Meta Analysis Of Fermented Cordyceps Sinensis Powder In The Treatment Of COPD And Its Mechanism On COPD Rats

Objective:To systematically evaluate the clinical efficacy of fermented Cordyceps sinensis powder in the treatment of chronic obstructive pulmonary disease;The model of COPD rats was established by cigarette smoke fumigation combined with intratracheal instillation of lipopolysaccharide,to compare the effects of different fermented Cordyceps sinensis powder on COPD rats,select the better process,and further explore the mechanism of fermented Cordyceps sinensis powder on COPD rats.Method:1.The clinical randomized controlled trials of fermented Cordyceps sinensis powder preparation in treating COPD were reviewed from CNKI,VIP,WanFang,CBM,PubMed,EBSCO and the Cochrane Library database until February 12,2019.RevMan 5.3 software was used for meta-analysis after screening literature,extracting data and evaluating quality according to Cochrane system evaluation methods.2.The COPD rat model was established by cigarette smoke fumigation combined with intratracheal instillation of lipopolysaccharide.The rats were fed with high(1.2g·kg^-1)and low doses(0.3g·kg^-1)of fermented Cordyceps sinensis powder of six different processes in batches.The lung function of rats was detected by WPB PLT-UNR-RT-2 small animal lung function detection system.The pathomorphological changes of lung tissue in rats were detected by HE staining and AB-PAS staining.3.The COPD rat model was established by cigarette smoke fumigation combined with intratracheal instillation of lipopolysaccharide.The rats were fed with low(0.3g·kg^-1),medium(0.6g·kg^-1),high dose(1.2g·kg^-1)of fermented Cordyceps sinensis powder A and F that were selected.The levels of IL-8 in serum,TNF-?,IL-6,IL-4,IFN-?in lung tissue,SOD,MDA,CAT in serum and SOD,CAT in bronchoalveolar lavage fluid of COPD rats were detected by kit method,and the pathomorphological changes of lung tissue in rats were detected by HE staining and AB-PAS staining4.The lung tissue protein was extracted and the protein sample was analyzed by Nano-LC-LTQ-Orbitrap technique.Protein identification using Protein Discovery software,relative quantitative and qualitative Analysis using SIEVE software.Using Uniprot database?https://www.uniprot.org/?to find protein-related information.Result:1.21 randomized controlled trials involving 1772 patients were included finally.Fermented Cordyceps sinensis powder?Cs-4?preparation can improve the total effective rate of patients with stable COPD[RR=1.27,95%CI?1.19,1.35?,P<0.00001],and reduce serum TNF-?content[MD=-10.86,95%CI?-15.15,-6.56?,P<0.00001],improve serum SOD content[MD=231.95,95%CI?52.92,410.97?,P=0.01],improve FEV1[MD=0.25,95%CI?0.08,0.42?,P=0.004],improve FEV₁%[MD=9.17,95%CI?5.01,13.32?,P<0.0001],reduce SGRQ score[MD=-6.02,95%CI?-8.97,-3.07?,increase serum IgA levels[MD=0.49,95%CI?0.40,0.58?,P<0.00001],improve peripheral blood Th17/Treg[MD=0.12,95%CI?0.05,0.18?,P=0.0002],improve arterial blood PaO₂[MD=3.54,95%CI?0.70,6.39?,P=0.01];there was no difference between the experimental group and the control group in improving TGF-?1,FVC,FEV1/FVC,PaCO2,and 6MWT.Fermented Cordyceps sinensis powder?Cs-4?preparation can improve FVC in patients with acute exacerbation[MD=0.56,95%CI?0.41,0.71?,P<0.00001],there is no difference between the experimental group and the control group in improving FEV₁.2.The PEF,EF50 and Cdyn of COPD model group rats were significantly decreased?P<0.01,P<0.05?,and LR was increased?P<0.05?.The high dose of CS F could decrease the LR level?P<0.05?;the high doses of fermented Cordyceps sinensis powders could increase the PEF and EF50 values in varying degrees,the high doses of CS A,CS D,CS E and CS F could increase Cdyn,high doses of CS B,CS C,CS D and CS E had a tendency to reduce LR,but it was not statistical significance.Low doses of CS A,CS D,CS E and CS F could increase PEF in varying degrees.Low doses of CS D,CS E and CS F could increase EF50 in varying degrees.Low doses of fermented Cordyceps sinensis powders could increase Cdyn.Low doses of CS A,CS D,CS E and CS F could reduce LR value in varying degrees,but there is no statistical significance.The results showed that the high doses of CS F could improve the LR value of COPD rats,but the high and low doses of other different processes fermented Cordyceps sinensis powders had no significant effect on the lung function of COPD rats.In the control group,the bronchial mucociliary columnar epithelial cells were arranged neatly,no goblet cells were observed,and less inflammatory cells infiltrated in the small bronchial wall and the surrounding area,and the alveolar structure was intact.In COPD model group,the epithelium of bronchial mucosa was necrotic,exfoliated and disordered,the folds of mucosa increased and towered,protruded into the lumen,the lumen became smaller and narrower,the mucus secreted in the lumen,obvious inflammatory cells infiltrated in the small bronchial wall and the surrounding area,smooth muscle had hypertrophied,partial alveolar had ruptured,alveolar cavity had enlarged and fused,appeared pulmonary bullae,consistent with the characteristic pathological changes of COPD.In the DEX group,there was no abnormal exfoliation of bronchial mucosal epithelium,few inflammatory cells in the wall of the small bronchus and the surrounding area,the lumen did not become small and narrow,there was no mucus secretion in the cavity,and the alveolar