Journal of Shandong University (Health Sciences)

Airway epithelium and epithelial-derived cytokines in asthma: reflection and outlook

ZHANG Jintao, DONG Liang

Journal of Shandong University (Health Sciences). 2024, 62(5): 1-6. doi:10.6040/j.issn.1671-7554.0.2024.0121

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The airway epithelium plays a central role in the pathogenesis of asthma by tightly interacting with immune cells and finely regulating the formation of the airway microenvironment. Epithelial-derived cytokines have been recognized as key players in triggering and sustaining airway inflammation in asthma, making them attractive targets for the development of novel asthma drugs. This article provides an overview of the role of the airway epithelium and its derived cytokines in asthma, as well as the progress in research on targeted drugs, offering new perspectives and insights for related studies.

Clinical research hotspots of chronic obstructive pulmonary disease in recent years

WANG Fengyan, LIANG Zhenyu, LI Xueping, CHEN Rongchang

Journal of Shandong University (Health Sciences). 2024, 62(5): 7-15. doi:10.6040/j.issn.1671-7554.0.2024.0137

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Chronic obstructive pulmonary disease(COPD)is the most common chronic respiratory disease, and has attracted much attention because of its disabling and fatal nature. Many important advances in clinical research have been made in recent years. The development of early diagnostic and screening tools, as well as multidimensional phenotyping based on lung function trajectories, quantitative imaging assessments and gene signature, have informed individualized treatment of COPD. Multi-omics studies have made important breakthroughs in exploring biomarkers of COPD, contributing to an in-depth understanding of the pathogenesis and progression of the disease. The comparisons of inhaled drug regimens and the efficacy of monoclonal antibodies targeting type 2 inflammation are also advancing, with a view to providing more individualized treatments for patients with COPD by targeting the pathogenesis of the disease.

Research progress of mitochondrial damage-associated molecular patterns as biomarkers for chronic obstructive pulmonary disease

SHEN Yongchun, WEN Fuqiang

Journal of Shandong University (Health Sciences). 2024, 62(5): 16-20. doi:10.6040/j.issn.1671-7554.0.2024.0136

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Chronic obstructive pulmonary disease(COPD)has high incidence rate, disability rate, mortality rate, and heavy economic burden, and it is a major disease burden that seriously affects the health of Chinese population. Finding reliable biomarkers for the diagnosis, evaluation, and prediction of mortality risk in COPD is currently a research hotspot. The mitochondrial damage-associated molecular patterns are closely related to COPD. Based on mitochondrial damage-associated molecular patterns, it is expected to find relevant biomarkers for COPD, providing further basis for the evaluation and treatment of COPD. This article reviews the research progress of the biomarker role of mitochondrial damage-associated molecular patterns for COPD.

Research progress of the treatment of asthma with macrolide antibiotics

DING Yiren, LIU Wanying, YAO Lei, YAO Xin

Journal of Shandong University (Health Sciences). 2024, 62(5): 21-27. doi:10.6040/j.issn.1671-7554.0.2024.0131

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Asthma is a chronic inflammatory disease of the airways, and inhaled corticosteroids are the main treatment. However, a small number of patients cannot be effectively controlled, and new treatment methods are urgently needed for such patients. In recent years, in addition to the research on biological agents, there has been considerable interest in the therapeutic potential of macrolide antibiotics in asthma. This article provides a systematic review of the efficacy, possible mechanisms, and adverse reactions of macrolide antibiotics in the treatment of asthma.

