Table of Content

Volume 27 Issue 3
26 March 2022

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Analysis on mechanism of frankincense volatile oil in prevention and treatment of cardiac hypertrophy based on in vitro cell experiment and network pharmacology

XIE Mengdie, WANG Chenchen, LI Bingtao, OUYANG Changsheng, QIU Yumei, LI Hongming, TU Jun, SHANG Guangbin, TANG Xilan

2022, 27(3):  241-252.  doi:10.12092/j.issn.1009-2501.2022.03.001

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AIM: To explore the potential mechanism of frankincense volatile oil in the prevention and treatment of cardiac hypertrophy based on in vitro cell experiment and network pharmacology.  METHODS: The anti-hypertrophic effect of frankincense volatile oil was investigated by isoproterenol induced H9c2 cardiomyocytes hypertrophy model. The active chemical components and targets of frankincense volatile oil and targets associated with cardiac hypertrophy were obtained by CNKI, Pubmed, Pubchem databases, etc. String database and Cytoscape 3.8.0 software were used to construct protein-protein interaction network (PPI) and a network of "drug-active component-key target-disease" of frankincense volatile oil in order to screen the key targets of frankincense volatile oil against cardiac hypertrophy. The fluorescent quantitative PCR experiments were performed to verify those key targets. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation analysis of key target genes were performed using David online analysis tool.RESULTS: In vitro cell experiments showed that frankincense volatile oil significantly inhibited the isoproterenol induced increases in cardiomyocytes surface area and protein synthesis, and upregulations of ANP and β-MHC mRNA. A total of 87 active components and 36 ingredient-disease targets of frankincense volatile oil were screened. Network analysis showed that ESR1, NOS3, PTGS2, TNF, MAPK14, and PPARG were key targets. Fluorescence quantitative PCR experiments results indicated that frankincense volatile oil inhibited isoproterenol induced upregulations of ESR1, PTGS2, TNF, and MAPK14 mRNA levels, and downregulations of NOS3, PPARG mRNA levels, respectively. In addition, the GO functional enrichment analysis showed that its biological pathways mainly included lipopolysaccharide-mediated signaling pathway, positive regulation of nitric oxide biosynthetic process, caveola, enzyme binding, etc. The KEGG pathway enrichment analysis included 22 KEGG pathways, which were closely related to VEGF signaling pathway, TNF signaling pathway, sphingolipid signaling pathway and others. CONCLUSION: The active components of frankincense volatile oil may regulate VEGF signaling pathway, TNF signaling pathway, Sphingolipid signaling pathway by acting on ESR1, NOS3, PTGS2, TNF, MAPK14 and PPARG targets, thereby affecting the regulation of lipopolysaccharide-mediated signaling pathway, positive regulation of nitric oxide biosynthetic process, caveola, and enzyme binding, and improving cardiac hypertrophy.

Role and mechanism of SIRT3 in attenuation of intestinal ischemia-reperfusion injury by dexmedetomidine in mice

REN Yixing, LENG Yufang, GUO Mingjun, ZHANG Jianmin, SHI Yajing, CHEN Feng, LIU Xin

