Ginsenoside Rb3 Alleviates CSE-induced TROP2 Upregulation through p38 MAPK and NF-κB Pathways in Basal Cells.

Smoking-mediated reprogramming of the phenotype and function of airway basal cells (BCs) disrupts airway homeostasis and is an early event in chronic obstructive pulmonary disease (COPD)-associated airway remodeling. Here, we examined the expression and regulation of the transmembrane glycoprotein TROP2 (trophoblast antigen 2), a putative stem cell marker in airway BCs, in lung tissue samples from healthy smokers and healthy nonsmokers and in models in culture to identify therapeutic targets. TROP2 expression was upregulated in the airway epithelia of smokers and positively correlated with the smoking index. In vitro, cigarette smoke extract (CSE) induced TROP2 expression in airway BCs in a time- and dose-dependent manner. The p38 MAPK and NF-κB pathways were also activated by CSE, and their specific antagonists inhibited CSE-induced TROP2 expression. A therapeutic component derived from traditional Chinese medicine, ginsenoside Rb3, inhibited CSE-induced TROP2 expression as well as activation of the p38 MAPK and NF-κB pathways in BCs in monolayer culture. Furthermore, ginsenoside Rb3 prevented the increase in TROP2 expression and antagonized CSE-induced BC hyperplasia and expression of inflammatory factors and epithelial-mesenchymal transition changes in an air-liquid culture model. Thus, CSE-induced TROP2 is a possible biomarker for early changes in the epithelium of smokers, and ginsenoside Rb3 may serve as a therapeutic molecule, preventing the disruption of epithelial homeostasis in COPD.

Pulmonary Function Test and Obstructive Sleep Apnea Hypopnea Syndrome in Obese Adults: A Retrospective Study.

Objective: We explore risk factors related to severe obstructive sleep apnea (OSA) in obese patients, including pulmonary ventilation function, diffusion function, and impulse oscillometry (IOS) data. Methods: The medical records of 207 obese patients who were prepared to undergo bariatric surgery in a hospital from May 2020 to September 2021 were retrospectively reviewed. Polysomnography (PSG), pulmonary ventilation function, diffusion function, and IOS parameters were collected according to the ethical standards of the institutional research committee (registration number: KYLL-202008-144). Logistic regression analysis was used to analyze the related independent risk factors. Results: There were significantly statistical difference in a number of pulmonary ventilation and diffusion function parameters among the non-OSAHS group, the mild-to-moderate OSA group, and the severe OSA group. However, only airway resistance parameters R5%, R10%, R15%, R20%, R25%, and R35% increased with increasing OSA severity and were positively correlated with apnea hypopnea index (AHI). Age (P = 0.012, 1.104 (1.022, 1.192)), body mass index (P< 0.0001, 1.12 (1.057, 1.187)), gender (P = 0.003, 4.129 (1.625, 10.49)), and R25% (P = 0.007, 1.018 (1.005, 1.031)) were independent risk factors for severe OSA. In patients aged 35 to 60, RV/TLC (P = 0.029, 1.272 (1.025, 1.577)) is an independent risk factor for severe OSA. Conclusion: R25% was an independent risk factor for severe OSA in obese individuals, while RV/TLC was also an independent risk factor in those aged 35 to 60. Pulmonary function tests (PFTs), particularly IOS levels, are recommended to assess severe OSA in obese patients.

Asymptomatic Patients with Airflow Limitation are at Higher Risk of Postoperative Pulmonary Complications After Lung Surgeries: An Ambispective Cohort Study.

