| Objective:The purpose of this study is to promote rational use of Chinese and chemical drugs that based on ascending, descending, floating and sinking natures. Firstly, analysis the characteristics of Chinese Medicine treating IPF combined with chemical drugs by summarize related clinical reports. Then, study the difference in efficacy、metabolism and bone protection when ascending and floating medicine Ephedra, sinking and descending medicine Schisandra respectively combined with DXM treating IPF. Finally, explore a new research model and approache when combined with traditional Chinese medicine.Methods:(1) Theoretical research:First, search for the related documents about Chinese medicine in combination with chemical drugs for the treatment of IPF from the China national knowledge internet, Wanfang, VIP database and Chinese Biomedical Literature Database. The key words are "IPF, integrative medicine". And period is 2000-2015. Second, establish a Chinese medicine characteristics database by EPIData3.02. Third, analysis and mine data the four properties, five flavors, meridian tropism, ascending descending floating sinking and effect from the characteristics of Chinese medicine database.(2) Experimental study on efficacy:Wistar rats of SPF level (n=106) were chosen and divided randomly into the sham-operation group, model group, Ephedra group, Schisandra group, Ephedra combined with DXM group, Schisandra combined with DXM group and DXM group. The model of Idiopathic Pulmonary Fibrosis was established by using instillation of blemycin (7 mg/kg). The samples of each group were collected on the 7th and 8th day. Observe the pathological changes of lung tissue by HE staining and the expression of HIF-1α、PDGF、PEDF and endostatin in rats serum by ELISA.(3) Metabolism experimental research:35 rats were randomly divided into seven groups.28 days later, prepared liver microsomes with fresh liver using calcium precipitation, observed CYP3A activity by detecting erythromycin N-demethylase activity and detected the expression of CYP3A4, mRNA by RT-PCR.(4) Experimental study of bone protection:Wistar rats of SPF level (n=37) were chosen and divided randomly into the sham-operation group, model group, Ephedra combined with DXM group, Schisandra combined with DXM group and DXM group. The model of Idiopathic Pulmonary Fibrosis was established by using instillation of blemycin (7 mg/kg). The samples of each group were collected on the 7th and 8th day. Observe the pathological changes of bone tissue by HE staining and the expression of Ca、P、BALP and TRACP.Results:(1) Theoretical research:A collection of 80 clinical reports about the compatibility of Chinese and chemical medicine treating IPF. There are 111 herbs combined with Western medicine and the drug characteristics as follows:Four properties, warm in nature 40.7%>cold 35.5%. Five tastes, bitter tastes 33.7%> sweet 28.1%> acrid 25.3%. Channel entry, mainly the lungs by 23.5%. Ascending descending floating and sinking natures, sinking and descending medicine53.0%> ascending and floating medicine 40.0%. Efficacy, among 41 herbs that frequency of more than 5 times, tonic medicine 36.9%>blood circulation drugs 28.0%.(2) Experimental study on efficacy:①HE staining showed obvious pathological changes of inflammatory infiltration and fibrosis in IPF lung tissue of rats, according to alveolitis and pulmonary fibrosis score level. Model group, treatment group and sham-operation group showed significant differences (P<0.05), and each treatment group and the model group also has a significant difference (P<0.05).② The expression of HIF-1α、PDGF、PEDF and endostatin in each modeling group were obviously increased compared with the sham-operation group(P<0.01); The contents of HIF-la on the 28th day were higher than those on the 7th day, and the contents of PEDF and endostatin were the opposite.③ The expression of HIF-laand PDGF obviously decreased in Ephedra group and Schisandra group compared with the model group(P<0.05),and the expression of PEDF and endostatin increased; The expression of HIF-1α and PDGF increased in Ephedra group on the 28th day than those on the 7th day, but the expression of PEDF and endostatin on the 28th day were lower than those on the 7th day; In the Schisandra group the expression changes of HIF-1α、PDGF、PEDF and endostatin were the opposite compared with the Ephedra group. ④ The expression of HIF-1α and PDGF obviously decreased in Ephedra combined with DXM group and Schisandra combined with DXM group compared with the model group(P<0.05), and the expression of PEDF and endostatin increased; In Schisandra combined with DXM group the contents of HIF-la were obviously higher than those in DXM group and the contents of PEDF were obviously lower(P<0.05).