| BackgroundWith the social and economic development, people's diet and lifestyle change greatly. Furthermore, aging of the population in the world has become more evident especially in China, so the prevalence of gout shows an increasing trend generally. It poses a threat to people's health. Because acute gouty arthritis leads to the repeated attack of pain, it will easily disabled, teratogenic, and affect joint function if not treated actively. Patients with acute gouty arthritis occupied the biggest percentage in visiting patients with gout. Prevention and treatment of acute gouty arthritis should be studied and solved urgently. Traditional Chinese Medicine(TCM) has been long for prevention and treatment of gout. TCM is rich in theory and effective herbs in the treatment of gout, so it is of great significance and prospects for further research and development of effective prescriptions.According to therapeutic thoughts of reinforcing Kidney and activating blood, eliminating heat and wetness evil, Professor Liu Youzhang created the TCM compound formula named as TongFengKang(TFK) on the basis of long-term clinical practice. Previous clinical researchs have confirmed preliminary that effect of TFK on the acute gouty arthritis. TFK not only can improve patients'joint symptoms with acute gouty arthritis, but also can effectually decrease uric acid in patients'blood. Preliminary animal experiments have shown that TFK can reduce inflammatory cells infiltration, relieve the damage of synovial tissue, and reduce hyperemia in model rats with acute gouty arthritis. TFK have significant effect on swelling inhibition and analgesia, but its action mechanism needs to be further clarified. Recent investigations provided novel evidence in the pathology of acute gout. A number of studies indicated that MSU crystals could act as a "danger signal" which resembled exogenous adjuvants, and toll-like receptors(TLRs) could recognize such "danger signals". Myeloid differentiation factor 88(MyD88) was a key adapter molecule in TLRs signaling pathway, which had an important role in passing the upstream signal and the development of disease. MyD88-dependent pathway was the common pathway of TLRs signals. In addition, TLRs were involved in triggering receptors expressed on myeloid cells 1 (TREM-1) pathways. Activation of TLRs could lead to up-regulation of TREM-1, and TREM-1 expression could change the expression of the key receptor and effector proteins in TLR4 pathway. Thus, TREM-1 and TLRs pathways might have a synergistic effect. Observing the effect of TFK on TLR2, TLR4, MyD88, TREM-1 will be beneficial to further reveal it action mechanism.ObjectivesStudy therapeutic effect and security of TFK on treatment of acute gouty arthritis, and observe the effect of TFK on expression of patients'serum (TREM-1) with acute gouty arthritis; Research the effect of TFK on joint symptom and TRL2, TLR4, MyD88 in rats synovial tissues with acute gouty arthritis, then further confirm efficacy of TFK and reveal its action mechanism.MethodsClinical research:40 patients with acute gouty arthritis were randomly divided into two groups:treatment group and control group,20 patients in each group. The treatment group was treated by "TFK granule" and "Tongfeng external application", the control group was treated with placebo. The treatment duration was 5 days. Recorded the index of the patients'joint pain, acute swelling and dysfunction. Recorded self-rating joint pain index. Detected patients'hepatic and renal function in pre and post treatment. Testing the expression of TREM-1 in patients'serum before and after the treatment by enzyme linked immunosorbent assay(ELISA). Experimental study:48 rats were randomly divided into normal group, model group, colchicine group, large dose TFK group, medium dose TFK group, small dose TFK group,8 rats in each group. TFK large, medium and small dose group were given TFK separately in the dose of 72g/kg per day,36g/kg per day,18g/kg per day. Colchicine group was given colchicine solution in the dose of 0.3mg/kg per day. Saline water was administered to the normal group and model group. All rats had been oral administered by the drugs for 5 days. On the third day of drug, acute gouty arthritis model was set up via articular cavity MSU injection except the normal group, the same volume of saline was injected to the normal group. Right ankle joint circumference of rats was measured dynamically. The indexes of rats'inflammation and dysfunction were observved. The pathological changes of rats joint synovial tissue were detected by HE staining. The expression of TLR2, TLR4, MyD88 in rats synovium were measured by immunohistochemistry.ResultsClinical research:(1)Compared with control group, self-rating joint pain index of TFK treated group was significantly lightened(day4:P<0.05; day5:P<0.01), articular pain was lightened (day 3:P<0.05; day 6:P<0.05), acute swelling was lightened (day 3:P<0.05; day 6:P<0.05), dysfunction was lightened(day6:P<0.05), analgesic use decreased(P<0.05).