PURPOSE: With the use of pulmonary function tests (PFTs) as a preoperative examination, it is not rare to screen out airflow limitation (AFL) in asymptomatic patients undergoing lung surgeries. This study aims to elucidate whether there is a difference in the prevalence and prognosis of postoperative pulmonary complications (PPCs) between asymptomatic patients with newly diagnosed AFL and the normal population undergoing lung surgeries. PATIENTS AND METHODS: The medical records of asymptomatic patients undergoing lung surgeries who were spirometrically diagnosed with AFL between January and October 2017 were collected in Qilu hospital. These patients were subsequently followed up until February 2021. The diagnosis of PPCs was based on a recommended consensus definition. The incidence of PPCs between the newly diagnosed AFL group and the normal group was compared and a propensity score-matched analysis (PSM) was performed. The survival analysis was performed to investigate the long-term prognosis of the two groups. RESULTS: Overall, 535 asymptomatic subjects were recruited and 126 subjects (11.4%) were spirometrically diagnosed as AFL. The incidence of PPCs was significantly higher in the newly diagnosed AFL group than in the normal population (28.6%VS 14.4%, P < 0.001), especially in the FEV1/FVC≤65% group (P < 0.001), which were all confirmed by PSM analysis. Furthermore, these patients were at a higher risk of ICU admissions (P < 0.001) and 90-day hospital readmissions secondary to PPCs (P < 0.001). No significant differences were found in the overall, in-hospital and 90-day mortality between the AFL group and the normal group (P values >0.05). CONCLUSION: Asymptomatic patients with AFL are at higher risk of PPCs than the general population after lung surgeries, along with an increase in ICU admissions and 90-day hospital readmissions secondary to PPCs. Although these patients tended to report worse current conditions, they were similar in the in-hospital, 90-day and overall mortality during the follow-up.

Impacts of Different Spirometry Reference Equations and Diagnostic Criteria on the Frequency of Airway Obstruction in Adult People of North China.

Background and Objective: The reference equations and diagnostic criteria play a critical role in the interpretation of pulmonary function tests (PFTs). The aim was to investigate the impacts of different reference equations and diagnostic criteria on the frequency of airway obstruction in adult people of a large teaching hospital of North China. Methods: The spirometry data of all adult people who underwent PFTs in Qilu hospital from April 2012 to November 2015 were collected. Two spirometry reference equations, namely, Zhongshan-2011 and Global Lung Function Initiative 2012 (GLI-2012) were compared. The frequency of airway obstruction using different spirometry prediction equations and diagnostic criteria including forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <92% of predicted value and FEV1/FVC 

Relationship Between Proteinase with a Disintegrin and a Metalloproteinase Domain-9 (ADAM9), Inflammation, Airway Remodeling, and Emphysema in COPD Patients.

Background and Objective: The link between ADAM9 and airway remodeling and emphysema severity in COPD patients has not been elucidated. Here, we investigated the relationship between ADAM9 levels in sputum and airway epithelium and the clinical characteristics of COPD patients. Methods: A sputum cohort and a lung tissue cohort were included in the study. Pulmonary function and computed tomography data were analyzed in COPD patients, non-COPD smokers, and non-smokers. Soluble ADAM9 and interleukin 8 (IL-8) levels in sputum supernatants as well as surface ADAM9 expression in airway epithelium were detected. Emphysema scores were calculated by the percentage of low attenuation area (%LAA-950), and airway remodeling was measured via airway thickening and loss of airway counts. Results: Both soluble ADAM9 levels in sputum and relative surface ADAM9 expression in airway epithelium were increased in COPD patients. Sputum ADAM9 levels were negatively correlated with forced expiratory volume in 1 s of predicted (FEV1% of predicted) and positively correlated with sputum IL-8 levels, but not with CT measured emphysema nor airway remodeling. The ADAM9 expression in airway epithelia was positively correlated with %LAA-950 and airway wall thickening parameters (wall area percentage, WA%; the square root of the wall area in a standard airway with a 10 mm internal perimeter, Pi-10), while negatively correlated with airway counts derived from the 4th to 9th bronchial generations. Conclusion: Airway ADAM9 levels in sputum and airway epithelium were both elevated in COPD patients compared to non-COPD controls. Sputum ADAM9 seemed to be associated with inflammatory responses in COPD, while epithelial ADAM9 was more correlated with emphysema and airway remodeling.

The link between chronic obstructive pulmonary disease phenotypes and histological subtypes of lung cancer: a case-control study.