Neuropsychological asthma

WANG Ting, ZHANG Li, WANG Gang

Journal of Shandong University (Health Sciences). 2024, 62(5): 28-34. doi:10.6040/j.issn.1671-7554.0.2024.0186

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Bronchial asthma(asthma)is a heterogeneous disease characterized by chronic airway inflammation. Application of multidimensional assessment to identify treatable traits in asthma is expected to improve asthma control and achieve clinical remission. Neuropsychological dysfunction, including anxiety and depression, is important component of the assessment of extrapulmonary treatable traits in asthma. Comorbid anxiety and/or depression can worsen asthma symptoms, reduce quality of life, and increase acute exacerbations, and thus neuropsychological asthma has gained attention as a specific asthma phenotype. This article reviews the epidemiology, clinical consequences, underlying mechanisms, screening tools, and treatments of neuropsychological asthma, in order to provide some information for future research and management of neuropsychological asthma.

Research progress on biological and cellular therapies for severe asthma

XU Fang, TIAN Guoxiong, SUN Beibei, CHEN Xinyi, CHEN Gaoying, ZHANG Ruiqi, YING Songmin, WU Miaolian, ZHANG Chao, WU Youqian

Journal of Shandong University (Health Sciences). 2024, 62(5): 35-42. doi:10.6040/j.issn.1671-7554.0.2024.0144

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Asthma is a highly heterogeneous disease with multiple effector cells and cytokines involved in its development. In severe asthma, conventional high-dose inhaled glucocorticoid therapy is usually difficult to control symptoms, and patients may present with persistent airflow limitation and worsening symptoms, leading to decreased quality of life and increased healthcare burden. Currently, the exploration of biological therapies targeting effector cells or cytokines offers novel treatment options as add-on therapies for severe asthma. In recent years, studies have also pioneered the application of novel cellular therapies, such as stem cell therapy or chimeric antigen receptor T(CAR-T)cell therapy, to the treatment of severe asthma. In this article, we will review the research progress of biological agents for severe asthma and novel cellular therapies as potential therapeutic strategies, describe promising biological therapies and their mechanisms of action, efficacy and safety, and on the basis of which, we will look forward to the future development of biological and cellular therapies as a strategy for the treatment of severe asthma in terms of long-term efficacy and safety, precision medicine, patient accessibility, and interdisciplinary cooperation.

Bioinformatics-based exploration of potential differential immune genes and immune infiltration signatures in bronchial asthma

SHI Shuochuan, ZENG Rong, ZHANG Jintao, ZHANG Dong, PAN Yun, LIU Xiaofei, XU Changjuan, WANG Ying, DONG Liang

Journal of Shandong University (Health Sciences). 2024, 62(5): 43-53. doi:10.6040/j.issn.1671-7554.0.2024.0079

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Objective To identify immunologically critical genes and immune cells that are differentially expressed during the development of asthma and to explore the correlation between them. Methods The asthma-related datasets and immune-related genes were downloaded from the Gene Expression Omnibus database(GEO)and Import database, respectively, and analyzed using R software to obtain differentially expressed immune-related genes(DE-IRGs)in GSE76262. The interactions between DE-IRGs were clarified in the STRING database. Key DE-IRGs were screened using the CytoHubba plugin in Cytoscape software and validated in GSE137268. Receiver operating characteristic(ROC)curves were used to assess the potential of critical DE-IRGs as biomarkers. The single-sample gene set enrichment analysis(ssGSEA)algorithm was used to examine the differential expression of 28 immune cells in asthmatic and healthy individuals. Spearman correlation coefficients were used to evaluate the correlation between key immune genes and immune cells. Results Seventeen DE-IRGs were identified in GSE76262, and CCL22, CCR7, IL1R2, IL18R1, TNFAIP3, and VEGFA were identified as critical DE-IRGs in induced sputum from asthmatics with high diagnostic value, as screened by the PPI network and validated in GSE137268. In addition, the results of ssGSEA suggested a significant immune imbalance in asthmatics, with 11 types of immune cells significantly infiltrated in the induced sputum of asthmatics compared to healthy individuals. Meanwhile, CCL22, CCR7, IL1R2, IL18R1, VEGFA, and TNFAIP3 were positively correlated with infiltrated immune cells. Conclusion CCL22, CCR7, IL1R2, IL18R1, VEGFA, and TNFAIP3 serve as potential biomarkers of asthma and may modulate infiltration of immune cells in its pathogenesis.

