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Asthma-COPD overlap (ACO) has been under intensive focus; however, the levels of damage-associated molecular patterns (DAMPs) that can activate the innate and adaptive immune responses of ACO are unknown. The present study aimed to examine the levels of some DAMPs in asthma, COPD, and ACO and to identify the associations between clinical characteristics and DAMPs in ACO. Sputum from subjects with asthma (n = 87) or COPD (n = 73) and ACO (n = 68) or from smokers (n = 62) and never-smokers (n = 62) was analyzed for high mobility group protein B1 (HMGB1), heat shock protein 70 (HSP70), LL-37, S100A8, and galectin-3 (Gal-3). The concentration of HMGB1, HSP70, LL-37, and S100A8 proteins in sputum from ACO patients was significantly elevated, whereas that of Gal-3 was reduced, compared to that of smokers and never-smokers. The levels of HMGB1 and Gal-3 proteins in ACO patients were elevated compared to those in asthma patients. The sputum from ACO patients showed an increase in the levels of LL-37 and S100A8 proteins compared to that of asthma patients, whereas the levels decreased compared to those of COPD patients. The concentrations of HMGB1, HSP70, LL-37, and S100A8 proteins in the sputum of 352 participants were negatively correlated, whereas the levels of Gal-3 were positively correlated, with FEV1, FEV1%pred, and FEV1/FVC. Sputum HMGB1 had a high AUC of the ROC curve while distinguishing ACO patients from asthma patients. Meanwhile, sputum LL-37 had a high AUC of the ROC curve in differentiating asthma and COPD. The release of sputum DAMPs in ACO may be involved in chronic airway inflammation in ACO; the sputum HMGB1 level might serve as a valuable biomarker for distinguishing ACO from asthma, and the sputum LL-37 level might be a biomarker for differentiating asthma and COPD.

The elevated S100A4 level has been found in some inflammatory diseases. However, the expression and role of S100A4 in asthma is unknown. The expression of S100A4 in induced sputum and plasma from healthy control and asthmatics were assessed by ELISA. Then an allergen-induced asthma mouse model treatment with anti-S100A4 antibody was used to explore the role of S100A4 in the pathogenesis of asthma. The S100A4 levels in sputum not in plasma in asthmatics were significantly increased than those of healthy controls and were negatively correlated with some lung function parameters and were positively correlated with sputum eosinophilia and lymphocyte. The expression of S100A4 in the lung as well as in BALF were also significantly higher in the asthma mouse model and treatment with anti-S100A4 antibody exhibited reductions in inflammatory cell accumulation, inflammatory mediators, and airway hyper-responsiveness. We further showed that LY294002, a specific inhibitor of PI3K, markedly decreased S100A4 expression in lung and S100A4 secretion in BALF in asthmatic mice. In conclusion, these data demonstrated that S100A4 may be involved in the pathogenesis of airway inflammation in asthma., (© 2018 Wiley Periodicals, Inc.)

The pro-inflammation factor high-mobility group box protein 1 (HMGB1) has been implicated in the pathogenesis of asthma. In this study, we used a murine model of chronic asthma to evaluate the effects of HMGB1 on airway remodeling. Female BALB/c mice were randomly divided into four groups: control, ovalbumin (OVA) asthmatic, OVA+isotype antibody and OVA+anti-HMGB1 antibody. Anti-HMGB1 antibody therapy was started on day 21 and was administered three times per week for 6 weeks before intranasal challenge with OVA. In this mouse model, HMGB1 expression is significantly elevated. The anti-HMGB1 antibody group exhibited decreased levels of immunoglobulin E (IgE) and inflammatory mediators and reduced inflammatory cell accumulation, airway hyperresponsiveness (AHR), mucus synthesis, smooth muscle thickness and lung collagen content compared with the OVA groups. Treatment with HMGB1 increased proliferation, migration, collagen secretion and α-smooth muscle actin (SMA) expression in MRC-5 cells. Treatment with the HMGB1/IL-1β complex significantly increased the expression and secretion of transforming growth factor (TGF-β1), matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF). Altogether, these results suggest that blocking HMGB1 activity may reverse airway remodeling by suppressing airway inflammation and modulating lung fibroblast phenotype and activation.