BACKGROUND: COPD is considered an independent risk factor for lung cancer. COPD and lung cancer are both very heterogeneous diseases, and the study herein investigates the link between COPD phenotypes and specific histological subtypes of lung cancer. METHODS: This case-control study comprised 2,283 patients with newly diagnosed pathological lung cancer and 2,323 non-lung cancer controls. All participants underwent pulmonary function tests. The diagnosis of COPD was based on Global Initiative for Chronic Obstructive Lung Disease criteria. Subtypes of the two diseases were categorized according to 2015 World Health Organization classification of lung cancer and computer quantification of airway collapse on maximum expiratory flow volume. ORs were estimated using logistic regression analysis. RESULTS: The prevalence of COPD was higher (32.8%) in lung cancer patients compared to controls (16.0%). After adjustment for age, sex, body-mass index, and smoking status, the presence of COPD significantly increased the risk of lung cancer (OR 2.88, 95% CI 2.48-3.34) and all common histological subtypes (ORs 2.04-5.26). Both emphysema-predominant and non-emphysema-predominant phenotypes of COPD significantly increased the risk of lung cancer (OR 4.43, 95% CI 2.85-6.88; OR 2.82, 95% CI 2.40-3.31). Higher risk of squamous-cell carcinoma and small-cell lung cancer was observed in patients with the emphysema-predominant than the non-emphysema-predominant phenotype (OR 1.73, 95% CI 1.03-2.89; OR 3.74, 95% CI 1.64-8.53). CONCLUSION: COPD was an independent risk factor for lung cancer and all common histological subtypes. Both emphysema-predominant and non-emphysema-predominant phenotypes of COPD significantly increased the risk of lung cancer. Relative to non-emphysema-predominant phenotype of COPD, emphysema-predominant phenotype had a higher risk of squamous-cell carcinoma and small-cell lung cancer.

Impact of COPD on prognosis of lung cancer: from a perspective on disease heterogeneity.

BACKGROUND: COPD is an important comorbidity of lung cancer, but the impact of COPD on the outcomes of lung cancer remains uncertain. Because both COPD and lung cancer are heterogeneous diseases, we evaluated the link between COPD phenotypes and the prognosis of different histological subtypes of lung cancer. METHODS: In this retrospective study, subjects with a newly and pathologically confirmed diagnosis of lung cancer were enrolled from patients preparing for lung cancer surgery. All participants underwent pulmonary function test (PFT). The diagnosis of COPD was based on GOLD criteria. Lung cancer subtypes and COPD phenotypes were categorized by WHO classification of lung tumors and computer quantitative analysis of PFT. The HRs were estimated by Cox regression analysis. RESULTS: Among 2,222 lung cancer patients, 32.6% coexisted with COPD. After adjustment for age, sex, body mass index (BMI), smoking status, and therapy method, COPD was significantly associated with the decreased overall survival (OS) of lung cancer (HR 1.28, 95% CI 1.05-1.57). With the increased severity of COPD, the OS of lung cancer was gradually worsened (HR 1.23, 95% CI 1.08-1.39). But surgical treatment and high BMI were independent prognostic protective factors (HR 0.46, 95% CI 0.37-0.56; HR 0.96, 95% CI 0.94-0.99). Moreover, in terms of disease heterogeneity, emphysema-predominant phenotype of COPD was an independent prognostic risk factor for squamous carcinoma (HR 2.53, 95% CI 1.49-4.30). No significant relationship between COPD phenotype and lung cancer prognosis was observed among adenocarcinoma, small cell lung cancer, large cell lung cancer, and other subtype patients. CONCLUSION: These findings suggest that COPD, especially emphysema-predominant phenotype, is an independent prognostic risk factor for squamous carcinoma only.

Co-existence of COPD and bronchiectasis: a risk factor for a high ratio of main pulmonary artery to aorta diameter (PA:A) from computed tomography in COPD patients.