Genetic association of lipids and lipid-lowering drugs with chronic obstructive pulmonary disease based on Mendelian randomization

WU Tong, YANG Jingyu, LIN Dang, XU Wanru, ZENG Yujun

Journal of Shandong University (Health Sciences). 2024, 62(5): 54-63. doi:10.6040/j.issn.1671-7554.0.2024.0159

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Objective To explore the causal role of lipid traits in chronic obstructive pulmonary disease(COPD)from a genetic perspective and to evaluate the potential impact of lipid-lowering medication targets on COPD by using Mendelian randomization(MR)analysis. Methods Genetic variants associated with lipid traits and genetic variants coding for lipid-lowering drug targets were extracted from The Global Lipids Genetics Consortium(GLGC)and the Expressed Quantitative Trait Loci Genome Consortium(eQTLGen Consortium). Lipid traits and lipid-lowering drug targets were extracted from GLGC and eQTLGen Consortium as exposure variables, and COPD was derived from the FinnGen database(https://www.finngen.fi/en)as the outcome variable. Single nucleotide polymorphism(SNP)strongly associated with the exposure variables were used as instrumental variables, and the inverse variance weighted(IVW)was used as the main method to explore the the causal role of lipid traits in COPD and the potential effects of lipid-lowering drug targets on COPD, MR-Egger regression and the weighted median was used as complementary evidence to the IVW results. A Leave-one-out sensitivity analysis was used to explore the effect of individual SNP on the results of IVW analysis, while the intercept of MR-Egger method and Cochrans Q test for horizontal multiplicity and heterogeneity were used to ensure the stability of the results, and funnel plots were used to analyze the potential biases of the study results. For the drug target CETP that reached COPD risk significance, co-localization analysis was used to test the exclusion restriction hypothesis. Results IVW analysis results indicated that increased genetic levels of LDL-C(OR=1.077, 95%CI: 1.001-1.159, P=0.046)and TC(OR=1.088, 95%CI: 1.002-1.181, P=0.044)were associated with an increased risk of COPD. Increased genetic levels of CETP were associated with an increased risk of COPD(OR=1.179, 95%CI: 1.052-1.321, P=0.004). MR-Egger regression, Cochrans Q test, and leave-one-out analysis suggested that the findings were reliable and robust. Conclusion Dyslipidemia is a causative factor in COPD. Increased levels of LDL-C and TC are associated with the pathogenesis of COPD. Among the three lipid-lowering drug targets, CETP is a promising candidate drug target for COPD.

Therapeutic effects of aconitum carmichaelii decoction on a rat model of knee osteoarthritis

WANG Lisha, WANG Shangzeng, SHI Dongliang, ZHANG Zhongbo, REN Bowen, WANG Yunfei, GUO Zhonghua, ZHOU Xiaoning

Journal of Shandong University (Health Sciences). 2024, 62(5): 64-71. doi:10.6040/j.issn.1671-7554.0.2023.0950