2022, 27(3):  253-259.  doi:10.12092/j.issn.1009-2501.2022.03.002

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AIM: To explore the role and mechanism of silent mating type information regulator 2 homolog 3 (SIRT3) in attenuation of intestinal ischemia-reperfusion (I/R) injury by dexmedetomidine in mice. METHODS: Twenty-four healthy male C57BL mice were divided into 4 groups randomly (n=6): sham operation group (Sham group), intestinal ischemia-reperfusion group (I/R group), dexmedetomidine group (Dex group), SIRT3 inhibitor 3-TYP group (3-TYP group). Superior mesenteric artery was clamped for 45 min followed by reperfusion for 2 h to establish intestinal I/R model in I/R group, Dex group, and 3-TYP group. Sham group received sole sham operation. 1 h prior to onset of ischemia, 3-TYP was injected into mice in 3-TYP group intraperitoneally (5 mg/kg, diluted to 0.3 mL), and 0.3 mL normal saline into mice in Dex group intraperitoneally. 30 min prior to onset of ischemia, dexmedetomidine was injected into mice in 3-TYP group and Dex group intraperitoneally (25 μg/kg, diluted to 0.3 mL). 1 h and 30 min prior to onset of ischemia, 0.3 mL normal saline was injected into mice in Sham group and I/R group intraperitoneally, respectively. 2 h of after reperfusion, the mice were sacrificed under anesthesia. Intestinal tissues were took and observed for pathological changes under light microscope after HE staining, and the injury was assessed via the Chiu's score method, and activities of SIRT3 and superoxide dismutase 2 (SOD2)   were detected via spectrophotometry, and malondialdehyde (MDA) via spectrophotometry. RESULTS: The pathological injury was exacerbated, and the Chiu's score, the MDA level elevated remarkably, while the activity level of SIRT3 and SOD2 declined remarkably in I/R group, Dex group and 3-TYP group compared to Sham group (P<0.05). The pathological injury was alleviated, and the Chiu's score declined remarkably in Dex group and 3-TYP group compared to I/R group (P<0.05); and the MDA level declined remarkably, while activity level of SIRT3 and SOD2 elevated remarkably in Dex group compared to I/R group (P<0.05); and there was no significant difference both in the activity level of SIRT3 and SOD2 and in the MDA level between 3-TYP group and I/R group. The pathological injury was exacerbated, and the Chiu's score, the MDA level elevated remarkably, while the activity level of SIRT3 and SOD2 declined remarkably in 3-TYP group compared to Dex group (P<0.05). CONCLUSION: SIRT3 and its downstream SOD2 are involved in mediating the effect of attenuation of intestinal ischemia-reperfusion injury through inhibiting oxidative stress response by dexmedetomidine.

Effects of oxypeucedanin on the resistance of breast cancer MCF-7/DOX cells to doxorubicin

DONG Wei, HUANG Xiaoying, XIE Bingbin, TANG Xilan, LI Hongming, QIU Yumei, ZHAO Guowei, LIANG Xinli

2022, 27(3):  260-266.  doi:10.12092/j.issn.1009-2501.2022.03.003

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AIM: To investigate the effect of oxypeucedanin (OPD) on doxorubicin resistance in human breast cancer MCF-7/DOX cells and its possible mechanism. METHODS: MCF-7/DOX cells were cultured in vitro, MTT assay was used to detect the effect of OPD on the survival of MCF-7/DOX cells, and the effect of OPD combined with different concentrations of doxorubicin on the proliferation of MCF-7/DOX cells were investigated. The effect of OPD combined with doxorubicin on the expression of genes including MDR1, MRP1, AGPAT2, CHKA, CEPT1, DGKA, PCYT1A, PLA2G15 in MCF-7/DOX cells was measured by qRT-PCR. The effect of OPD combined with doxorubicin on the protein expression of MDR1, MRP1, CHKA and CCTα in MCF-7/DOX cells was determined by Western blot. RESULTS: The IC50 value of doxorubicin in combination with OPD in MCF-7/DOX cells was lower than that of doxorubicin alone. The reversal fold is 1.56. Compared with control group, the mRNA level of MDR1, MRP1, AGPAT2, CHKA, CEPT1, DGKA, PCYT1A and PLA2G15 in the doxorubicin group was significantly downregulated (P<0.05 or P<0.01), the protein expression of MDR1, MRP1, CHKA and CCTα was not significantly affected (P>0.05), while the expression of the gene and protein above in OPD 50 μg/mL combined with doxorubicin group was significantly downregulated (P<0.05 or P<0.01). Compared with doxorubicin group, the expression of the gene above in OPD 50 μg/mL combined with doxorubicin group was further downregulated (P<0.05 or P<0.01), but the expression of the protein above was not significantly affected (P>0.05).CONCLUSION: OPD can enhance the sensitivity of MCF-7/DOX cells to doxorubicin chemotherapy, reverse drug resistance, which may be related to inhibition of glycerophospholipid metabolism.