Background: Pulmonary vascular disease, especially pulmonary hypertension, is an important complication of COPD. Bronchiectasis is considered not only a comorbidity of COPD, but also a risk factor for vascular diseases. The main pulmonary artery to aorta diameter ratio (PA:A ratio) has been found to be a reliable indicator of pulmonary vascular disease. It is hypothesized that the co-existence of COPD and bronchiectasis may be associated with relative pulmonary artery enlargement (PA:A ratio >1). Methods: This retrospective study enrolled COPD patients from 2012 through 2016. Demographic and clinical data were collected. Bhalla score was used to determine the severity of bronchiectasis. Patient characteristics were analyzed in two ways: the high (PA:A >1) and low (PA:A ≤1) ratio groups; and COPD with and without bronchiectasis groups. Logistic regression analysis was used to assess risk factors for high PA:A ratios. Results: In this study, 480 COPD patients were included, of whom 168 had radiographic bronchiectasis. Patients with pulmonary artery enlargement presented with poorer nutrition (albumin, 35.6±5.1 vs 38.3±4.9, P<0.001), lower oxygen partial pressure (74.4±34.5 vs 81.3±25.4, P<0.001), more severe airflow obstruction (FEV1.0, 0.9±0.5 vs 1.1±0.6, P=0.004), and a higher frequency of bronchiectasis (60% vs 28.8%, P<0.001) than patients in the low ratio group. Patients with both COPD and bronchiectasis had higher levels of systemic inflammation (erythrocyte sedimentation rate, P<0.001 and fibrinogen, P=0.006) and PA:A ratios (P<0.001). A higher PA:A ratio was significantly closely correlated with a higher Bhalla score (r=0.412, P<0.001). Patients with both COPD and bronchiectasis with high ratios presented higher levels of NT-proBNP (P<0.001) and systolic pulmonary artery pressure (P<0.001). Multiple logistic analyses have indicated that bronchiectasis is an independent risk factor for high PA:A ratios in COPD patients (OR =3.707; 95% CI =1.888-7.278; P<0.001). Conclusion: Bronchiectasis in COPD has been demonstrated to be independently associated with relative pulmonary artery enlargement.

Spirometric Reference Equations for Elderly Chinese in Jinan Aged 60-84 Years.

BACKGROUND: The interpretation of spirometry varies on different reference values. Older people are usually underrepresented in published predictive values. This study aimed at developing spirometric reference equations for elderly Chinese in Jinan aged 60-84 years and to compare them to previous equations. METHODS: The project covered all of Jinan city, and the recruitment period lasted 9 months from January 1, 2017 to September 30, 2017, 434 healthy people aged 60-84 years who had never smoked (226 females and 208 males) were recruited to undergo spirometry. Vital capacity (VC), forced VC (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC, FEV1/VC, FEV6, peak expiratory flow, and forced expiratory flow at 25%, 50%, 75%, and 25-75% of FVC exhaled (FEF25%, FEF50%, FEF75%, and FEF25-75%) were analyzed. Reference equations for mean and the lower limit of normal (LLN) were derived using the lambda-mu-sigma method. Comparisons between new and previous equations were performed by paired t-test. RESULTS: New reference equations were developed from the sample. The LLN of FEV1/FVC, FEF25-75%computed using the 2012-Global Lung Function Initiative (GLI) and 2006-Hong Kong equations were both lower than the new equations. The biggest degree of difference for FEV1/FVC was 19% (70.46% vs. 59.29%, t = 33.954, P < 0.01) and for maximal midexpiratory flow (MMEF, equals to FEF25-75%) was 22% (0.82 vs. 0.67, t = 21.303, P < 0.01). The 1990-North China and 2009-North China equations predicted higher mean values of FEV1/FVC and FEF25-75%than the present model. The biggest degrees of difference were -4% (78.31% vs. 81.27%, t = -85.359, P < 0.01) and -60% (2.11 vs. 4.68, t = -170.287, P < 0.01), respectively. CONCLUSIONS: The newly developed spirometric reference equations are applicable to elderly Chinese in Jinan. The 2012-GLI and 2006-Hong Kong equations may lead to missed diagnoses of obstructive ventilatory defects and the small airway dysfunction, while traditional linear equations for all ages may lead to overdiagnosis.

