| Background:Acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are common clinical critical illnesses with high mortality,rapid progression,and sequelae that pose a huge economic burden to individuals and society.The damage is widespread and far-reaching,and there is no specific treatment in the clinic.Another problem that needs to be solved is the difficulty of early recognition and low diagnosis rate of ALI/ARDS.Based on the theory of"interior and exterior between the lung and the large intestine",and based on years of clinical experience,he added flavor to the famous formula Xuan Bai Cheng Qi Decoction and created Xin Jia Xuan Bai Cheng Qi Decoction,which highlights the use of the lower method in the treatment of ALI/ARDS and has achieved significant clinical results.Current research shows that excessive inflammatory response is one of the important pathological mechanisms of ALI/ARDS,and TLR4/MyD88/NF-κB pathway is a key pathway in the inflammatory response,and several clinical and experimental studies have confirmed that Xuan Bai Cheng Qi Decoction inhibits inflammatory response by affecting this pathway,thus treating ALI/ARDS.Our team’s previous network pharmacology study also found that Xuan Bai Cheng Qi Decoction may act through the interleukin-related pathway in the treatment of ARSD.However,the effect of Xuanbai Chengqi Decoction on this pathway has not been reported.In this study,we firstly summarized the academic thought of Chao Enxiang a master of Chinese medicine,in treating acute diseases,and his valuable clinical experience in treating severe respiratory diseases by using the following method,and then further investigated the effect of Xinjia Xuanbai Chengqi Decoction on the TLR4/MyD88/NF-κB pathway in ALI rats to investigate its pharmacological mechanism We also attempted to explain the connotation of the theory of"interior and exterior between the lung and the large intestine" from the histological perspective.The clinical warning system was designed based on the MIMIC-IV database(Medical Information Mart for Intensive Care Ⅳ)to analyze the risk factors of ALI and to establish a prediction model and warning system in order to identify ALI/ARDS at an early stage and reduce its mortality.early intervention and reduce its mortality.1 Summary of experience of National Medical Master Chao EnxiangThrough a retrospective study,we reviewed the literature and books on the treatment of acute illnesses,especially respiratory illnesses,and collected relevant cases.We also interviewed Chao Enxiang,the master of Chinese medicine,and his academic successors to summarize the academic thought and clinical experience of Chao Enxiang,the master of Chinese medicine,in treating acute illnesses,especially respiratory illnesses,and to provide ideas for clinical prescriptions and medications.In the treatment of acute illnesses,National Medical Master Chao Enxiang emphasizes "treating the symptoms when it is urgent",prioritizes the elimination of evil,and gives the evil Qi a way out by taking advantage of the situation,especially in the treatment of acute and critical respiratory illnesses.Based on the theory of "the lung and the large intestine are on top of each other" and the academic thought of "the first thing to do is to get rid of the evil" by Chao Enxiang,the new formula Xuan Bai Cheng Qi Tang is made by adding flavor to Xuan Bai Cheng Qi Tang,which is more powerful than the original formula in promoting the lung and resolving phlegm,and the lung and intestine are treated together,with outstanding clinical efficacy.With its effect of clearing heat and resolving phlegm,promoting the rebellious lung qi in patients with acute lung injury(lung heat and solid evidence from the internal organs),and restoring the normal function of the lung in declaring and purging.2 Experimental studyObjective:2.1 To investipte the effects of Xinjia Xuanbai Chengqi Decoction on the expression of inflammatory factors,TLR4/MyD88/NF-κB pathway genes and proteins in serum and alveolar lavage fluid of ALI rats through the intervention of Xinjia Xuanbai Chengqi Decoction in Lipopolysaccharide(LPS)-induced acute lung injury rat model,and to clarify the effects of Xinjia Xuanbai Chengqi Decoction in the treatment of acute The possible mechanism of action of Xinjia Xuanbai Chengqi Decoction in the treatment of acute lung injury in terms of inflammation regulation.2.2 To search for possible biomarkers of acute lung injury by microbiomics and metabolomics,and to explain the connotation of the Chinese medicine theory that "interior and exterior between the lung and the large intestine".Methods:2.1 Rats were randomly divided into control group,model group,low-dose Chinese medicine group,medium-dose Chinese medicine