Comparison of prediction accuracy between warfarin PPK/PD model and multiple regression dose models

LIAN Jinfang, LIU Yiwei, LIN Cuihong, HUANG Pinfang, LIN Rongfang

2022, 27(3):  267-273.  doi:10.12092/j.issn.1009-2501.2022.03.004

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AIM: To provide reference for clinical application of warfarin PPK/PD model, the prediction accuracy of warfarin PPK/PD model and 6 dose models established by multiple linear regression were compared.  METHODS: Clinical data of inpatients who took warfarin tablets for oral anticoagulant therapy in our hospital were collected, and the predictive values were simulated by PPK/PD model and other 6 models, respectively. SPSS 23.0 software was used for paired t-test of measured value and predicted value. MAE and percentage of prediction deviation were used to evaluate the results, and the prediction deviation box-plot was drawn to compare the total data, different dose groups and different genotypes. RESULTS: A total of 50 patients were included in the study. Among 7 models, only PPK/PD model, Wen et al., and Du Liping et al.'s model had no statistical difference in predicted values and measured values (P>0.05). The prediction accuracy of PPK/PD model was higher among the total data, low and medium doses, and patients with different genotypes.The prediction accuracy of Wen et al. 's model and Li Chuanbao et al.'s model was higher in the high-dose group. CONCLUSION: The PPK/PD model of warfarin has good clinical prediction performance, which is expected to provide reference for accurate administration of warfarin.

Design and implementation of electronic identity application for gene-directed personalized medicine

SUN Yuanyuan, DENG Kunhong, WANG Siyi, KUANG Yun, ZOU Chan, GUO Chengxian, HE Qingnan, LIU Helin, YANG Guoping

2022, 27(3):  274-280.  doi:10.12092/j.issn.1009-2501.2022.03.005

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AIM: In order to bridge the gap between pharmacogenomic research and its clinical application, we propose the concept of genetic electronic identity, named "GeneFace", and developed an electronic information system which integrated "drug-gene" interactions and recommendations for personalized medicine.  METHODS: Based on the self-developed Precision Medicine knowledgebase, which concludes drug directions, guidelines or important literatures with high level of evidence, we developed GeneFace with Java-based open-resource application framework Spring Boot, further developed a mobile App with cross-platform framework Uni-APP. RESULTS: The App includes six modules: genetic testing appointment, genetic knowledge introduction, individualized medication advice, medication records, Geneface interpretation, and Precision Medicine knowledgebase. By detecting the genotype of more than 300 gene loci upon first use, users import the results to form a personal "drug-gene identity card". Then scan or enter the drug name in "GeneFace", the App would automatically give corresponding medication recommendations, including: risks for possible adverse drug reactions, risks for reducing the efficacy or even ineffectiveness, and possibility for dose adjustment, etc., which increase the safety of clinical drug use. People can obtain pharmacogenomics knowledge and basic drug information in the "GeneFace" app. CONCLUSION: Development as a digital therapeutic product, the expanded application of GeneFace can rapidly promote clinical applications of basic pharmacogenomics research and significantly improve drug use safety, which creating a new model for accelerating the clinical application of personalized medicine.

Bioequivalence trial of fasting oral sorafenib tosylate tablets in healthy Chinese subjects

WU Juan, WANG Zhiqiang, ZHOU Renpeng, YANG Jingjing, QIN Huiling, ZHANG Qian, LU Chao, HU Wei

2022, 27(3):  281-286.  doi:10.12092/j.issn.1009-2501.2022.03.006

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AIM: To compare the pharmacokinetic behavior of a single oral sorafenib tosylate tablets in Chinese healthy subjects under fasting conditions and evaluate the bioequivalence of the test reagent (T) and the reference reagent (R).  METHODS: A single-center, randomized, open-labeled, two-agent, three-period, three-sequence (TRR, RTR, RRT), and partially repeated crossover trial design was adopted. The trial was administered once per cycle (0.2 g) under fasting conditions. 36 healthy subjects were randomly divided into 3 groups, each with 12 cases. RESULTS: Thirty-six healthy subjects (9 females, average age 31 years) were enrolled in the trial. The upper limits of the one-sided 95% confidence interval of the pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of the test reagent and the reference reagent after natural logarithmic transformation were －0.0908, －0.0577, －0.0541. The one-sided 95% upper limit of the confidence interval was less than 0; the ratios of the geometric mean values of the pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of sorafenib of the test preparation and the reference preparation were 101.65%, 100.12%, and 99.24%, respectively. In the range of 80.00%-125.00%, the bioequivalence of Cmax, AUC0-t and AUC0-∞ of the test reagent and the reference reagent sorafenib was established under the fasting state. CONCLUSION: The safety and tolerability of a single oral 0.2 g sorafenib tosylate tablet by subjects under fasting conditions were good. The test reagent and the reference reagent are bioequivalent under fasting administration.