High prevalence of bronchiectasis in emphysema-predominant COPD patients.

Background: COPD has been identified as an etiology or related disease of bronchiectasis, and bronchiectasis has been classified as a comorbidity of COPD. In this study, we investigated the prevalence of bronchiectasis in different phenotypes of COPD subjects and the correlation between bronchiectasis and different phenotypes, especially emphysema. Methods: COPD patients were recruited from April 2012 to December 2015. The presence of bronchiectasis and related information were statistically analyzed. COPD subjects were separated into subgroups in two ways: COPD with and without bronchiectasis groups and emphysema-predominant (emphysema index, EI≥9.9%) and non-emphysema-predominant (EI<9.9%) groups. Results: In total, 1,739 COPD patients were incorporated into the study, among which 140 cases (8.1%) were accompanied with radiological bronchiectasis. COPD patients with concomitant bronchiectasis presented worse pulmonary function (FEV1% predicted, P<0.001), higher EI (15.0% vs 13.4%, P<0.001), and higher proportion of pulmonary hypertension and cor pulmonale (6.4% vs 2.4%, P=0.005 and 23.6% vs 16.1%, P=0.022) than patients without bronchiectasis. Of all the COPD patients, 787 with EI data were divided into emphysema-predominant (n=369) and non-emphysema-predominant groups (n=418). The proportion of bronchiectasis was 16.5% and 10.3% (P=0.01), respectively. Severity of bronchiectasis increased as the degree of airflow limitation (r=-0.371, P<0.001) and emphysema increased (r=0.226, P=0.021). After adjusting confounding factors, FEV1% predicted (OR, 1.636; 95% CI, 1.219-2.197; P=0.001) and EI (OR, 1.993; 95% CI, 1.199-3.313; P=0.008) were significantly related with the presence of bronchiectasis in COPD patients. Conclusion: The proportion of bronchiectasis is higher in emphysema-predominant COPD subjects. Emphysema measured by EI and FEV1% predicted are independent predictors for bronchiectasis in COPD subjects, while the underlying mechanism deserves further investigation.

Role of inspiratory capacity on dyspnea evaluation in COPD with or without emphysematous lesions: a pilot study.

BACKGROUND: Since forced expiratory volume in 1 second (FEV1) shows a weak correlation with patients' symptoms in COPD, some volume parameters may better reflect the change in dyspnea symptoms after treatment. In this article, we investigated the role of inspiratory capacity (IC) on dyspnea evaluation among COPD patients with or without emphysematous lesions. METHODS: In this prospective study, 124 patients with stable COPD were recruited. During the baseline visit, patients performed pulmonary function tests and dyspnea evaluation using the modified Medical Research Council (mMRC) scale. Partial patients underwent quantitative computerized tomography scans under physicians' recommendations, and emphysematous changes were assessed using the emphysema index (EI; low attenuation area [LAA]% -950). These subjects were then divided into the emphysema-predominant group (LAA% -950≥9.9%) and the non-emphysema-predominant group (LAA% -950<9.9%). After treatment for ~1 month, subjects returned for reevaluation of both pulmonary function parameters and dyspnea severity. Correlation analysis between the change in IC (ΔIC) and dyspnea (ΔmMRC) was performed. RESULTS: Correlation analysis revealed that ΔIC was negatively correlated with ΔmMRC (correlation coefficient [cc], -0.490, P<0.001) in the total study population, which was stronger than that between ΔFEV1 and ΔmMRC (cc, -0.305, P=0.001). Patients with absolute ΔmMRC >1 were more likely to exhibit a marked increase in IC (≥300 mL) than those with absolute ΔmMRC ≤1 (74.36% versus 35.29%; odds ratio [OR], 5.317; P<0.001). In the emphysema-predominant group, only ΔIC strongly correlated with ΔmMRC (cc, -0.459, P=0.005), while ΔFEV1 did not (P>0.05). CONCLUSION: IC could serve as an effective complement to FEV1 in COPD patients undergoing dyspnea evaluation after treatment. For COPD patients with predominant emphysematous lesions, an increase in IC is particularly more suitable for explaining dyspnea relief than FEV1.

