| Sepsis is a life-threatening organ dysfunction caused by the host's imbalance in response to infection,which is a serious threat to human health.The systemic inflammatory response caused by infection runs through the course of sepsis.Due to the significant susceptibility of lung tissue to inflammatory mediators,lung is the earliest target organ involved in sepsis.Acute respiratory distress syndrome(ARDS),is characterized by progressive respiratory failure and intractable hypoxemia.Among the several causes of ARDS,sepsis is the most common extrapulmonary factor,accounting for 40%-60%.With the application of mechanical ventilation such as low tidal volume ventilation,prone position ventilation and lung dilatation,the treatment of ARDS has made great progress,but the mortality of severe ARDS is still as high as 70%.There is no record of sepsis in the ancient books of traditional Chinese medicine.According to the clinical manifestations of infection and inflamnation,sepsis is classified as febrile disease.Lung is the delicate viscera,the cover of the five intermal organs,and is most vulnerable to external evil invasion.Toxic pathogens obstruct in the lungs,the eliminating and descending function of the lung is abnormal,the qi cannot spread throughout the body,and a large number of pathological products are cohesive,aggravating the systemic inflammatory reaction.The comprehensive effect of Tongfu Xiefei on ARDS was evaluated by meta analysis.According to the theory of"six Fu organs are used to pass,descending to pass","cold the hot ones,clear the warm ones",Self-made Tongfu Xiefei decoction(TFXF)was used for simultaneous treatment of lung and intestine.Clinical trial was conducted to observe the effect of Tongfu Xiefei decoction on oxygenation,intestinal mucosal barrier and inflammatory mediators in patients with sepsis-related ARDS.In view of the fact that the NLRP3/Caspase-1/IL-1? signal axis is a key signal pathway involved in the innate immune system and the inflammatory progression of sepsis,further animal experiments were conducted to observe the effects of Tongfu Xiefei decoction on the general condition,72h survival rate,and the expressions of inflaumatory factors such as NLRP3,Caspase-1,IL-1? and IL-8 in sepsis-related ARDS rats by molecular biological techniques such as ELISA,Western blot and so on.In order to provide a scientific theoretical basis for the research and development of the method of Tongfu Xiefei in the treatment of septic-related ARDS.Objective:[1]To systematically evaluate the clinical randomized controlled study of integrated traditional Chinese Tongfu Xiefei decoction in the treatment of ARDS,so as to provide theoretical basis for the application of traditional Chinese medicine in ARDS.[2]Tongfu Xiefei decoction was used in clinic to evaluate its clinical effect and to explore its effect on oxygenation,intestinal mucosal barrier function and the level of inflammatory mediators in patients with sepsis-related ARDS.[3]To clarify whether the molecular mechanism of Tongfu Xiefei decoction in the treatment of sepsis-related ARDS is related to affecting the expression of key molecules in the NLRP3/Caspase-1/IL-1? signal axis by establishing an animal experimental model of sepsis-related ARDS.Methods:[1]Randomized controlled studies on the treatment of ARDS with the method of Tongfu Xiefei were searched from January 1st,2001 to June 30th,2019.Finally,27 studies were included.In-hospital mortality,incidence of complications(abdominal distension,ventilator-associated pneumonia,watery airway secretions,stress ulcer),clinical curative effect,duration of mechanical ventilation,ICU hospital stay,APACHE ? score,Murray lung injury score,oxygenation index,pressure of carbon dioxide,expression of inflammatory mediators(C-reactive protein,tumor necrosis factor-?,interleukin-6,interleukin-2,interleukin-8),and the influence of ventilator paraneters(peak airway pressure,airway plateau pressure,mean airway pressure,airway resistance,lung compliance)were observed with the method of Tongfu Xiefei.The risk ratio(RR)of 95%confidence interval(Cl)is used to describe the general measure of the correlation between binary classification results.Mean and standard deviation are used in the continuity variable.Random effect models were built according to Mantel-Haenszel method.Statistical heterogeneity was evaluated by Cochrane Q and I2 statistics.[2]A total of 40 patients with sepsis-related ARDS,were collected from department of Intensive Care Unit,affiliated hospital of Nanjing University of Chinese Medicine,from March 2016 to March 2018,which accorded with the syndrome of phlegm-heat obstructing the lung.The patients were randomly divided into the control group and the experimental group.The experimental group was given Tongfu Xiefei non-decoction granules:rhubarb 12g,Fructus Aurantii 12g,Magnolia officinalis 9g,Fructus Scutellariae 20g,mulberry bark 20g,green bark 12g,mixed with 100ml warm water,twice a day.The control group was given nasal feeding with constant temperature warm water.The course of treatment in both groups was 7 days.The oxygenation index,intestinal mucosal permeability index(serum diamine oxidase,malondialdehyde)and the levels of inflammatory mediators(serum tumor necrosis factor-?,interleukin-6)were compared between the two groups after 0 day,4 days and 7 days.28-day cumulative mortality of the two groups was also calculated.