group,high-dose Chinese medicine group,and western medicine group.All rats except the control group were intra-tracheally dosed with 4 mg/kg of LPS,and the control group was dripped with equal volume of saline.24 hours after the modeling operation the drug was administered starting from 24 hours after the modeling operation,and three different concentrations were gavaged in the Xinjia Xuanbai Chengqi Decoction Chinese medicine group,equal volume of distilled water was gavaged in the control group,the model group and the western medicine group,and the western medicine group was injected intraperitoneally,and equal volume of saline was injected intraperitoneally in the rest of the groups,and the volume of drug was 10 ml/kg/d.The drug was administered twice a day,and the material was taken after 3 days of continuous treatment.After 3 days of treatment,the rats were observed for body temperature,blood routine,blood gas analysis,pathological morphology,levels of inflammatory factors such as IL-1β,IL-6,IL-10,TNF-α in serum and alveolar lavage fluid,inflammatory cell count in alveolar lavage fluid,mRNA level expression of TLR4,MyD88,IRAK1,TRAF6,NF-κB in lung tissues,TLR4,MyD88,P-IKBa,IKBa,pNF-κB protein expression levels in lung tissue.2.2 The animals were modeled and grouped as in Chapter 3.The feces and serum of 5 rats in the control group,model group and high-dose Chinese medicine group were collected,and 16S rDNA high-throughput sequencing was used to detect changes in the fecal flora of rats,and Alpha diversity and Beta diversity were analyzed;liquid chromatography and mass spectrometry(LC-MS)was used to detect metabolites in the serum of rats,and enrichment analysis of metabolic pathways was performed.The enrichment analysis of metabolic pathways was performed by LC-MS.Results:2.1 The lymphocytes and neutrophils in the BALF of rats in the model group increased significantly,which was statistically significant compared with the control group(P<0.05),and the total cell count,lymphocytes and neutrophils in each treatment group decreased to different degrees compared with the model group,and all of them were statistically significant(P<0.05),among which the decreasing trend was more obvious in the high-dose Chinese medicine group.In the model group,IL-1β,IL-6 and TNF-α in serum and alveolar lavage fluid were significantly higher than those in the control group,and IL-10 was significantly lower than that in the control group.IL-10 in serum and alveolar lavage fluid was significantly increased,which was statistically significant(P<0.05).Compared with the control group,the expression of TLR4,IRAKI,TRAF6,MyD88 and NF-κB genes in lung tissues of the model group and each treatment group were elevated to different degrees.Compared with the model group,the expression of TLR4,IRAKI,TRAF6,MyD88,and NF-κB genes were significantly lower in each treatment group,with statistical differences(P<0.05).MicroRNA146a expression was down-regulated in lung tissues of the model group and each treatment group compared with the control group,and MicroRNA146a expression was elevated in lung tissues of each treatment group compared with the model group,which was statistically significant,and MicroRN A155 expression was up-regulated in lung tissues of the model group and each treatment group compared with the control group,and MicroRNA155 expression was up-regulated in lung tissues of each treatment group compared with the model group MicroRNA155 expression was decreased in all treatment groups,which was statistically significant.Compared with the control group,TLR4,MyD88,P-IKB-α/IKB-α and P-NF-κB protein expressions were increased in the lung tissues of the model group and each treatment group.Compared with the model group,the expressions of TLR4,MyD88,P-IKB-α/IKB-α and P-NFκB were significantly decreased in the low-dose Chinese medicine group,medium-dose Chinese medicine group and high-dose Chinese medicine group and the western medicine group,which were statistically significant.2.2 16S rDNA sequencing detected some possible biomarkers of acute lung injury.Multiple metabolites and some metabolic pathways detected by histology were associated with inflammatory response.Conclusion:2.1 Xinjia Xuanbai Chengqi Decoction can affect the condition of acute lung injury rats,up-regulate the expression of MicroRNA146a,down-regulate the expression of MicroRNA155,down-regulate the expression of genes and proteins related to TLR4/MyD88/NF-κB pathway,reduce the release of inflammatory factors IL-1β,IL-6 and TNF-α in serum and lung tissues,and suppress the inflammatory response,which may be the result of the treatment with Xinjia Xuanbai Chengqi Decoction.This may be one of the mechanisms of action of Xinjia Xuanbai Chengqi Decoction