蠲痹历节清方对急性痛风性关节炎大鼠的影响及其作用机制
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摘要
目的:探讨蠲痹历节清方对急性痛风性关节炎大鼠的影响及其作用机制。方法:将96只2月龄雄性清洁级健康SD大鼠随机分为正常对照组、模型组、蠲痹历节清方组、依托考昔组,每组24只。模型组、蠲痹历节清方组、依托考昔组大鼠以氧嗪酸钾溶液连续腹腔注射后,于大鼠右侧踝关节腔内注射尿酸钠溶液;正常对照组大鼠腹腔及右侧踝关节腔分别注入等剂量生理盐水。关节腔内注射后即刻给予药物干预,正常对照组和模型组以10 m L·kg~(-1)生理盐水灌胃,蠲痹历节清方组以22 g·kg~(-1)剂量的蠲痹历节清方悬混液灌胃,依托考昔组以5.5 mg·kg~(-1)剂量的依托考昔悬混液灌胃;每日2次,连续灌胃2 d。分别于药物干预开始后4 h、12 h、24 h、48 h采用免疫组化法检测各组大鼠踝关节滑膜组织中肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)、白细胞介素(interleukin,IL)-1β、IL-6蛋白含量;于药物干预开始后48 h采用全自动生化分析仪检测血尿酸含量,并观察各组大鼠踝关节滑膜组织形态。结果:(1)踝关节滑膜组织中TNF-α蛋白含量。药物干预开始后4 h、12 h、24 h、48 h,4组大鼠踝关节滑膜组织中TNF-α蛋白含量比较,差异均有统计学意义[(14.72±0.98)pg·m L~(-1),(40.05±1.31)pg·m L~(-1),(19.59±2.63)pg·m L~(-1),(19.00±1.32)pg·m L~(-1),F=72.528,P=0.012;(16.14±0.86)pg·m L~(-1),(40.95±2.56)pg·m L~(-1),(24.10±2.50)pg·m L~(-1),(21.02±2.68)pg·m L~(-1),F=59.314,P=0.000;(14.95±0.39)pg·m L~(-1),(38.65±0.75)pg·m L~(-1),(19.49±0.59)pg·m L~(-1),(18.64±0.62)pg·m L~(-1),F=35.681,P=0.001;(14.83±1.26)pg·m L~(-1),(37.91±1.30)pg·m L~(-1),(18.16±0.84)pg·m L~(-1),(17.32±0.83)pg·m L~(-1),F=37.553,P=0.000];正常对照组大鼠踝关节滑膜组织中TNF-α蛋白含量均低于模型组、蠲痹历节清方组和依托考昔组(P=0.000,P=0.000,P=0.003,P=0.001;P=0.000,P=0.000,P=0.001,P=0.008;P=0.000,P=0.000,P=0.000,P=0.001);模型组踝关节滑膜组织中TNF-α蛋白含量均高于蠲痹历节清方组和依托考昔组(P=0.000,P=0.001,P=0.000,P=0.000;P=0.000,P=0.000,P=0.000,P=0.000);蠲痹历节清方组踝关节滑膜组织中TNF-α蛋白含量与依托考昔组比较,差异均无统计学意义(P=0.212,P=0.079,P=0.091,P=0.088)。(2)踝关节滑膜组织中IL-1β蛋白含量。药物干预开始后4 h、12 h、24 h、48 h,4组大鼠踝关节滑膜组织中IL-1β蛋白含量比较,差异均有统计学意义[(3.43±0.68)pg·m L~(-1),(7.40±0.51)pg·m L~(-1),(4.84±0.21)pg·m L~(-1),(4.67±0.18)pg·m L~(-1),F=64.473,P=0.028;(3.61±0.34)pg·m L~(-1),(7.95±0.63)pg·m L~(-1),(5.28±0.34)pg·m L~(-1),(4.91±0.42)pg·m L~(-1),F=50.119,P=0.006;(3.51±0.50)pg·m L~(-1),(6.98±0.60)pg·m L~(-1),(4.73±0.25)pg·m L~(-1),(4.47±0.23)pg·m L~(-1),F=41.346,P=0.002;(3.47±0.29)pg·m L~(-1),(6.90±0.68)pg·m L~(-1),(4.58±0.27)pg·m L~(-1),(4.12±0.11)pg·m L~(-1),F=68.784,P=0.000];正常对照组大鼠踝关节滑膜组织中IL-1β蛋白含量均低于模型组、蠲痹历节清方组和依托考昔组(P=0.003,P=0.000,P=0.001,P=0.000;P=0.000,P=0.000,P=0.002,P=0.004;P=0.000,P=0.000,P=0.001,P=0.000);模型组踝关节滑膜组织中IL-1β蛋白含量均高于蠲痹历节清方组和依托考昔组(P=0.000,P=0.001,P=0.003,P=0.000;P=0.000,P=0.008,P=0.000,P=0.000);蠲痹历节清方组踝关节滑膜组织中IL-1β蛋白含量与依托考昔组比较,差异均无统计学意义(P=0.198,P=0.081,P=0.101,P=0.097)。(3)踝关节滑膜组织中IL-6蛋白含量。药物干预开始后4 h、12 h、24 h、48 h,4组大鼠踝关节滑膜组织中IL-6蛋白含量比较,差异均有统计学意义[(3.72±0.31)pg·m L~(-1),(7.83±0.33)pg·m L~(-1),(4.87±0.12)pg·m L~(-1),(4.75±0.23)pg·m L~(-1),F=32.582,P=0.018;(4.07±0.38)pg·m L~(-1),(8.04±0.13)pg·m L~(-1),(5.62±0.38)pg·m L~(-1),(5.12±0.20)pg·m L~(-1),F=86.127,P=0.007;(3.77±0.14)pg·m L~(-1),(7.86±0.27)pg·m L~(-1),(4.79±0.53)pg·m L~(-1),(4.68±0.11)pg·m L~(-1),F=49.038,P=0.001;(3.55±0.14)pg·m L~(-1),(7.85±0.24)pg·m L~(-1),(4.67±0.38)pg·m L~(-1),(4.57±0.13)pg·m L~(-1),F=33.115,P=0.000];正常对照组大鼠踝关节滑膜组织中IL-6蛋白含量均低于模型组、蠲痹历节清方组和依托考昔组(P=0.001,P=0.000,P=0.001,P=0.000;P=0.000,P=0.000,P=0.001,P=0.006;P=0.000,P=0.000,P=0.000,P=0.003);模型组踝关节滑膜组织中IL-6蛋白含量均高于蠲痹历节清方组和依托考昔组(P=0.000,P=0.000,P=0.002,P=0.000;P=0.000,P=0.001,P=0.000,P=0.000);蠲痹历节清方组踝关节滑膜组织中IL-6蛋白含量与依托考昔组比较,差异均无统计学意义(P=0.256,P=0.075,P=0.933,P=0.108)。(4)血尿酸含量。药物干预开始后48 h,4组大鼠血尿酸含量比较,差异有统计学意义[(132.52±3.32)μmol·L~(-1),(352.30±14.42)μmol·L~(-1),(165.08±3.57)μmol·L~(-1),(321.08±16.44)μmol·L~(-1),F=46.176,P=0.000];正常对照组大鼠血尿酸含量低于模型组、蠲痹历节清方组和依托考昔组(P=0.000,P=0.028,P=0.000),模型组血尿酸含量高于蠲痹历节清方组和依托考昔组(P=0.000,P=0.032),蠲痹历节清方组血尿酸含量低于依托考昔组(P=0.001)。(5)踝关节滑膜组织形态。药物干预开始后48 h,正常对照组踝关节滑膜上皮排列完整,无炎性细胞浸润;模型组踝关节滑膜上皮脱落,大量白细胞浸润;蠲痹历节清方组和依托考昔组踝关节滑膜上皮较完整,炎性细胞浸润较少。结论:蠲痹历节清方能有效降低急性痛风性关节炎大鼠的血尿酸水平,抑制其关节滑膜组织炎症反应,其作用机制可能与其能下调TNF-α、IL-1β、IL-6的蛋白表达有关。