[3]The sepsis model was established by intraperitoneal injection with LPS,and the oxygenation index<200mmHg was used as the criterion to evaluate the complication of sepsis-related ARDS.The general condition and vital signs of rats were observed,and the expressions of key molecules in NLRP3/Caspase-1/IL-1? signal axis and inflammatory mediators such as IL-8,HMGB1 and IL.27 were detected by ELISA,and Western Blot methods,so as to explore the regulatory mechanism of Tongfu Xiefei decoction on sepsis-related ARDS.Results:[1]The systematic review study found that the combination of traditional Chinese medicine in the treatment of ARDS could significantly reduce the in-hospital mortality of ARDS patients and the incidence of complications such as abdominal distension,stress ulcer,ventilator-associated pneumonia and airway watery secretion.For the treatment of ARDS,the eombination of traditional Chinese medicine with the strategy of Tongfu Xiefei had outstanding advantages in reducing APACHE ? score,lung injury score,improving pulmonary oxygenation,reducing the expressions of inflammatory mediators,reducing the time of mechanical ventilation,improving respiratory mechanics and so on.[2]Clinical study found that the oxygenation index in the Tongfu Xiefei treatment group was significantly higher than that in the control group after 4 days and 7 days of treatment(P<0.05).After 4 days of treatment,the level of serum MDA in the treatment group was significantly lower than that in the control group(P<0.05).After 7 days of treatment,the levels of serum DAO and IL-6 in the treatment group were significantly lower than those in the control group(P<0.05).However,there was no significant difference in the expressions of TNF-? and NO between the two groups.There was no significant difference in 28-day cumulative mortality between the two groups either(P=0.563).[3]Animal experimental study showed that the survival rate of rats in the Tongfu Xiefei decoction group was significantly better than that in the model group(P<0.05).The results showed that Tongfu Xiefei decoction could effectively inhibit the expressions of inflammatory factors HMGB1,IL-1?,IL-8 and IL-27 in peripheral serum and lung tissue of sepsis-related ARDS rats(P<0.05).The inhibitory effect of high dose Tongfu Xiefei group was more obvious(P<0.05).Western Blot results showed that the expression of NLRP3 protein in the model group was significantly higher than that in the control group,and the expression of NLRP3 in the large and low dose TFXF groups was lower than that in the model group.The expression of activated Caspase-1 p20 protein in the model group was significantly higher than that in the control group.After the intervention of Tongfu Xiefei decoction,the expression of Caspase-1 p20 in the high and low dose TFXF group was lower than that in the model group.The expression of HMGB1 protein in the model group was significantly higher than that in the control group.After intervention with Tongfu Xiefei decoction,the expression of HMGB1 protein in the low-dose TFXF group did not decrease significantly.The expression of IL-1?,IL-8 and IL-27 protein in the model group was significantly higher than that in the control group,and the expression of IL-1?,IL-8 and IL-27 protein in the high and low dose TFXF group was significantly lower than that in the model group.The high-dose TFXF group had a significant inhibitory effect on IL-1?expression.Conclusions:[1]The results of Meta analysis showed that Tongfu Xiefei treatment could effectively inhibit the growth of pathogenic bacteria,reduce the absorption of endotoxin,relieve abdominal distension caused by gastrointestinal dysfunction,prevent bacterial migration and repair the damaged gastrointestinal mucosal barrier.It can clear endotoxin,reduce the permeability of pulmonary capillary,effectively improve the symptoms of pulmonary edema,which is conducive to the relief of ARDS,so as to reduce ventilator supportive parameters,reduce airway resistance and improve oxygenation in patients with ARDS.The mechanism of Tongfu Xiefei therapy in the treatment of AR/DS may be related to the reduction of the accunulation of inflammatory mediators in the lungs and regulation of the balance between pro-inflammatory mediators and anti-inflaumatory mediators in the body.[2]Clinical studies suggest that Tongfu Xiefei therapy can inhibit the inflammatory reaction of sepsis-related ARDS patients to some extent,reduce the lung injury caused by excessive inflammatory reaction and improve oxygenation.Tongfu Xiefei therapy can also reduce lipid peroxidation and oxidative stress,reduce the release of intestinal endotoxin,protect the integrity of intestinal mucosal barrier,and then reduce the occurrence of lung injury caused by intestinal dysfunction.[3]Animal experimental studies showed that Tongfu Xiefei decoction could significantly inhibit the expressions of proteins of NLRP3 inflammatory bodies in rats with sepsis-related ARDS,and further regulate the synthesis of NLRP3 inflammatory bodies.Tongfu Xiefei decoction could also inhibit the activation of Caspase-1 and the protein expressions of downstream inflammatory mediators such as IL-1?,IL-8,IL-27 and HMGB1. |
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