Background and Aim: Eosinophilic phenotype, sputum eosinophil count ≥3%, of asthma is a valuable clinical parameter. However, measurement of sputum inflammatory cells is time-consuming and requires specialized personnel. A simpler surrogate, such as peripheral eosinophil count, would be beneficial. The aim of this study was to assess the value of peripheral eosinophil count for predicting the eosinophilic phenotype of adult asthmatics., Materials and Methods: This retrospective study was conducted in 192 adult asthmatics. Sputum and venous blood were collected at the same visit and analyzed for cell differential. Receiver-operating characteristic (ROC) curve analysis was used to assess the relationship between eosinophilic phenotype and peripheral eosinophil count., Results: Peripheral eosinophil count, derived from the ROC curve, of more than 210 cells/mm(3) yielded 67.7% sensitivity and 66.2% specificity [area under the curve (AUC)=0.698, p=0.0001] for identifying the eosinophilic phenotype in the total patients. Multiple regression analysis revealed that steroid treatment and atopy significantly influenced the peripheral eosinophil count. Within the steroid-naïve subgroup, a peripheral eosinophil count of >190 cells/mm(3) yielded 76.3% sensitivity and 67.4% specificity (AUC=0.730, p<0.0001) for identifying eosinophilic phenotype, while in the steroid treated subgroup, the AUC was 0.554 (p=0.4985). Within the steroid-naïve non-atopic subgroup, a peripheral eosinophil count of >190 cells/mm(3) yielded 73.1% sensitivity and 79.3% specificity (AUC=0.809, p=0.0001) for identifying the eosinophilic phenotype, while in the steroid-naïve atopic subgroup, the AUC was 0.588 (p=0.2723)., Conclusion: Peripheral eosinophil count is able to identify the presence of eosinophilic phenotype in steroid-naïve non-atopic adult asthmatics with moderate accuracy.

Damage-associated molecular pattern molecules such as high-mobility group box 1 protein (HMGB1) and heat shock protein 70 (HSP70) have been implicated in the pathogenesis of asthma. The aim of our study was to examine the induced sputum and plasma concentrations of HSP70 in asthmatic patients to determine their relationship with airway obstruction. Thirty-four healthy controls and 56 patients with persistent bronchial asthma matched for gender and age were enrolled in this study. Spirometry measurements were performed before sputum induction. HSP70 levels in induced sputum and plasma were measured using the ELISA Kit. Sputum and plasma concentrations of HSP70 in asthmatics patients were significantly higher than that in control subjects (sputum, (0.88 ng/ml (0.27-1.88 ng/ml) versus 0.42 ng/ml (0.18-0.85 ng/ml), p < 0.001); plasma, (0.46 ng/ml (0.20-0.98 ng/ml) versus 0.14 ng/ml (0.11-0.37 ng/ml), p < 0.001) and were significantly negatively correlated with forced expiratory volume in 1 s (FEV1), FEV1 (percent predicted), and FEV1/FVC in all 90 participants and 56 patients with asthma. There were no significant differences in HSP70 levels between patients with eosinophilic and non-eosinophilic asthma. HSP70 levels in plasma were positively correlated with neutrophil count, and HSP70 levels in induced sputum were positively correlated with lymphocyte count. In multivariate analysis, independent predictors of sputum HSP70 were diseases and disease severity but not smoking, age, or gender, and independent predictors of plasma HSP70 were also diseases and disease severity. In conclusion, this study indicates that induced sputum and plasma HSP70 could serve as a useful marker for assessing the degree of airway obstruction in patients with asthma. However, further investigation is needed to establish the role of circulating and sputum HSP70 in the pathogenesis of asthma.