(3) Metabolism experimental research: ①Compared with the sham group, model group and Ephedra group ERD activity showed no significant changes. Schisandra group, DXM group and Ephedra+DXM group, Schisandra+DXM group ERD activity was increased with a significant difference (P<0.05). Compared with DXM group, Ephedra group, Schisandra group activity at a low level with a significant difference (P<0.05), Ephedra+DXM group activity group increased compared with Ephedra, but there was no significant difference between DXM group. Schisandra+DXM group ERD activity increased compared with Schisandra group, but were lower than the DXM group and showed significant differences (P<0.05). ② Compared with sham group, model group, Ephedra group CYP3A4 mRNA expression showed increase trend, but there was no significant difference between groups. Schisandra group, DXM group and Ephedra+DXM group, Schisandra+ DXM group significantly promote the CYP3A4 mRNA expression (P<0.05). Ephedra group, Schisandra group induce CYP3A4 mRNA expression was weaker than DXM group, and the difference was significant (P<0.05). Ephedra+DXM group and DXM group induce CYP3A4 mRNA expression was no significant difference, Schisandra+ DXM group induce CYP3A4 mRNA was lower than DXM group and showed significant differences (P<0.05).(4) Experimental study of bone protection:① IPF rats showed healing slowly of surgical wounds, and weight gain is not obvious in DXM group. Individual rats appear neck chest swollen, severe hair removal, dull eyes, hair standing, arched back, abdominal swelling and other symptoms. Compatibility groups showed different degrees of hair removal, slow weight gain and other symptoms. Femoral HE staining was observed that the number of trabecular bone significantly reduced, sparse fracture, the bone marrow cavity increased significantly, and a larger blank area appears in DXM rats. When combined with DXM Ephedra and Schisandra, trabecular bone significantly increased and the bone marrow cavity volume smaller than the DXM group.② Bone metabolic biochemical results as follows, After 28 days of administration, DXM serum Ca levels decreased and P content increased compared with sham-operated group. Compatibility group may be elevated Ca levels, decreased P levels, and has a significant difference (P<0.05). DXM group BALP expression levels reduced, and increased TRACP levels. Compatibility group can be increased BALP content, reduced TRACP expression, and compared with DXM group had a significant difference (P<0.01).Conclusion:①The clinical literature analysis shows as follow:there are many clinical uses of treating IPF by Chinese combined with Chemical medicine. The main type of Chemical drugs is glucocorticoid.The main Chinese medicine characteristics are warm in nature, bittersweetacrid tastes and mainly the lungsin Channel entry. ②The experimental study on efficacy shows as follow:The regulatory factors on angiogenesis lose their balance in rats with Idiopathic Pulmonary Fibrosis. Ephedra and Schisandra can achieve the selective inhibition to the expression of HIF-1α、 PDGF, and selectively promote the expression of PEDF、endostatin. When combined with DXM, the selectivity might be weakened in different pathological stages. ③The metabolism experimental research shows as follow:CYP3A activity and CYP3A4 mRNA expression has differences when Ephedra, Schisandra combined with DXM. Ephedra is not metabolized by CYP3A, and Schisandra can induce CYP3A activity and CYP3A4 mRNA expression after repeated doses. Schisandra and DXM competitive induce CYP3A activity, and reduced CYP3A4 mRNA expression in Schisandra+DXM group, which resulting in CYP3A activity decreased. This metabolic difference illustrates the metabolism of angiogenic factors differentially expressed.④The experimental study of bone protection shows as follow:When using DXM treating IPF, bone tissue form in rats showed osteoporosis. The abnormal bone metabolism of low bone formation and high bone resorption may be changed by ascending and floating medicine Ephedra, sinking and descending medicine Schisandra. It shows that there is a bone protective effect when Ephedra, Schisandra combined with DXM treat IPF rats. |
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