Computer quantification of "angle of collapse" on maximum expiratory flow volume curve for diagnosing asthma-COPD overlap syndrome.

BACKGROUND: In a previous study, we demonstrated that asthma patients with signs of emphysema on quantitative computed tomography (CT) fulfill the diagnosis of asthma-COPD overlap syndrome (ACOS). However, quantitative CT measurements of emphysema are not routinely available for patients with chronic airway disease, which limits their application. Spirometry was a widely used examination tool in clinical settings and shows emphysema as a sharp angle in the maximum expiratory flow volume (MEFV) curve, called the "angle of collapse (AC)". The aim of this study was to investigate the value of the AC in the diagnosis of emphysema and ACOS. METHODS: This study included 716 participants: 151 asthma patients, 173 COPD patients, and 392 normal control subjects. All the participants underwent pulmonary function tests. COPD and asthma patients also underwent quantitative CT measurements of emphysema. The AC was measured using computer models based on Matlab software. The value of the AC in the diagnosis of emphysema and ACOS was evaluated using receiver-operating characteristic (ROC) curve analysis. RESULTS: The AC of COPD patients was significantly lower than that of asthma patients and control subjects. The AC was significantly negatively correlated with emphysema index (EI; r=-0.666, P<0.001), and patients with high EI had a lower AC than those with low EI. The ROC curve analysis showed that the AC had higher diagnostic efficiency for high EI (area under the curve =0.876) than did other spirometry parameters. In asthma patients, using the AC ≤137° as a surrogate criterion for the diagnosis of ACOS, the sensitivity and specificity were 62.5% and 89.1%, respectively. CONCLUSION: The AC on the MEFV curve quantified by computer models correlates with the extent of emphysema. The AC may become a surrogate marker for the diagnosis of emphysema and help to diagnose ACOS.

Quantitative computed tomography measurements of emphysema for diagnosing asthma-chronic obstructive pulmonary disease overlap syndrome.

BACKGROUND: The diagnostic criteria of asthma-COPD overlap syndrome (ACOS) are controversial. Emphysema is characteristic of COPD and usually does not exist in typical asthma patients. Emphysema in patients with asthma suggests the coexistence of COPD. Quantitative computed tomography (CT) allows repeated evaluation of emphysema noninvasively. We investigated the value of quantitative CT measurements of emphysema in the diagnosis of ACOS. METHODS: This study included 404 participants; 151 asthma patients, 125 COPD patients, and 128 normal control subjects. All the participants underwent pulmonary function tests and a high-resolution CT scan. Emphysema measurements were taken with an Airway Inspector software. The asthma patients were divided into high and low emphysema index (EI) groups based on the percentage of low attenuation areas less than -950 Hounsfield units. The characteristics of asthma patients with high EI were compared with those having low EI or COPD. RESULTS: The normal value of percentage of low attenuation areas less than -950 Hounsfield units in Chinese aged >40 years was 2.79%±2.37%. COPD patients indicated more severe emphysema and more upper-zone-predominant distribution of emphysema than asthma patients or controls. Thirty-two (21.2%) of the 151 asthma patients had high EI. Compared with asthma patients with low EI, those with high EI were significantly older, more likely to be male, had more pack-years of smoking, had more upper-zone-predominant distribution of emphysema, and had greater airflow limitation. There were no significant differences in sex ratios, pack-years of smoking, airflow limitation, or emphysema distribution between asthma patients with high EI and COPD patients. A greater number of acute exacerbations were seen in asthma patients with high EI compared with those with low EI or COPD. CONCLUSION: Asthma patients with high EI fulfill the features of ACOS, as described in the Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease guidelines. Quantitative CT measurements of emphysema may help in diagnosing ACOS.