| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 99 === Osteoarthritis (OA), a slowly progressing disease resulting in articular cartilage fibrillation and loss, is the most common form of arthritis. Approximately 10–50% of the elderly population is affected by OA, a quarter of who are severely disabled due to joint symptoms. Rheumatoid arthritis (RA) is a chronic autoimmune disease, which leads to joint disfiguration caused by synovial inflammation, leukocyte infiltration, pannus formation, cartilage matrix degradation and destruction. Imbalance of inflammatory and anti-inflammatory cytokines thus plays a critical role in the pathogenesis of RA.
In order to precisely determinate anti-inflammation property of resveratrol and carbon monoxide (CO), reliable experimental arthritis model should be set up. At present time, mouse is considered as the most ideal animal model for studying the molecular backgrounds of physiological and pathological conditions, which is based on the rapid progress in mouse genomics and the availability of transgenic and knockout (KO) mice. In this study, we demonstrate and set up several murine experimental arthritis models such as Collagen antibody-induced arthritis (CAIA), surgical destabilization of the medial meniscus (DMM) model and surgical patella strengthening (SPS)-induced model of OA.
In resveratrol experiment, resveratrol (30 mg/kg in 30 μL DMSO) was injected into the knee joint of BALB/c mice from days 0 to 9. In CO experiment, BALB/c mice were housing in chamber maintained in room air or exposed to CO in a concentration of 250 parts per million (ppm) continuously since 7 days before induced arthritis to 10 days after antibody injection. The footpad thickness was recorded with non-contact measurement system and data was calculated by software in the computer. The total splenocytes were harvest for T cell proliferation. On day 10, the joints were examined histopathologically. Serum cytokine levels were measured by ELISA. mRNA levels in paws or synovium of knee joint were measured by real-time PCR.
In the resveratrol-treated mice, the severity of inflammation was obviously reduced. Acute inflammation was induced on day 7 and continued until day 10. Expression levels of IL-1β, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) were decreased in the treated mice; however, tumour necrosis factor-α (TNF-α) levels did not change significantly after the treatment. The anti-inflammatory mechanism of resveratrol is associated with NF-κB inhibition. Further investigations of the clinical applications of resveratrol are thus required.
In CO treated group, the acute inflammation happened on day 7 to 10 and obviously weakened inflammation. The IL-1β protein level and relative mRNA expression were significantly decreased in CO treated group. The T cell proliferation study showed lower proliferation level in mice housing with 250 ppm CO. The IL-2 expression is lower in the group of administration of CO in T cell proliferation and it could be reserved by IL-2 administration. Anti-inflammation effect of CO in rheumatoid arthritis mice model was examined, and indiacted the benefit in anti-inflammatory effect. The mechanisms involved the inhibition of cytokine secretion and T cell proliferation. Further investigation in clinical application are considered.
These investigations indicate that monitor cytokine profile during pathogenesis of experimental arthritis and treat with resveratrol and CO may provide some hint of experimental arthritis therapy.
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