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Objective To investigate the therapeutic effects of aconitum carmichaelii decoction based on the nuclear factor E2 related factor 2(Nrf2)/heme oxygenase-1(HO-1)pathway on a rat model of knee osteoarthritis(KOA). Methods KOA rat model was established by injecting papain solution into the knee joint; the rats after modeling were randomly grouped into KOA group, aconitum carmichaelii decoction group(4.2 g/kg aconitum carmichaelii decoction), inhibitor group(30 mg/kg ML385), aconitum carmichaelii decoction+inhibitor group(4.2 g/kg aconitum carmichaelii decoction+30 mg/kg ML385), with 10 rats in each group, and another 10 rats were injected intracavitally with physiological saline as the control group. Hematoxylin-eosin staining was used to observe the histopathological changes of cartilage in cartilage and to score the damage; serum indicators of inflammatory factor ［tumor necrosis factor-α(TNF-α)/interleukin-1β(IL-1β)］ and oxidative stress ［malondialdehyde(MDA)and superoxide dismutase(SOD)］ were measured by ELISA; Nrf2 and HO-1 expressions were detected by qRT-PCR and Western blotting. Results Compared with the control group, the cartilage surface of KOA group was rough and uneven, disordered cell arrangement, and disappearance of lamellar structure, increased content of IL-1β, TNF-α and MDA, and decreased expressions of SOD, Nrf2, and HO-1 mRNA and protein(P<0.05); compared with the KOA group, the pathological damage of aconitum carmichaelii decoction group was relieved, with decreased contents of IL-1β, TNF-α, and MDA, and increased expressions of SOD, Nrf2, and HO-1 mRNA and protein(P<0.05); however, the pathological damage in the inhibitor group was further aggravated, with increased content of IL-1β, TNF-α, and MDA, and decreased expressions of SOD, Nrf2, and HO-1 mRNA and protein(P<0.05); compared with the aconitum carmichaelii decoction group, aconitum carmichaelii decoction+inhibitor group had more serious pathological damage, with increased content of IL-1β, TNF-α, and MDA, and decreased expressions of SOD, Nrf2, and HO-1 mRNA and protein(P<0.05); compared with the inhibitor group, the pathological damage in the aconitum carmichaelii decoction+inhibitor group was slightly improved, with decreased content of IL-1β, TNF-α, and MDA, and increased expressions of SOD, Nrf2, and HO-1 mRNA and protein(P<0.05). Conclusion Aconitum carmichaelii decoction can treat KOA rats by activating Nrf2/HO-1 pathway.

Expression and correlation of α5-nAChR and MHC-I in lung adenocarcinoma

WANG Jingting, WANG Jing, LU Yi, LI Jingtan, LI Qiang, JIA Yanfei, MA Xiaoli

Journal of Shandong University (Health Sciences). 2024, 62(5): 72-78. doi:10.6040/j.issn.1671-7554.0.2024.0061

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Objective To investigate the expression and correlation between alpha5-nicotinic acetylcholine receptor(α5-nAChR)and the major histocompatibility complex class I molecule(MHC-I)in lung adenocarcinoma. Methods TCGA database were used to study the expression, correlation, and clinical significance of encoding α5-nAChR gene(CHRNA5)and encoding MHC-I gene(HLA-B)in lung adenocarcinoma. The expressions of α5-nAChR and MHC-I were tested by immunohistochemistry staining in human lung adenocarcinoma specimans and nude mouse lung adenocarcinoma xenografts tissues. Furthermore, the expression and correlation of FHIT and MHC-I at different expression levels of α5-nAChR were detected by Western blotting in human A549 cells and mice LLC cells. Results Patients with lung adenocarcinoma with high expression of CHRNA5 or low expression of HLA-B had reduced survival, and CHRNA5 was negatively correlated with the expression of HLA-B(P<0.05). The expressions of α5-nAChR and MHC-I were negatively correlated in human lung adenocarcinoma and nude mouse lung adenocarcinoma xenografts tissues(P<0.05). In lung adenocarcinoma cells, the expression of α5-nAChR was negatively correlated with the expressions of FHIT and MHC-I, and the expression of FHIT and MHC-I was positively correlated(P<0.05). Conclusion The expressions of α5-nAChR and MHC-I are negatively correlated and involved in lung adenocarcinogenesis.