Objective: To explore the effects of Juanbi Lijie Qing Fang( 蠲痹历节清方,JBLJQF) on rats with acute gouty arthritis and its mechanism of action. Methods: Ninety-six 2-month-old healthy clean-grade male SD rats were randomly divided into normal control group,model group,JBLJQF group and etoricoxib group,24 cases in each group. The rats in model group,JBLJQF group and etoricoxib group were intraperitoneal injected continuously with oteracil potassium solutions,and then the sodium urate solutions were injected into their right ankles,while the rats in normal control group were administrated with intraperitoneal injection and intra-articular injection of the same dose of normal saline( NS) respectively. Drug interventions were performed on the rats immediately after intra-articular injection. The rats in normal control group,model group,JBLJQF group and etoricoxib group were intragastric administrated with NS( 10 m L/kg),NS( 10 m L/kg),JBLJQF suspension( 22 g/kg) and etoricoxib suspension( 5. 5 mg/kg) respectively,twice a day for 2 consecutive days. The contents of tumor necrosis factor-α( TNF-α) protein,interleukin-1β( IL-1β) protein and interleukin-6( IL-6) protein in ankle synovial tissues were detected by using immunohistochemical method at 4,12,24 and 48 hours after the beginning of drug intervention respectively. The blood uric acid( UA) contents were detected by using full-automatic biochemical analyser at 48 hours after the beginning of drug intervention,and the ankle synovial tissue morphologies of rats in each group were observed. Results: There was statistical difference in content of TNF-α protein in ankle synovial tissues between the 4 groups at 4,12,24 and 48 hours after the beginning of drug intervention( 14. 72 +/-0. 98,40. 05 +/-1. 31,19. 59 +/-2. 63,19. 00 +/-1. 32 pg/m L,F = 72. 528,P = 0. 012; 16. 14 +/-0. 86,40. 95 +/-2. 56,24. 10 +/-2. 50,21. 02 +/-2. 68 pg/m L,F = 59. 314,P = 0. 000; 14. 95 +/-0. 39,38. 65 +/-0. 75,19. 49 +/-0. 59,18. 64 +/-0. 62 pg/m L,F = 35. 681,P = 0. 001; 14. 83 +/-1. 26,37. 91 +/-1. 30,18. 16 +/-0. 84,17. 32 +/-0. 83 pg/m L,F = 37. 553,P =0. 000). The content of TNF-α protein in ankle synovial tissues was lower in normal control group compared to model group,JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 000,P = 0. 003,P = 0. 001; P = 0. 000,P = 0. 000,P = 0. 001,P = 0. 008; P = 0. 000,P =0. 000,P = 0. 000,P = 0. 001),and was higher in model group compared to JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 001,P =0. 000,P = 0. 000; P = 0. 000,P = 0. 000,P = 0. 000,P = 0. 000). There was no statistical difference in content of TNF-α protein in ankle synovial tissues between JBLJQF group and etoricoxib group( P = 0. 212,P = 0. 079,P = 0. 091,P = 0. 088). There was statistical difference in content of IL-1β protein in ankle synovial tissues between the 4 groups at 4,12,24 and 48 hours after the beginning of drug intervention( 3. 43 +/-0. 68,7. 40 +/-0. 51,4. 84 +/-0. 21,4. 67 +/-0. 18 pg/m L,F = 64. 