in the treatment of acute lung injury.2.2 The mechanism of action of Xinjia Xuanbai Chengqi Decoction on acute lung injury may be related to the improvement of intestinal flora,which improves the inflammatory response of lung tissue by regulating the levels of metabolites related to amino acid metabolism.Several metabolites and metabolic pathways were detected to be related to the inflammatory response,which explains to a certain extent the TCM theory that "the lung and the large intestine are in sympathy with each other".3 Clinical studyObjective:Based on MIMIC-Ⅳ,an intensive care unit database,we investigated the independent risk and protective factors affecting the prognosis of ALI patients,and established ALI risk prediction models,prognostic scales and early warning systems to achieve early identification and intervention.Methods:Clinical data were derived by retrospective,observational studies using diagnostic codes to screen the MIMIC-IV database of patients hospitalized in the ICU with a diagnosis of acute lung injury between 2008 and 2019.Screening was performed using STATA software to obtain medical records and laboratory indicators of the above patients for descriptive statistical analysis.Patients were divided into survival and death groups according to their survival status at discharge,and singte-fector and multi-factor logistic regression analyses were used to determine the risk and protective factors affecting the death of ALI patients and to establish prediction models,in which the first 3/4 of 6270 patients were selected for modeling and the last 1/4 for validation,which were counted as the modeling and validation groups.Validation was performed according to the Hosmer-Lemeshow test,and the ROC curves were drawn.Further,a quick Acute Lung Injury Evaluation(qALIE)prognostic scale was established.Finally,an ALI early warning system for critically i1l patients was established based on the results of existing studies.Results:3.1 A total of 6270 patients were enrolled according to the screening criteria,and 1760 died during hospitalization,with a morbidity and mortality rate of 28.07%.41-60 and 61-80 years old were the two age groups at high risk of ALI in ICU inpatients.Among the ALI patients enrolled in this study,the presence of sepsis or septic shock accounted for 33.67%,and among them,there were 856 deaths,with a mortality rate of 40.55%.3.2 This study showed that coronary artery disease,acidosis,cardiac arrest,sepsis or septic shock,creatinine,bilirubin,platelets,urea nitrogen,aspirin,dobutamine,dopamine,and overweight were all significantly associated with death in patients with ALI(P<0.05).3.3 Binary logistic regression analysis showed that coronary artery disease,acidosis,cardiac arrest,sepsis or septic shock were independent risk or protective factors for death in ALI.A prognostic prediction model for ALI was developed with the model equation=1/(1+exp-(-0.005+coronary artery disease x 0.319+acidosis × 0.506+cardiac arrest × 1.456+sepsis or septic shock × 0.690+bilirubin × 0.040-platelets × 0.001+urea nitrogen × 0.006aspirin × 0.554+dobutamine × 0.816 + dopamine 0.816+dopamine × 0.558-overweight ×0.005)),the area under the ROC curve for this model was 0.7165.3.4 The OR values of each factor were assigned their corresponding points according to the rounding principle.Prognostic score=coronary heart disease × 1+ acidosis × 2+ cardiac arrest × 4+sepsis or septic shock × 2+bilirubin × 1-platelets × 1+urea nitrogen × 1-aspirin× 1+dobutamine × 2+dopamine × 2-overweight× 1.Testing of the scoring system confirmed no statistical difference in morbidity and mortality between the modeling and validation groups(P=0.290>0.05),indicating a good fit The results of this study showed that there was no statistical difference between the modeled and validated groups in terms of mortality rate(P=0.290>0.05),indicating a good fit.Based on the above results,a rapid ALI prognostic scale and an ALI early warning system for critically ill patients were established.Conclusion:3.1 Analysis of the data derived from the MIMIC-Ⅳ database suggests a 28.07%mortality rate for patients with ALI in the ICU.3.2 Coronary artery disease,acidosis,cardiac arrest,sepsis or septic shock,creatinine,bilirubin,urea nitrogen,dobutamine,and dopamine were all independent risk factors for death in ALI patients,while platelets,aspirin,and overweight were protective factors for ALI patients,which supported the "obesity paradox" in this study.3.3 This study established a rapid ALI prognostic scale and an early warning system for ALI in critically ill patients,which may have strong practical significance for the prognostic risk assessment of acute lung injury. |
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