefore been made of the types of arthropathy thus benefited and the anatomopathological features of the thyroid in patients with concomitant joint diseases. An account is given of the arthropathies associated with nontoxic nodular goitre (NTG). METHODS: Three cell markers are examined to identify immunocytokine elements differentiating thyroid diseases. RESULTS: Immunohistochemical examination shows extravasal lymphocyte infiltrates; thyrocytes were negative for HLA-Cl II, CD38 and IL-6R, and only dim-positive for HLA-Cl I. Endothelial cells were positive for HLA-Cl I and II and CD38, and negative for IL-6R. The lymphocyte were positive for HLA-Cl I, HLA-Cl II and CD38, but negative for IL-6R. The follow-up of 6 thyroidectomised patients disclosed improvement in joint pain and remission of rheumatoid arthritis and spondylarthritis. Association of nodular goitre with arthro-pathies is demonstrated. CONCLUSION: Arthritis and arthralgia are frequent in patients with thyroid diseases, we particularly found the association with MHNG and Hurthle cell adenoma. Arthritis and arthralgia quickly improve after thyroidectomy. Immunohistochemical NTG thyrocytes are still normal cells (HLA-Cl II negative) by contrast with their HLA-Cl II positivity in autoimmune thyroiditis.
12415579 Increased expression of arginase II in patients with different forms of arthritis. Implica 2002 Nov OBJECTIVE: To investigate the expression of arginase isoforms in patients with different forms of arthritis and the possible implications of the synthesis of nitric oxide (NO). METHODS: Arginase activity was measured in synovial fluid (SF) cells from patients with different forms of arthritis, either directly or after in vitro stimulation with cytokines. The identity of the isoform expressed was confirmed by reverse transcription polymerase chain reaction. We measured both arginase activity and NO production in SF macrophages and synovial membrane fibroblasts from patients with rheumatoid arthritis (RA). RESULTS: Arginase II was the isoform expressed in SF cells. In SF macrophages, dibutyryl-cAMP (dBt-cAMP), prostaglandin E2 (PGE2), and lipopolysaccharide (LPS) further increased the enzyme activity, while NO production was not detected even in the presence of Th1-like cytokines. In contrast, synovial membrane fibroblasts from patients with RA released NO into the culture media. Moreover, dBt-cAMP, PGE2, and transforming growth factor-beta, which induced arginase II, reduced the levels of NO. Reciprocally, the induction of NO by Th1 cytokines inhibited arginase activity levels. CONCLUSION: Arginase II expression is upregulated in RA and may increase cell proliferation by providing L-ornithine, which is the substrate of polyamine biosynthesis. In cells where both arginase II and inducible NO synthase activity occurs, there is a reciprocal regulation, suggesting that agents that induce arginase II in synovial cells could downregulate the levels of NO and divert L-arginine metabolism toward cell proliferation and/or tissue regeneration.
15553217 The arthrotropism of macromolecules in adjuvant-induced arthritis rat model: a preliminary 2004 Oct PURPOSE: To study the accumulation of macromolecules into the arthritic joints and the possible applications of such phenomenon. METHODS: The accumulation of plasma albumin in the joints of adjuvant-induced arthritis (AIA) rat model was first visualized with Evans blue injection. A N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer contrast agent was then synthesized and injected into the AIA rats to allow qualitative examination of biodistribution and pharmacokinetics of the injected macromolecule with magnetic resonance imaging (MRI). Vital organs and the diseased joints were isolated and examined histologically to correlate with the MRI findings. RESULTS: Deep blue color developed around the arthritic joints of the AIA rat a few hours after the injection of Evans blue. MR imaging of the AIA rats injected with polymer contrast agent demonstrated a gradual but very strong accumulation of the injected polymer in the arthritic joints, which lasted for 1-2 days. Observed differences in the concentration of the injected polymer in the joints correlated with disease severity as assessed histologically. CONCLUSIONS: Profound arthrotropism of macromolecules in the AIA rat model was demonstrated with various imaging tools. These observations should help in the conceptual and practical design of novel macromolecular delivery systems for the imaging and treatment of rheumatoid arthritis.
12846443 Generation of innovative anti-inflammatory and anti-arthritic glucocorticoid derivatives t 2003 May Addition to the prednisolone structure of a chemical moiety (linker+nitric ester) that releases NO species yielded a novel glucocorticoid (nitro-prednisolone or NCX-1015) with enhanced anti-inflammatory activities. Nitro-prednisolone was much more potent than prednisolone and the derivative devoid of the nitric ester in an acute peritonitis model (higher impact on neutrophil migration and soluble mediator generation) as well as in models of chronic inflammation (air-pouch granuloma and collagen II-induced arthritis). In the collagen II-induced arthritis model, NCX-1015 abrogated the plasma levels of a catabolite of cartilage and bone metabolism, indication of a disease modifying action. In an in vitro assay of bone resorption, NCX-1015 did not activate osteoclast activity, whereas prednisolone did. This lack of effect of NCX-1015 was chiefly due to NO. We propose that NCX-1015 is the prototype of a new class of glucocorticoids, the nitro-steroids, endowed with enhanced anti-inflammatory properties and reduced side effects. These and other experimental observations here reviewed may prompt the assessment of the clinical impact of the nitro-steroids on rheumatoid arthritis and inflammatory bowel disease.