Expression and diagnostic value of plasma exosomal miR-548k in esophageal squamous cell carcinoma

FENG Xumei, SONG Xiangqing, JI Guanhong, ZHAO Xiaogang, XIAO Zhaohua

Journal of Shandong University (Health Sciences). 2024, 62(5): 79-88. doi:10.6040/j.issn.1671-7554.0.2024.0134

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Objective To screen out the candidate plasma exosomal microRNAs(miRNAs)which play crucial role in esophageal squamous cell carcinoma(ESCC)occurrence and evaluate their potential in ESCC diagnosis. Methods A total of 55 ESCC patients who underwent surgical resection at The Second Hospital of Shandong University from March 2020 to June 2021 and 55 healthy volunteers were enrolled in this study. After identified by transmission electron microscopy(TEM), NanoSight tracking analysis(NTA)and Western blotting assays, RNA sequencing was performed to determine the miRNA profiles of plasma exosomes from 5 ESCC patients and 5 healthy control. Then, quantitative real-time PCR(qRT-PCR)was used to detect the expression level of differential exosomal miRNAs in the training and validation sets. Then, receiver operating characteristic(ROC)curve was conducted to evaluate their diagnostic value. Results Five miRNAs(miR-548k, miR-6516-5p, let-7b-3p, miR-3934-5p, miR-196a-5p)were significantly higher, and 8 miRNAs(miR-34c-5p, novel_167, miR-548u, miR-548ah-3p, miR-548p, miR-200a-5p, miR-200b-3p,miR-1228-5p)were obviously decreased in plasma exosomes of ESCC group than that of control group. Additionally, through the training cohort, we verified that miR-548k was significantly up-regulated in plasma exosomes of ESCC group(P<0.001). ROC curve analysis revealed that exosomal miR-548k exhibited higher accuracy than miR-34c-5p, miR-548u, miR-6516-5p in ESCC diagnosis, and the area under ROC curve(AUC)value was 0.918. Finally, through the validation cohort, we further confirmed that miR-548k was highly expressed in plasma exosomes of ESCC group(P<0.001), and plasma exosomal miR-548k could be used for ESCC diagnosis(AUC=0.889). Conclusion MiR-548k is significantly up-regulated in plasma exosomes of ESCC patients and plasma exosomal miR-548k has high clinical diagnostic value for ESCC.

Intratumor heterogeneity of SP1 expression in colorectal cancer and its clinical significance

WEI Yanruoxue, LI Ziqi, LIU Chuncheng, LIU Xiaohan, ZHAO Ran, LIU Yukun

Journal of Shandong University (Health Sciences). 2024, 62(5): 89-94. doi:10.6040/j.issn.1671-7554.0.2024.0212

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Objective To investigate the intratumor heterogeneity(ITH)of specificity protein 1(SP1)protein expression in colorectal cancer(CRC)and its clinical significance. Methods Clinical specimens of CRC were collected. The expression level and pattern of SP1 protein were detected by immunohistochemical EnVision method. The ITH characteristics of SP1 protein expression were identified, and the ITH level of SP1 protein was defined. The relationship between ITH level of SP1 protein and clinicopathological characteristics and prognosis of CRC patients was analyzed. Results SP1 protein showed typical ITH expression in CRC. The ITH level of SP1 protein was associated with lymph node metastasis(P<0.001)and TNM stage(P<0.001). Survival analysis showed that the overall survival(OS)of patients with high ITH level of SP1 protein was significantly lower than that with low ITH level(61.25% vs 81.82%, P=0.004). Univariate and multivariate Cox regression analyses showed that high SP1 protein ITH was an independent predictor of poor OS in CRC patients(HR=2.680, P=0.017). Conclusion The expression of SP1 protein in CRC has significant ITH characteristics, and defines the quantitative criteria of SP1 ITH level for the first time. It is demonstrated that a high ITH level of SP1 protein is significantly associated with CRC progression and poor prognosis.