473,P = 0. 028; 3. 61 +/-0. 34,7. 95 +/-0. 63,5. 28 +/-0. 34,4. 91 +/-0. 42 pg/m L,F = 50. 119,P = 0. 006; 3. 51 +/-0. 50,6. 98 +/-0. 60,4. 73 +/-0. 25,4. 47 +/-0. 23 pg/m L,F = 41. 346,P = 0. 002; 3. 47 +/-0. 29,6. 90 +/-0. 68,4. 58 +/-0. 27,4. 12 +/-0. 11 pg/m L,F = 68. 784,P = 0. 000). The content of IL-1β protein in ankle synovial tissues was lower in normal control group compared to model group,JBLJQF group and etoricoxib group( P = 0. 003,P =0. 000,P = 0. 001,P = 0. 000; P = 0. 000,P = 0. 000,P = 0. 002,P = 0. 004; P = 0. 000,P = 0. 000,P = 0. 001,P = 0. 000),and was higher in model group compared to JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 001,P = 0. 003,P = 0. 000; P = 0. 000,P = 0. 008,P =0. 000,P = 0. 000). There was no statistical difference in content of IL-1β protein in ankle synovial tissues between JBLJQF group and etoricoxib group( P = 0. 198,P = 0. 081,P = 0. 101,P = 0. 097). There was statistical difference in content of IL-6 protein in ankle synovial tissues between the 4 groups at 4,12,24 and 48 hours after the beginning of drug intervention( 3. 72 +/-0. 31,7. 83 +/-0. 33,4. 87 +/-0. 12,4. 75 +/-0. 23 pg/m L,F = 32. 582,P = 0. 018; 4. 07 +/-0. 38,8. 04 +/-0. 13,5. 62 +/-0. 38,5. 12 +/-0. 20 pg/m L,F = 86. 127,P = 0. 007; 3. 77 +/-0. 14,7. 86 +/-0. 27,4. 79 +/-0. 53,4. 68 +/-0. 11 pg/m L,F = 49. 038,P = 0. 001; 3. 55 +/-0. 14,7. 85 +/-0. 24,4. 67 +/-0. 38,4. 57 +/-0. 13 pg/m L,F = 33. 115,P = 0. 000). The content of IL-6 protein in ankle synovial tissues was lower in normal control group compared to model group,JBLJQF group and etoricoxib group( P = 0. 001,P = 0. 000,P = 0. 001,P = 0. 000; P = 0. 000,P =0. 000,P = 0. 001,P = 0. 006; P = 0. 000,P = 0. 000,P = 0. 000,P = 0. 003),and was higher in model group compared to JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 000,P = 0. 002,P = 0. 000; P = 0. 000,P = 0. 001,P = 0. 000,P = 0. 000). There was no statistical difference in content of IL-6 protein in ankle synovial tissues between JBLJQF group and etoricoxib group( P = 0. 256,P = 0. 075,P =0. 933,P = 0. 108). There was statistical difference in blood UA content between the 4 groups at 48 hours after the beginning of drug intervention( 132. 52 +/-3. 32,352. 30 +/-14. 42,165. 08 +/-3. 57,321. 08 +/-16. 44 μmol/L,F = 46. 176,P = 0. 000). The blood UA content was lower in normal control group compared to model group,JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 028,P = 0. 000),and was higher in model group compared to JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 032),and was lower in JBLJQF group compared to etoricoxib group( P = 0. 001). At 48 hours after the beginning of drug intervention,the ankle synovial epithelium of rats in normal control group was complete without inflammatory cell infiltration,and the ankle synovial epithelium of rats in model group was exfoliated with a large amount of leukocytic infiltration,and the ankle synovial epithelium of rats in JBLJQF group and etoricoxib group were relatively complete with less inflammatory cell infiltration. Conclusion: JBLJQF can effectively reduce the blood UA level and inhibit the inflammatory reaction in synovial tissue in rats with acute gouty arthritis,and its mechanisms of action may be that it can down-regulate the protein expression of TNF-α,IL-1β and IL-6.
