We have examined the expression and function of the angiogenic factor, vascular endothelial growth factor (VEGF) during the evolution of type II collagen-induced arthritis (CIA). Biologically active VEGF was expressed along a time course that paralleled the expression of two specific VEGF receptors, Flk-1 and Flt-1, and the progression of joint disease. Moreover, levels of VEGF expression correlated with the degree of neovascularization, as defined by vWF levels, and arthritis severity. Macrophage- and fibroblast-like cells, which infiltrated inflamed sites and were then activated by other inflammatory mediators, are probably important sources of VEGF and may thus regulate angiogenesis during the development of CIA. Administration of anti-VEGF antiserum to CIA mice before the onset of arthritis delayed the onset, reduced the severity, and diminished the vWF content of arthritic joints. By contrast, administration of anti-VEGF antiserum after the onset of the disease had no effect on the progression or ultimate severity of the arthritis. These data suggest that VEGF plays a crucial role during an early stage of arthritis development, affecting both neovascularization and the progression of experimentally induced synovitis.
To test the scavenging of reactive oxygen species (ROS), we added synovial fluids from patients with rheumatoid arthritis (RA) and osteoarthritis, as well as hyaluronic acid (HA) and its 2 subcomponents, Dglucuronic acid and N-acetyl-D-glucosamine, to 2 ROSgenerating systems, activated neutrophils and xanthine xanthine oxidase. Synovial fluid from RA patients, HA, and D-glucuronic acid markedly decreased the 0 2 -, H,O,, OH-, and chemiluminescence measured in both systems. HA and synovial fluid, which are known to be susceptible to degradation by excessive ROS in RA patients, also seem to play an active role in protecting articular tissues from oxidative damage.Hyaluoronic acid (HA) is a glucosaminoglycan with a repeating disaccharide structure that is composed of D-glucuronic acid in / 3 1+3 linkage to Nacetyl-D-glucosamine, which in turn, is in p 1+4 linkage to the next D-glucuronic acid. HA is contained in synovial fluids as one of many proteins, proteoglycan, to which HA is bound. In the joint, HA plays an important role in the protection of articular cartilage and the transport of nutrients to cartilage (1-3). In patients with rheumatoid arthritis (RA), it has been reported that HA acts as an antiinflammatory substance by inhibiting the adherence of immune complexes to neutrophils through the Fc receptor (4), or by protecting the synovial tissues from the attachment of inflammatory mediators (5).We have previously verified that reactive oxygen species (ROS) (02-, H20,, OH-, and chemiluminescence) are generated in abundance by synovial neutrophils from RA patients, as compared with synovial neutrophils of osteoarthritis (OA) patients and peripheral neutrophils of both RA and OA patients (6). McCord (7) demonstrated that HA was susceptible to degradation by ROS in vitro, and that this could be protected by superoxide dismutase (SOD) and/or catalase, which suggests the possibility that there is pathologic oxidative damage to synovial fluid components in RA patients. Dahl et a1 (8) recently reported that there are reduced HA concentrations in synovial fluids from RA patients. It has also been reported that ROS scavengers inhibit the degradation of HA by ROS (9,101. These findings appear to support the hypothesis that ROS are responsible for the accelerated degradation of HA in the rheumatoid joint. In this study, the oxygen radical scavenging activities of synovial fluids
Objective. To determine levels of the soluble form of the chemokine fractalkine (sFkn) and its receptor, CX 3 CR1, in patients with systemic lupus erythematosus (SLE) with neuropsychiatric involvement (NPSLE) and in SLE patients without neuropsychiatric involvement, and to assess their relationship with disease activity and organ damage.Methods. Levels of sFkn in serum and cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. Expression of Fkn and CX 3 CR1 was quantified using real-time polymerase chain reaction. Surface expression of CX 3 CR1 on peripheral blood mononuclear cells (PBMCs) was determined by flow cytometry. Disease activity and organ damage were assessed using the SLE Disease Activity Index (SLE-DAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ ACR) Damage Index, respectively.Results. Serum sFkn levels were significantly higher in patients with SLE than in patients with rheumatoid arthritis (RA) or healthy controls. In addition, significant correlations between serum sFkn levels and the SLEDAI, the SLICC/ACR Damage Index, antidouble-stranded DNA and anti-Sm antibody titers, immune complex levels (C1q), and serum complement levels (CH50) were observed. Expression of CX 3 CR1 was significantly greater in PBMCs from patients with active SLE than in those from RA patients or healthy controls. Levels of sFkn were also significantly higher in CSF from untreated patients with newly diagnosed NPSLE than in SLE patients without neuropsychiatric involvement; treatment reduced both serum and CSF levels of sFkn in patients with SLE.Conclusion. Soluble Fkn and CX 3 CR1 may play key roles in the pathogenesis of SLE, including the neuropsychiatric involvement. Soluble Fkn is also a serologic marker of disease activity and organ damage in patients with SLE, and its measurement in CSF may be useful for the diagnosis of NPSLE and followup of patients with NPSLE.
Objective. To determine levels of soluble fractalkine (sFkn) in rheumatoid arthritis (RA) patients with and without rheumatoid vasculitis (RV), and to assess the relationship of sFkn levels to disease activity.Methods. Serum was obtained from 98 RA patients (54 without vasculitis, 36 with extraarticular manifestations but without histologically proven vasculitis, and 8 with histologically proven vasculitis) and from 38 healthy individuals. Levels of sFkn were measured by enzyme-linked immunosorbent assay. Expression of Fkn and CX 3 CR1 was quantified by real-time polymerase chain reaction. Vasculitis disease activity was assessed using the Birmingham Vasculitis Activity Score and the Vasculitis Activity Index.Results. Serum sFkn levels were significantly higher in patients with RA than in controls and were significantly higher in RA patients with RV than in those without vasculitic complications. Statistically significant correlations were observed between serum sFkn levels in RA patients and levels of C-reactive protein, rheumatoid factor, immune complex, and complement. In the RV group, sFkn levels also correlated with disease activity. Immunohistochemical analysis indicated that Fkn levels were associated mainly with endothelial cells in vasculitic arteries. In addition, expression of CX 3 CR1 messenger RNA was significantly greater in peripheral blood mononuclear cells from patients with active RV than in those from other RA patients or controls. Notably, serum sFkn levels were significantly diminished following successful treatment and clinical improvement.Conclusion. These findings suggest that Fkn and CX 3 CR1 play crucial roles in the pathogenesis of RV and that sFkn may serve as a serologic inflammatory marker of disease activity in RA patients with vasculitis.
Most of the leucocytes infiltrating rheumatoid synovial fluid (SF) are neutrophils capable of producing a variety of inflammatory mediators known to contribute significantly to the disease process during active RA. In the present study, we investigated the contribution made by SF neutrophils to the elevated levels of vascular endothelial growth factor (VEGF) seen in rheumatoid SF. Rheumatoid SF neutrophils were found to contain significantly larger amounts of both VEGF protein and its mRNA than peripheral blood neutrophils from either RA patients or healthy controls. Levels of cell‐associated VEGF were well correlated with free VEGF in SF, which was significantly higher than in SF from osteoarthritis patients. Levels of SF neutrophil‐associated VEGF also correlated with RA disease activity and cell surface integrin expression. Thus, SF neutrophil‐associated VEGF may be considered an indicator of both local and systemic inflammation of RA, contributing to the neovascularization seen during RA synovitis.
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