Predictive factors associated with weight response to exenatide in patients with type 2 diabetes mellitus

SHAO Xi, YU Yanan, HUANG Yuhan, WANG Xiaotong, LING Hongwei, LV Dongmei, WANG Tao

2022, 27(3):  287-294.  doi:10.12092/j.issn.1009-2501.2022.03.007

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AIM: To explore which variables can predict the weight response to exenatide and to individualize specific therapies for patients with type 2 diabetes mellitus (T2DM) who need treatment with exenatide. METHODS: We performed a study among T2DM patients who were treated with exenatide twice daily for at least 12 months from January 2017 to December 2020. Data of the height, weight, body mass index (BMI) calculated, and HbA1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting serum insulin (FINS), postprandial serum insulin (PINS), blood lipids and concurrent diabetic medications at baseline, 3 months, 6 months and 12 months after exenatide initiation were collected. Patients were categorized into two cohorts based on weight loss ≥3%: responders and non-responders. The binary logistic regression analysis was used to identify the major variables of weight response to exenatide. RESULTS: The duration of diabetes in the responder group was shorter than that in patients in the non-responder group (P<0.05). For patients in the responder and non-responder groups, there was a significant decrease in weight, BMI, HbA1c, FPG, PPG, homeostasis model assessment of insulin resistance (HOMA-IR) and increase in homeostasis model assessment for beta cell function (HOMA-B) compared with the prarameters before treatment with exenatide (P<0.001). The baseline weight and baseline HbA1c were associated with weight loss after 6 months of treatment with exenatide (P<0.05). CONCLUSION: Baseline weight and HbA1c improvement were positively correlated with weight loss after 6 months of treatment with exenatide and the major predictors of weight response to exenatide.

Clinical analysis of the effect of fludarabine combined with post-transplantation cyclophosphamide in haploid hematopoietic stem cell transplantation

WANG Tiantian, CAO Junjie, LIU Xuhui, PEI Renzhi, LU Ying

2022, 27(3):  295-301.  doi:10.12092/j.issn.1009-2501.2022.03.008

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AIM: To investigate the therapeutic method of fludarabine combined with subsequent cyclophosphamide in the prevention of GVHD in haploid hematopoietic stem cell transplantation.  METHODS: A total of 52 patients receiving PTCY (50 mg/kg, on days 3 and 4) were matched with 29 patients receiving ATG. RESULTS: The median follow-up time was 359 days. Complete donor chimerism was achieved in all patients by STR DNA detection on days +30, +60. The median time to neutrophils ≥0.5×109/L and platelets ≥20×109/L were (11.5 vs. 12) days and (12 vs. 13) days respectively, between PTCy group and ATG group, The cumulative incidence of grade II-IV acute GVHD (aGVHD), grade Ⅲ-IV aGVHD, and chronic GVHD were (30.8%vs. 31%), (19.2%vs. 24.1%) and (5.8%vs. 24.1%) respectively. The cumulative overall survival (OS) and disease-free survival (DFS) were 65.5%vs. 62.1%, the non-relapse-mortality (NRM) at 1 years were 75% and 77%. Incidence of CMV infection and EBV infection were (48.3%vs. 50%) and (6.9%vs. 3.7%). CONCLUSION: HLA-haploidentical HSCT with PTCy is a viable option when lack of HLA matched sibling and unrelated donors. The rate of severe GVHD is acceptable. But post-transplant relapse and infection still are major hinder,and the protocol should be modified.