Objective: To explore the effects of Juanbi Lijie Qing Fang( 蠲痹历节清方,JBLJQF) on rats with acute gouty arthritis and its mechanism of action. Methods: Ninety-six 2-month-old healthy clean-grade male SD rats were randomly divided into normal control group,model group,JBLJQF group and etoricoxib group,24 cases in each group. The rats in model group,JBLJQF group and etoricoxib group were intraperitoneal injected continuously with oteracil potassium solutions,and then the sodium urate solutions were injected into their right ankles,while the rats in normal control group were administrated with intraperitoneal injection and intra-articular injection of the same dose of normal saline( NS) respectively. Drug interventions were performed on the rats immediately after intra-articular injection. The rats in normal control group,model group,JBLJQF group and etoricoxib group were intragastric administrated with NS( 10 m L/kg),NS( 10 m L/kg),JBLJQF suspension( 22 g/kg) and etoricoxib suspension( 5. 5 mg/kg) respectively,twice a day for 2 consecutive days. The contents of tumor necrosis factor-α( TNF-α) protein,interleukin-1β( IL-1β) protein and interleukin-6( IL-6) protein in ankle synovial tissues were detected by using immunohistochemical method at 4,12,24 and 48 hours after the beginning of drug intervention respectively. The blood uric acid( UA) contents were detected by using full-automatic biochemical analyser at 48 hours after the beginning of drug intervention,and the ankle synovial tissue morphologies of rats in each group were observed. Results: There was statistical difference in content of TNF-α protein in ankle synovial tissues between the 4 groups at 4,12,24 and 48 hours after the beginning of drug intervention( 14. 72 +/-0. 98,40. 05 +/-1. 31,19. 59 +/-2. 63,19. 00 +/-1. 32 pg/m L,F = 72. 528,P = 0. 012; 16. 14 +/-0. 86,40. 95 +/-2. 56,24. 10 +/-2. 50,21. 02 +/-2. 68 pg/m L,F = 59. 314,P = 0. 000; 14. 95 +/-0. 39,38. 65 +/-0. 75,19. 49 +/-0. 59,18. 64 +/-0. 62 pg/m L,F = 35. 681,P = 0. 001; 14. 83 +/-1. 26,37. 91 +/-1. 30,18. 16 +/-0. 84,17. 32 +/-0. 83 pg/m L,F = 37. 553,P =0. 000). The content of TNF-α protein in ankle synovial tissues was lower in normal control group compared to model group,JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 000,P = 0. 003,P = 0. 001; P = 0. 000,P = 0. 000,P = 0. 001,P = 0. 008; P = 0. 000,P =0. 000,P = 0. 000,P = 0. 001),and was higher in model group compared to JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 001,P =0. 000,P = 0. 000; P = 0. 000,P = 0. 000,P = 0. 000,P = 0. 000). There was no statistical difference in content of TNF-α protein in ankle synovial tissues between JBLJQF group and etoricoxib group( P = 0. 212,P = 0. 079,P = 0. 091,P = 0. 088). There was statistical difference in content of IL-1β protein in ankle synovial tissues between the 4 groups at 4,12,24 and 48 hours after the beginning of drug intervention( 3. 43 +/-0. 68,7. 40 +/-0. 51,4. 84 +/-0. 21,4. 67 +/-0. 18 pg/m L,F = 64. 473,P = 0. 028; 3. 61 +/-0. 34,7. 95 +/-0. 63,5. 28 +/-0. 34,4. 91 +/-0. 42 pg/m L,F = 50. 119,P = 0. 006; 3. 51 +/-0. 50,6. 98 +/-0. 60,4. 73 +/-0. 25,4. 47 +/-0. 23 pg/m L,F = 41. 346,P = 0. 002; 3. 47 +/-0. 29,6. 90 +/-0. 