Experimental Study Of Pentoxifyline On Treatment Of Collagen-induced Arthritis In Rats

Objective:To evaluate the efficacy and safety of pentoxifyline on the treatment of collagen-induced arthritis in rats and to supply theoretical basis for exploring new treatments for inflammatory arthritis. Methods:Rat arthritis was setup by injecting bovine II collagen (BIIC) to Wistar rats. The rats were randomly divided into four groups including normal control group, CIA control group treated with normal saline, indometacin group and pentoxifyline (PTX) group. The body weight, the hind paw volumes, the arthritic index of all rats at different time points were observed and measured. At the end of experiment the radiographic changes and the synovial pathology score of rat ankle joints were evaluated. The changes of index of all rats were analyzed separately. The treatment role of PTX on CIA inflammation was analyzed. Results:1. The model of collagen-induced arthritis was constituted successfully at 11-13 days after first immunization of type II collagen. The toes of Wistar rats turned red and swollen slightly. At the 17^th day, the swelling of dorsum of hind feet and ankle joints deteriorated. The sole of feet got thick with the ability of activity and appetite decreased.2. The weights of rats in all groups except normal control group were declined at the 11^th day after first immunization. After administration, the rat weights of PTX group were higher than that of CIA group (P<0.01) and no significant difference was found between PTX group and normal control group since week three. Whereas the rat appetite in indometacin group was decreased since week two, the weights were increased slowly and significantly lower thanthat in normal control group (P<0.01). No difference was found between indometacin group and CIA group.3. The degree of swelling of ankle joints in PTX group was decreased since the 17^th day. At week five, the volumes of hind paw in PTX group and indometacin group was not different from that in normal control group (P>0.05). At the 35^th day, the arthritis index of two groups was 2.52±0.38 and 3.11±0.44, respectively. Both of them were lower than that of CIA group (P<0.01). No statistical difference was found between PTX group and indometacin group.4. Histopathologic results: Compared with CIA group, the degree of synovial swelling of PTX group and indometacin group was decreased, synovial proliferation and inflammatory cell infiltrations were slight, and vascular hyperplasia and pannus were significantly declined. No cartilage erosion and necrosis were found. The pathological score of PTX group and indometacin group was significantly decreased (P<0.01) .5. Radiologic finding: The parenchyma of ankle joint was swollen and no osteoporosis and bone erosion were found in PTX group and indometacin group. Conclusion:1 .Pentoxifyline significantly ameliorates the symptoms of CIA rats, and inhibits the development of inflammatory swelling.2. Pentoxifyline can decline the severity of synovial proliferation and inflammatory cell infiltrations, and inhibit the cartilage erosion in pathology, with indicates pentoxifyline has anti-inflammatory effect.Objective:1. To compare the therapeutic effects and histopathologic changes of pentoxifyline, thalidomide, infliximab and etanercept on collagen-induced arthritis in rats.2. To evaluate serum TNF-α level of every group at different time point and to study whether the therapeutic effect of different reagent was achevied by decreasing serum TNF-α level.3. To evaluate the expression of MCP-1 and RANTES in the synovium of ankle joint and to analyze the role of MCP-1 and RANTES on the pathogenesis of CIA in rats.Methods:The CIA rats were randomly divided into different groups, including normal control group, CIA group treated with normal saline, pentoxifyline (PTX) group, thalidomide group, infliximab group and etanercept group. Several index (weight, volume of hind paw, arthritic index, radiography of ankle joint) was observed in different group. The histopathology of synovium was scored. The serum TNF-α level of every group at different time point was measured by ELISA. The expression of MCP-1 and RANTES was detected by immunohistochemistry.Results:1. The therapeutic effect: The rat weights were increased slowly on the first week after arthritis developing. Since the 21^st day the weights of PTX group were not different from that of normal control group, but since the 28^th day they werehigher than that of CIA group (P<0.01). There was no difference in comparison among groups. The volumes of hind paw in every treatment group were not stastistically differente from that in normal control group at the 35^th day (P>0.05). By comparison among groups, the volumes of hind paw of PTX group, thalidomide group and etanercept group were less than that of infliximab group (P<0.05) at the 21^st day. At the 42^nd day, the volumes of hind paw of PTX group were less than that of infliximab group and etanercept group (P<0.05). But during the course of the experiment the volumes of hind paw of each drug group were not different from that of CIA group (P>0.05). The arthritic index of each treatment group was less than that of CIA group from the 28^th day to the end. The inhibition of swelling in PTX group was strongestt.2. At the 48^th day, the rats were killed for pathological detection. The pathological changes of ankle joint in infliximab group and etanercept group were similar to that in CIA group and no difference in pathological score was found (P>0.05). While the pathological changes of ankle joint in thalidomide group and PTX group were alleviated. The pathological score in PTX group was 0.6±0.22 and less than that in CIA group (P<0.01). It was 1.3±0.98 in thalidomide group and similar to that in CIA group (P>0.05).3. At the 42^nd day, the rats were anesthetized for radiography. The parenchyma of ankle joint in each drug group was swelled. There was no osteoporosis and bone destroy were found in PTX group. In thalidomide group and etanercept group slight hyperosteogeny was observed in hind paw of rats, but no bone destroy was found. The bone destroy and osteoporosis were observed in infliximab group.4. The serum TNF-α level of every group was decreased since the 34^th day. The serum TNF-α level of infliximab group was less than that of CIA group (P<0.05). There was no difference between each drug group and normal control group (P>0.05) at the 48^th day. The TNF-α level of etanercept, thalidomide andPTX group was less than that of CIA group (P<0.05).5. At the 48^th day the rats were killed for immunohistochemistry. The cells expressing MCP-1 and RANTES were found in the interface layer of synovium and cartilage in CIA group. But no positive cell was found in normal control group. No positive cell of MCP-1 was observed in drug groups except etanercept group. As far as the expression of RANTES, the positive cells were found in etanercept, infliximab and thalidomide group. No cell expressing MCP-1 and RANTES was found in PTX group.Concluion:1. Among different treatment groups, PTX has the best effect on alleviating symptoms and increasing body weights of CIA rats. The suppression of swelling of PTX, thalidomide and etanercept was better than that of infliximab.2. Etanercept, thalidomide and PTX can decrease the serum TNF-α level, indicating PTX and thalidomide may take effect by inhibiting the serum TNF-α level.3. MCP-1 and RANTES are important in the pathogenesis of collagen-induced arthritis. PTX may play a protective role on joint erosion through regulating the expression of MCP-1 and RANTES.