Effects of preoperative dezocine patient-controlled analgesia pump on stress response and cognitive function in elderly patients with lower extremity fractures

LI Yongliang, LIN Haiyan, ZHANG Lingling, DONG Yilong

2022, 27(3):  302-306.  doi:10.12092/j.issn.1009-2501.2022.03.009

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AIM: To explore the effects of preoperative application of dezocine patient-controlled analgesia pump on stress response and cognitive function in elderly patients with lower extremity fractures.  METHODS: A total of 80 elderly patients with lower extremity fractures who were treated from November 2018 to June 2020 were selected and randomly divided into a control group and a study group, 40 cases in each. The control group was not given a patient-controlled analgesia pump before anesthesia, and the study group was given intravenous analgesia with a dezocine patient-controlled analgesia pump before surgery. The postoperative stress response, cognitive function and safety were compared between the two groups.RESULTS: There were no significant differences in cognitive function MMSE score, stress response index (cortisol, epinephrine) levels, and inflammatory factors (IL-6, TNF-α) levels between the two groups before intervention (P>0.05). Compared with the indexes after operation, the MMSE scores of the study group at 12 h, 24 h and 3 days after operation were higher than those in the control group (P<0.05); The levels of cortisol, epinephrine, IL-6 and TNF-α in the study group were lower than those in the control group at 12 h and 24 h after operation (P<0.05); At the same time, the incidences of respiratory depression, urinary retention and nausea and vomiting in the study group were significantly lower than those in the control group (P<0.05).CONCLUSION: Preoperative application of dezocine patient-controlled analgesia pump in elderly patients with lower extremity fracture can significantly reduce postoperative stress response, reduce inflammatory response, and improve postoperative cognitive function, which is worthy of clinical application.

Research progress on the relationship between thyroid hormone and idiopathic pulmonary fibrosis

WEI Jifang, YUE Hongmei, LIU Nanyu, SONG Peipei, XIE Yingying, WANG Jiaqi, WEI Yaqian

2022, 27(3):  307-313.  doi:10.12092/j.issn.1009-2501.2022.03.010

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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with unknown etiology, which is characterized by scarring of lung parenchyma, leading to reduced quality of life and premature death. At present, some studies have confirmed that hypothyroidism (HT) may play a role in the development of fibrosis. Many animal experiments have proved that thyroid hormone (TH) can inhibit pulmonary fibrosis by regulating glucose metabolism, improving mitochondrial function and inhibiting inflammation. This paper summarizes the correlation between TH and IPF, and deeply understands the relationship between TH and IPF, in order to have new treatment strategies for IPF in the future.

Mechanism of ferroptosis and its research progress in lymphoma

LI Wenxia, FANG Liuyuan, QIAN Shenxian

2022, 27(3):  314-321.  doi:10.12092/j.issn.1009-2501.2022.03.011

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Lymphoma is a common hematological malignant tumor which poses a great threat to human health. Chemotherapy, molecular targeted therapy, and hematopoietic stem cell transplantation constitute the main treatment methods for lymphoma, however, there are still some patients with lymphoma suffer from drug resistance, relapse and refractory. Ferroptosis is a newly discovered mode of programmed cell death, which is related to iron-dependent lipid peroxidation damage. Targeting ferroptosis provides a novel landscape for inhibiting the growth of lymphoma. We reviewed the mechanism of ferroptosis from the initial signals, intermediate events, effect stages, defense mechanisms and summarized the research progress of ferroptosis in lymphoma, providing novel therapeutic targets in the treatment of lymphoma.

Ethical analysis and countermeasures of artificial intelligence application in clinical trials

LIU Xing, LU Xiaoran, WU Ying, YU Haitao, WANG Xiaomin

2022, 27(3):  322-327.  doi:10.12092/j.issn.1009-2501.2022.03.012

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The development of artificial intelligence is becoming more and more mature, and has penetrated into every field of clinical trials. Artificial intelligence has brought new development opportunities for clinical trials. However, the application of artificial intelligence in clinical trials is still in the exploratory stage, facing many ethical issues, including trial risk caused by data quality, privacy protection caused by data regulation, and contradiction between data authorization and informed consent. We should precisely position the realizable application of artificial intelligence in clinical trials, understand its practical ethical issues, and formulate corresponding coping strategies to ensure the maximum improvement of the whole process performance of clinical trials, including strengthening data quality management and reducing clinical trial risks; optimizing data monitoring mechanisms to ensure data security and privacy; building a data authorization platform and improving judicial protection of informed consent, etc.