68,4. 58 +/-0. 27,4. 12 +/-0. 11 pg/m L,F = 68. 784,P = 0. 000). The content of IL-1β protein in ankle synovial tissues was lower in normal control group compared to model group,JBLJQF group and etoricoxib group( P = 0. 003,P =0. 000,P = 0. 001,P = 0. 000; P = 0. 000,P = 0. 000,P = 0. 002,P = 0. 004; P = 0. 000,P = 0. 000,P = 0. 001,P = 0. 000),and was higher in model group compared to JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 001,P = 0. 003,P = 0. 000; P = 0. 000,P = 0. 008,P =0. 000,P = 0. 000). There was no statistical difference in content of IL-1β protein in ankle synovial tissues between JBLJQF group and etoricoxib group( P = 0. 198,P = 0. 081,P = 0. 101,P = 0. 097). There was statistical difference in content of IL-6 protein in ankle synovial tissues between the 4 groups at 4,12,24 and 48 hours after the beginning of drug intervention( 3. 72 +/-0. 31,7. 83 +/-0. 33,4. 87 +/-0. 12,4. 75 +/-0. 23 pg/m L,F = 32. 582,P = 0. 018; 4. 07 +/-0. 38,8. 04 +/-0. 13,5. 62 +/-0. 38,5. 12 +/-0. 20 pg/m L,F = 86. 127,P = 0. 007; 3. 77 +/-0. 14,7. 86 +/-0. 27,4. 79 +/-0. 53,4. 68 +/-0. 11 pg/m L,F = 49. 038,P = 0. 001; 3. 55 +/-0. 14,7. 85 +/-0. 24,4. 67 +/-0. 38,4. 57 +/-0. 13 pg/m L,F = 33. 115,P = 0. 000). The content of IL-6 protein in ankle synovial tissues was lower in normal control group compared to model group,JBLJQF group and etoricoxib group( P = 0. 001,P = 0. 000,P = 0. 001,P = 0. 000; P = 0. 000,P =0. 000,P = 0. 001,P = 0. 006; P = 0. 000,P = 0. 000,P = 0. 000,P = 0. 003),and was higher in model group compared to JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 000,P = 0. 002,P = 0. 000; P = 0. 000,P = 0. 001,P = 0. 000,P = 0. 000). There was no statistical difference in content of IL-6 protein in ankle synovial tissues between JBLJQF group and etoricoxib group( P = 0. 256,P = 0. 075,P =0. 933,P = 0. 108). There was statistical difference in blood UA content between the 4 groups at 48 hours after the beginning of drug intervention( 132. 52 +/-3. 32,352. 30 +/-14. 42,165. 08 +/-3. 57,321. 08 +/-16. 44 μmol/L,F = 46. 176,P = 0. 000). The blood UA content was lower in normal control group compared to model group,JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 028,P = 0. 000),and was higher in model group compared to JBLJQF group and etoricoxib group( P = 0. 000,P = 0. 032),and was lower in JBLJQF group compared to etoricoxib group( P = 0. 001). At 48 hours after the beginning of drug intervention,the ankle synovial epithelium of rats in normal control group was complete without inflammatory cell infiltration,and the ankle synovial epithelium of rats in model group was exfoliated with a large amount of leukocytic infiltration,and the ankle synovial epithelium of rats in JBLJQF group and etoricoxib group were relatively complete with less inflammatory cell infiltration. Conclusion: JBLJQF can effectively reduce the blood UA level and inhibit the inflammatory reaction in synovial tissue in rats with acute gouty arthritis,and its mechanisms of action may be that it can down-regulate the protein expression of TNF-α,IL-1β and IL-6.
引文
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[7]吕军,吕芳,方和金,等.高尿酸血症并急性痛风性关节炎大鼠模型的建立[J].中国现代医学杂志,2013,23(27):11-16.
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