High mobility group protein B1 (HMGB1) has been implicated as an important mediator in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). However, the expression of HMGB1 in plasma and sputum of patients with asthma and COPD across disease severity needs to be defined. The objective of the study was to examine the induced sputum and plasma concentrations of HMGB1 in COPD and asthmatic patients to determine differences in HMGB1 levels between these diseases and their relationship with airway obstruction and inflammatory patterns. A total of 147 participants were enrolled in this study. The participants included 34 control subjects, 61 patients with persistent asthma (according to the Global Initiative for Asthma [GINA] guidelines) and 47 patients with stable COPD (stratified by Global Initiative for Chronic Obstructive Lung Disease [GOLD] status). Spirometry was performed before sputum induction. HMGB1 levels in induced sputum and plasma were determined by enzyme-linked immunosorbent assay. Sputum and plasma concentrations of HMGB1 in patients with asthma and COPD were significantly higher than concentrations in control subjects and were significantly negatively correlated with forced expiratory volume in 1 s (FEV(1)), FEV(1) (% predicted) in all 147 participants. The levels of HMGB1 in induced sputum of COPD patients were significantly higher than those of asthma patients and healthy controls (P < 0.001). This difference was present even after adjusting for sex, age, smoking status, daily dose of inhaled corticosteroids and disease severity. There were no significant differences in HMGB1 levels between patients with eosinophilic and noneosinophilic asthma. HMGB1 levels in asthmatic and COPD patients were positively correlated with neutrophil counts and percentage of neutrophils. In multivariate analysis, the two diseases (asthma and COPD) and disease severity were independent predictors of sputum HMGB1, but not smoking, age or use of inhaled corticosteroids. In conclusion, these data support a potential role for HMGB1 as a biomarker and diagnostic tool for the differential diagnosis of asthma and COPD. The importance of this observation on asthma and COPD mechanisms and outcomes should be further investigated in large prospective studies.

Background: The abnormal proliferation and migration of airway smooth muscle (ASM) cells contributes to airway remodeling during asthma. MiR-19a has been demonstrated to promote cell proliferation and angiogenesis of several cancer types by regulating the PTEN/PI3K/AKT pathway. Our previous study has shown that High-mobility group box protein 1 (HMGB1) is involved in the pathogenesis of airway remodeling using a mouse model of chronic asthma. However, the effects of HMGB1 on proliferation and migration of ASM cells and its underlying mechanisms remain unknown. Methods: Human ASM cells were obtained by primary explant techniques. MiR-19a expression was evaluated using qRT-PCR. Cell proliferation and migration were evaluated by the CCK-8 and the transwell migration assays, respectively. Transfection studies of ASM cells were performed to identify the underlying mechanisms. Results: HMGB1 stimulated ASM cell proliferation and migration in a dose-dependent manner. The expression levels of miR-19a and the PTEN and AKT signaling proteins were also modulated by HMGB1. Functional studies indicated that overexpression of miR-19a enhanced the proliferation and migration of ASM cells, whereas inhibition of miR-19a decreased the proliferation and migration of ASM cells. Western blot analysis demonstrated that miR-19a negatively regulated PTEN expression and positively regulated p-AKT expression. MiR-19 only regulates the proliferation of HASM cells induced by HMGB1, but not PDGF, EGF, TGF-β1. Furthermore, we demonstrated that miR-19 contributed to the promoting effects of HMGB1 on ASM cells by targeting PTEN 3’-UTR. Conclusion: Our results demonstrated that HMGB1 induced proliferation and migration of ASM cells via the miR-19a /PTEN/AKT axis and provided direct evidence on the role of HMGB1 in ASM cells proliferation in vitro. The present study further indicated that miR-19a may be explored as a potential novel therapeutic target to reverse proliferation and migration of ASM cells. [ABSTRACT FROM AUTHOR]