Research progress on bone metabolism disorders associated with PCOS elucidated from endocrine hormones

DU Chen, TIAN He, CAO Yang, WANG Yongjun, ZHANG Yan

2022, 27(3):  328-333.  doi:10.12092/j.issn.1009-2501.2022.03.013

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Polycystic ovary syndrome (PCOS) is a common endocrine metabolic disease of women. Clinical studies have shown that PCOS patients are likely having abnormal bone metabolism, and with increased risk of osteoporosis. This review summarized the common pathological mechanisms for both PCOS and osteoporosis, and elucidated the research progress on PCOS-inducing bone metabolism disorders from emphasizing on the regulation of endocrine hormones including insulin, androgen, growth hormone, vitamin D, parathyroid hormone and calcitonin. It is expected that this review will shed new light on monitoring and intervention for bon health of PCOS patients.

Research progress on antipyretic effect of Chinese medicine

CHEN Shengfu, LI Xiaolin, WANG Weigang, DU Weize, LI Maoxing

2022, 27(3):  334-344.  doi:10.12092/j.issn.1009-2501.2022.03.014

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Fever is a sign of infection and inflammatory diseases in the body. Persistent high fever will lead to cell degeneration, causing multiple organ dysfunction, and seriously affecting brain nerve and tissue function. Although the fever process is common and ordinary, its pathological mechanism involves multiple signaling pathways, such as nuclear transcription factor κB signaling pathway, Toll-like receptor 4 signaling pathway. A large number of studies have shown that traditional Chinese medicine compound and its active components can reduce serum inflammatory factors (TNF-α, IL-1β and IL-6) and hypothalamic thermoregulatory mediators (PGE2, cAMP), inhibit NF-κB signaling pathway, and effectively inhibit the pathological increase of body temperature. This paper summarizes the relevant literature in PubMed and CNKI database, and systematically expounds the active components of traditional Chinese medicine and the antipyretic effect of compound prescription, in order to provide theoretical basis and research ideas for the use of traditional Chinese medicine in the treatment of fever and the excavation of new anti-fever drugs.

Research progress of the relationship between autophagy and inflammatory bowel disease

CAO Ying

2022, 27(3):  345-352.  doi:10.12092/j.issn.1009-2501.2022.03.015

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Autophagy is regulated by autophagy-related genes (ATGs), so that the aged and damaged cellular substances in cells are sent to lysosomes for degradation and recycling, thereby maintaining cellular homeostasis. Inflammatory bowel disease (IBD) is an autoimmune disease, and the ability of autophagy to selectively target intracellular pathogens for destruction is considered a key aspect of the innate immune response. Genetic studies suggest that several autophagy-related genes are clinically relevant in the pathogenesis of IBD. This article will describe the role of autophagy in IBD and the latest advances in its clinical relevance, as well as autophagy-targeted therapeutic strategies for IBD.

Induced bronchial associated lymphoid tissue (iBALT) formation and research of related lung diseases

ZHAO Ziwen, FAN Fangtian, JIANG Zhijun

2022, 27(3):  353-360.  doi:10.12092/j.issn.1009-2501.2022.03.016

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Lung is the breathing organ of the human body. The respiration of the lung enables the body to exchange oxygen with the outside world to maintain the body's life activities. The physiological properties of the lungs expose the mucosal surfaces of the lungs to harmful external irritants, including pathogens, allergens, harmful gases and smoke particles, which can lead to lung injury and infection. Induced by lung inflammation, immune cells (B lymphocytes and T lymphocytes) in the lungs gather around the bronchi, forming induced bronchial associated lymphoid tissue (iBALT). Studies have found that iBALT is involved in the pathological development of asthma, COPD, lung cancer and other lung diseases. iBALT is regulated by a variety of cytokines, but the formation process and its effect on disease remain unclear.  The purpose of this paper is to review the formation factors of iBALT and its pathological status in lung, and to provide new treatment ideas for chronic pulmonary inflammatory diseases.