| The research backgrounds Lung cancer has become the malignant tumor with the highest incidence in the world,and also the malignant tumor with the highest incidence in China.Non-small cell lung cancer is the most common pathological type of lung cancer,and Epidermal Growth Factor Receptor(EGFR)mutation is the most common pathogenesis of non-small cell lung adenocarcinoma in China.For example,the first-generation targeted drug Gefitinib,with a total effective rate of over 95% and a total median survival period of over 37 months,is still one of the preferred drugs in clinical practice.However,clinical observation showed that in the treatment of lung cancer with EGFR-TKI targeted drugs,the incidence of common adverse reactions skin-rash was the highest,which generally appeared within 1-2 weeks after treatment and peaked at 4-6 weeks.Moderate to severe skin rashes are most common clinically,which can affect the quality of life of patients and even interrupt treatment.Currently,the treatment methods for skin rash caused by targeted drugs are limited,mainly including local treatment and systematic treatment,but the long-term effect is not very obvious,and the long-term use of antibiotics is prone to occur,such as hepatorenal toxicity.EGFR-TKI cause skin reactions is mainly influence the formation of cutin cell proliferation and differentiation process,causes the skin cutin layer,with dry skin desquamation,loss of skin moisture,cause skin barrier function obstacle,eventually cause skin inflammatory reaction,recruit a large number of inflammatory cytokines and chemokines,cause skin helps inflammatory cycle.Therefore,to find an intervention strategy that does not affect the anti-tumor effect of EGFR-TKI,but also can improve side effects(such as skin rash)is the key to improve the quality of life of patients and ensure the smooth implementation of treatment.The prescription of "Qi Yin Three-liang-Three" is strict compatibility and proper medication,and the main treatment is "benefiting qi and blood,clearing heat and detoxifying".Through observation of skin rashes induced by EGFR-TKI targeted drugs,it was found that skin rash in patients was dry and itchy,even chapping,accompanied by fatigue,shortness of breath,and irritability,etc.The tongue image was mostly dark red color,less moss,and more heavy and thin pulse,with qi deficiency and toxic accumulation and desiccative heat knot in blood,and a new treatment method of "invigorating qi and blood,clearing heat and detoxifying" was proposed.Through previous clinical case collection,it has been confirmed that " Qi Yin Three-liang-Three" can significantly improve the effect of EGFR-TKI targeting drug-related rashes without other toxic and side effects.In order to further study the anti-rash mechanism of the EGFR-TKI targeted drugs,basic experimental studies were carried out.The research purposes Since there is no suitable rashes animal model induced by EGFR-TKI at home and abroad,it first established rash animal model induced by EGFR-TKI.Based on the successful establishment of rash animal model,the mechanism of Chinese medicine to improve EGFR-TKI-related rashes was further explored.The research methods This study is divided into five experiments: Experiment 1: The establishment of an animal model of gefitinib-induced rash.The treatment by lavage administration with different doses gefitinib in female BN rats,by observing the rat skin rash appears,cutin cell proliferation and differentiation of formation,the skin's barrier function and related inflammatory cells and the expression of inflammatory factor,combined with clinical patients with EGFR-TKI induced skin rash appear time and mechanism,etc.Experiment 2: The effect of "Qi Yin Three-liang-Three " on body weight,food intake and liver function of animal model with gifetinib-induced rash.The body weight of rats in each group was measured regularly and the biochemical indexes related to liver function in the blood of rats were analyzed.Experiment 3: The experimental study of "Qi Yin Three-liang-Three" on skin keratinocytes apoptosis in skin rash animal model.Through immunohistochemistry and HE staining,the proliferation and differentiation of keratinocytes were compared after TCM treatment in skin rash animal model.Experiment 4: The experimental studies on improvement of skin barrier function and skin inflammation in the animal model after treatment with "Qi Yin Three-liang-Three".By evaluating the pruritic behavior of rats,skin moisture loss,skin inflammatory status score and the number of related inflammatory cells in blood routine,the barrier function of the skin and the improvement of skin inflammation in rats after "Qi Yin Three-liang-Three" treatment.Experiment 5: The study on the mechanism of "Qi Yin Three-liang-Three" on the secretion of inflammatory factors related to macrophages in the skin rash induced by gefitinib.The immunohistochemistry,flow cytometry and skin inflammatory protein chip were used to compare the infiltration of macrophages and the expression of related inflammatory factors in the skin of rats after treatment with "Qi Yin Three-liang-Three" medicine.The experimental results Experiment 1: The establishment of an animal model of gefitinib-induced rash.By analyzing the occurrence time of BN rats' rashes and pruritus,it was found that the occurrence time of BN rats was consistent with that of clinical patients after taking targeted drugs.Through to the cutin cell formation,the skin barrier dysfunction and skin infiltration and expression of inflammatory cytokines in the comprehensive analysis of the treatment found induced BN rats and the mechanism of a skin rash clinical targeted drug leads to rash mechanism has a certain consistency,therefore,ultimately successful building skin-rash animal model induced by geifitinib.Experiment 2: The effect of "Qi Yin Three-liang-Three" on body weight,food intake and liver function of animal model with gifetinib-induced rash."Qi Yin Three-liang-Three" can improve the weight loss of the model rats,and it does not affect the liver function of the model rats.Experiment 3: The experimental study of "Qi Yin Three-liang-Three" on skin keratinocytes apoptosis induced by gefetinib in animal model of skin rash.By comparing the expression of related positive cells in the skin of the rats in each treatment group and the thickness of the epidermis layer of the skin,and conducting quantitative analysis,it was found that "Qi Yin Three-liang-Three" had a good effect on improving the hyperplasia disorder and excessive apoptosis of keratinocytes in the skin.Experiment 4: The experimental studies on improvement of skin barrier function and skin inflammation in the animal model after treatment with "Qi Yin Three-liang-Three".Through urticant ethology score,skin moisture loss situation,"Qi Yin Three-liang-Three" can improve skin barrier function obstacle,through study of the grade of inflammatory skin and routine blood related inflammatory cells,and it found that "Qi Yin Three-liang-Three" can improve the skin inflammatory state,and reduce the number of inflammatory cells in the blood.Experiment 5: The study on the mechanism of "Qi Yin Three-liang-Three" on the secretion of inflammatory factors related to macrophages in the skin rash induced by gefitinib.Through quantitative analysis of the infiltration of related macrophages and the expression of inflammatory cytokines in the skin of rats in each treatment group,the improvement of skin inflammation by "Qi Yin Three-liang-Three" was mainly related to the reduction of the infiltration of macrophages in the skin and the secretion of related inflammatory factors,and the IL-17 signaling pathway were most closely related.Conclusion "Qi Yin Three-liang-Three " can effectively repair the rash,reduce the excessive apoptosis horniness cells,improve skin rash model rats skin barrier function,and can reduce the number of inflammatory cells in the blood,at the same time reduce the infiltration of macrophages in the inflammatory factors and its associated cells,eventually to improve the EGFR-TKI induced skin rash,and its main is adjusted by IL-17 signaling pathways. |
PDF Full Text Request