(2)Security indexes such as alanine aminotransferase(ALT), urea nitrogen (BUN), creatinine(CREA) of TFK treated group did not show significant change in pre and post treatment(ALT:P>0.05;BUN:P>0.05;CREA:P>0.05).(3) Compared with control group, TREM-1 concentration of TFK treated group decreased significantly after treatment(P<0.05).The decrease before and after treatment of TFK treated group was more significant(decreased by 42.4%), whereas 28.9% in control group. Experimental study:(1)Compared with normal group, the joint swelling index of model group was significantly increased(4h after model:P<0.01; 10h:P<0.01;24h:P<0.01; 72h: P<0.01). Compared with model group, the joint swelling index of colchicines group was significantly lightened(4h:P<0.05; 10h:P<0.05;24h:P<0.05; 72h: P<0.01); The joint swelling index of TFK large, medium and small dose group showed a decreasing trend at 4h, 10h and 24h, but was significantly lightened (TFK large dose group:P<0.01, TFK medium dose group:P<0.01 and TFK small dose group:P<0.01), but did not show significant change compared with colchicines group9 (TFK large dose group:P>0.05, TFK medium dose group:P>0.05 and TFK small dose group:P>0.05), and the joint swelling index of TFK large and medium dose group showed a decreasing trend compared with small dose group.Model group showed significant joint inflammation(10h), and a gradually catabatic trend(24h,72h); Compared with model group, the joint inflammation of colchicines group, TFK small, medium and large dose group was significantly lightened, and was slight swelling at 72h.Model group showed significant joint dysfunction(10h), and a catabatic gradually trend(24h,72h); Compared with model group, the joint dysfunction of colchicines group, TFK small, medium and large dose group was significantly lightened, and almost disappeared at 72h.(2)The abnormalities of the rat's joint synovial tissue included obvious inflammation, synovial cells proliferation, inflammatory cell infiltration, small vessels proliferation, fibroblast cell by HE staining, which shown the animal model was successfully produced. After the treatment TFK and colchicines, these histological abnormalities were lessened.(3)The TLR2 very few expression in joint synovial tissue of normal group. Compared with normal group, The TLR2 expression in joint synovial tissue of model group increased significantly(P<0.01). Compared with model group, The TLR2 expression in joint synovial tissue of colchicines group decreased significantly (P<0.01), The TLR2 expression in joint synovial tissue of TFK small, medium and large dose group decreased significantly(TFK small dose group:P<0.01; TFK medium dose group:P<0.01; TFK large dose group:P<0.01). TFK small, medium and large dose group showed a decreasing trend. Compared with colchicines group, The TLR2 expression in joint synovial tissue of TFK small, medium and large dose group did not show significant change.(4)The TLR4 very few expression in joint synovial tissue of normal group. Compared with normal group, The TLR4 expression in joint synovial tissue of model group increased significantly(P<0.01). Compared with model group, The TLR4 expression in joint synovial tissue of colchicines group decreased significantly (P<0.05), The TLR2 expression in joint synovial tissue of TFK small, medium and large dose group decreased significantly(TFK small dose group:P<0.01; TFK medium dose group:P<0.05; TFK large dose group:P<0.01). Compared with colchicines group, The TLR4 expression in joint synovial tissue of TFK small, medium and large dose group did not show significant change.(5)The MyD88 less expression in joint synovial tissue of normal group. Compared with normal group, The MyD88 expression in joint synovial tissue of model group increased significantly(P<0.01). Compared with model group, The MyD88 expression in joint synovial tissue of colchicines group decreased significantly(P<0.01), The MyD88 expression in joint synovial tissue of TFK small, medium and large dose group decreased significantly(TFK small dose group:P<0.01;TFK medium dose group:P<0.01; TFK large dose group: P<0.01). The MyD88 expression of TFK large and medium dose group showed a decreasing trend compared with small dose group. Compared with colchicines group, The TLR4 expression in joint synovial tissue of TFK small, medium and large dose group did not show significant change.Conelusion(1) TFK not only can significantly improve joint pain, swelling, dysfunctiong of acute gouty arthritis, but also was safe, there was no obvious impact on hepatic and renal function.(2)TFK can significantly improve joint pain, swelling, dysfunctiong of rat with MSU-induced acute gouty arthritis.(3)TFK can significantly reduce the expression of TREM-1 in patients'serum with acute gouty arthritis. The inhibition effect of TFK on the expression of TREM-1 was one of TFK mechanism in acute gouty arthritis treatment.(4)TFK can significantly reduce the TLR2, TLR4 and MyD88 expression of synovium from inflammatory arthritis. The regulatory effect of TFK on TLRs/MyD88 pathways was one of TFK mechanism in acute gouty arthritis treatment. |
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