Establishment and application of three-dimensional computed tomography reconstruction-guided percutaneous lateral approach for foramen ovale puncture

LIANG Yuanhao, XIAO Wenshan, PENG Shengxin, ZHANG Yixiang, SHI Bin, YU Gongchang, LIU Lei

Journal of Shandong University (Health Sciences). 2024, 62(5): 95-102. doi:10.6040/j.issn.1671-7554.0.2024.0193

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Objective To investigate three-dimensional computed tomography(CT)-guided percutaneous lateral approach for foramen ovale puncture and introduce a novel method for treating trigeminal neuralgia through selective radiofrequency thermocoagulation. Methods Three adult skull specimens with sawn parietal bones were scanned using a 22 G radiofrequency puncture needle. The Hartel anterior and lateral approaches for puncture were simulated. The needle tips were inserted into the foramen ovale, followed by skull CT scan with the puncture needles in place. The specimens were scanned to establish a standard image for CT perforations. Using the CT reconstruction data, the relationship between the needle positions and tips for the two pathways was measured and analyzed. This analysis helped determine the techniques and skills required for the lateral approach puncture to accurately target the semilunar ganglion. Additionally, the clinical data of 64 patients with primary trigeminal neuralgia types 2 and 3, who were treated with radiofrequency thermocoagulation in the Gasserian ganglion from March 2022 to February 2023, were retrospectively analyzed to assess treatment efficacy and sensory loss. Results Using the needle and skull specimen, complemented by CT scan and image reconstruction, two puncture pathways were compared. The CT-guided percutaneous lateral approach facilitated the successful establishment of a foramen ovale perforation, which was applied to treat 64 patients with primary trigeminal neuralgia, achieving successful entry into the foramen ovale and enabling selective ganglion radiofrequency thermocoagulation. The patients were followed for 1 week to 12 months, with an average of(6.0±1.9)months, and reported treatment satisfaction and no recurrence. Conclusion The application of CT-guided percutaneous lateral perforation technique provides a new and feasible therapeutic approach for treating trigeminal neuralgia by selective radiofrequency thermocoagulation of the semilunar ganglion.

Causal correlation between antimicrobial use density and durg resistance rates of Klebsiella pneumoniae and drug control thresholds

QIAN Fengtong, LI Hongkai, YU Jinlong, XUE Fuzhong

Journal of Shandong University (Health Sciences). 2024, 62(5): 103-111. doi:10.6040/j.issn.1671-7554.0.2024.0164

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Objective To explore the causal association between antimicrobial use density and Klebsiella pneumoniae drug resistance rate, and to determine the control thresholds of antimicrobial use density. Methods Based on the data of antimicrobial use density and Klebsiella pneumoniae resistance rates in the Second Hospital of Shandong University from 2015 to 2023, the effect of total antimicrobial use density on Klebsiella pneumoniae resistance rate was analyzed by breakpoint regression. Nonlinear time-series analyses using generalized additive models(GAMs)were used to assess the association between antimicrobial use density and Klebsiella pneumoniae resistance rate and to determine the control thresholds for antimicrobial use density. P<0.05 and adjusted R² > 0.3 were considered statistically significant differences. Results During the study period, the density of all types of drug use remained stable from 2015 to 2019, trended downward through 2021, and then gradually increased through 2023. Klebsiella pneumoniae drug resistance rates trended upward from 2015 to 2019, gradually declined through 2022, and then gradually increased through 2023. The results of breakpoint regression analysis showed that an increase in total antimicrobial use density led to an increase in the total resistance rate of Klebsiella pneumoniae, and the difference was statistically significant(β=1.071, P=0.041). Nonlinear time-series analyses showed that the resistance rates of Klebsiella pneumoniae were significantly associated with the density of carbapenems, aminoglycosides, penicillins, and glycopeptides(lag coefficient ranged from 1 to 5, all P<0.05, adjusted R² ranged from 0.589 to 0.808). The control thresholds of carbapenems, aminoglycosides, and third-generation cephalosporins use were 5.82, 0.06 and 5.62 DDDs/(100 patient-days), respectively. Conclusion Increased intensity of antimicrobial drug use leads to an increase in the overall resistance rate of Klebsiella pneumoniae; thresholds of antimicrobial use density were identified in this study to inform more appropriate therapeutic strategies and effective control of antimicrobial resistance rates in clinical practice.

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