cavity was slightly enlarged and fused.The bronchial mucosal epithelium of rats treated with different processes fermented Cordyceps sinensis powders had exfoliated and disordered,mucosal folds were higher,lumen became smaller and narrower,inflammatory cells infiltrated the wall and the surrounding area,and alveolar cavity had enlarged and fused changes in varying degrees,which was relatively mild compared with the model group.Combined with the HE staining score,the pathological section score of COPD model group was significantly higher than that of control group?P<0.01?,the HE staining scores of the high dose groups of the different processes fermented Cordyceps sinensis powders decreased,but there was no statistical significance,while the HE staining score of the low dose group of CS A and F decreased significantly?P<0.01?.The secretion of glycogen in the small bronchial lumen in the control group was very little,the secretion of glycogen significantly increased in the COPD model group?P<0.01?,decreased significantly in high dose group of CS B,CS D,CS E and CS F?P<0.01,P<0.05?,and decreased significantly in low dose group of CS A,CS D,CS E and CS F?P<0.01,P<0.05?.3.The levels of IL-8 in serum and TNF-?and IL-6 in lung tissue homogenate of rats in COPD model group were significantly higher than those in control group?P<0.01?.The levels of IL-8 in serum and IL-6 in lung tissue homogenate of rats in low,medium and high dose groups of CS F were significantly lower?P<0.01,P<0.05?,and the level of TNF-?in lung tissue homogenate of rats in low dose group of CS F were significantly lower?P<0.05?,the level of IL-6 in lung tissue homogenate of rats in high dose group CS A were lower?P<0.01?which compared with model group.The IFN-?level in the lung tissue homogenate of rats in COPD model group was lower than that in the control group?P<0.05?.Compared with the model group,the IFN-?level in the low and middle dose groups of the CS A increased?P<0.01,P<0.05?;the levels of IL-4 and IL-4/IFN-?in the lung tissue homogenate of rats in COPD model group were higher than those in the control group?P<0.01,P<0.05?,the levels of IL-4 in low and medium dose groups of CS F were lower?P<0.05?,and the levels of IL-4/IFN-?in each dose groups of CS A and CS F were lower?P<0.01,P<0.05?which compared with model group.The content of MDA in serum of rats in COPD model group was higher than that in the control group?P<0.05?,compared with model group,the content of MDA in low dose group of CS A and low and medium dose group of CS F were lower?P<0.01,P<0.05?.The contents of SOD and CAT in serum and bronchoalveolar lavage fluid of rats in COPD model group were lower than those in control group?P<0.01,P<0.05?,the contents of SOD and CAT in serum and bronchoalveolar lavage fluid of rats in medium dose group of CS F were significantly higher?P<0.01,P<0.05?,the contents of SOD in bronchoalveolar lavage fluid of rats in high dose group of CS A were significantly higher?P<0.01?,and the contents of CAT in serum of CS A medium and high dose group were significantly higher?P<0.01?which compared with model group.In DEX group,smooth muscle of lumen slightly proliferated and alveolar fusion was not obvious.The mucus secretion,stenosis and bronchial mucosal injury of rats in the medium and high dose groups of CS A and the low and medium dose groups of CS F were significantly improved than those in the model group.the bronchial injury in the low dose group of CS A and the high dose group of CS F was not significantly improved compared with the model group.HE staining scores of rats in medium,high dose group of CS A and low,medium dose group of CS F were significantly decreased?P<0.01,P<0.05?,and glycogen secretion of rats in medium dose group of CS A and low dose group of CS F was decreased?P<0.01,P<0.05?.4.Proteomic analysis showed that compared with the model group,the differentially expressed proteins were mainly involved in epithelial-mesenchymal transition,extracellular matrix,cytoskeletal protein-related airway remodeling,injury and apoptosis,immune inflammation,biological oxidation,energy metabolism,sugar metabolism,lipid metabolism and other related proteins.Conclusion:1.Fermented Cordyceps sinensis powder?Cs-4?is efective in treating COPD,especially in improving the total effective rate,reducing the level of inflammatory factor TNF-?,increasing the activity of antioxidant enzyme SOD,improving the lung function and immune function related indicators in stable COPD patients.Limited by the quality and quantity of the included studies,large sample and high quality clinical studies are still needed to confirm the conclusion.2.The six different processes of fermented Cordyceps sinensis powder did not significantly improve the lung function of COPD rats,but it could reduce the degree of pathological damage and mucus hypersecretion of lung tissue in COPD rats in varying degrees.The effects of CS A and F were better.3.CS A and CS F can play a preventive and therapeutic role in COPD rats by reducing the degree of pathological damage and mucus hypersecretion of lung tissue,reducing the level of proinflammatory factors in COPD rats,regulating the imbalance of Th2/Th1 and reducing the degree of oxidative damage,and the effect of CS F is more prominent4.S100 A11 calcium binding protein,?-catenin,collagen IV,cathepsin B,cathepsin D and other proteins may be the target of fermented Cordyceps sinensis powder to prevent and treat COPD.