Zhenyu Liang

High mobility group protein B1 (HMGB1) in Asthma: comparison of patients with chronic obstructive pulmonary disease and healthy controls.

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 (FEV1), FEV1 (% 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.

Mechanism of E-cadherin redistribution in bronchial airway epithelial cells in a TDI-induced asthma model☆

E-cadherin (epithelial cadherin), a transmembrane protein, provides essential architecture and immunological function to the airway epithelium, a barrier structure that plays an essential role in asthma pathogenesis. Toluene diisocyanate (TDI) is currently one of the leading causes of occupational asthma. However, relatively few studies have been undertaken to determine the biological effects of TDI on the barrier properties of airway epithelium, but it is known that TDI can damage airway epithelial tight junctions in vitro. Here, we hypothesize that TDI can injure E-cadherin both in normal and allergic-induced airway epithelium. To test this, we developed a murine model of TDI-induced asthma characterized by neutrophil-dominated airway inflammation, epithelial shedding, and obvious aberrant distribution of E-cadherin. Pretreatment with dexamethasone (DEX) significantly rescued the immunoreactivity of E-cadherin, accompanied by increased neutrophils in bronchoalveolar lavage fluid (BALF). In vitro, TDI-human serum albumin (HSA)-induced redistribution of E-cadherin was associated with extracellular signal-regulated kinase (ERK)1/2 activation. The inhibition of phospho-ERK (p-ERK)1/2 by DEX can partly reverse this reaction. These results indicate that E-cadherin redistribution may be an important contributor in the generation of TDI-induced asthma.

Erratum to: Increased heat shock protein 70 levels in induced sputum and plasma correlate with severity of asthma patients

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.

A Systemic Inflammatory Endotype of Asthma With More Severe Disease Identified by Unbiased Clustering of the Serum Cytokine Profile.

AbstractAsthma is considered as a clinical and molecularly heterogeneous disorder. Systemic inflammation is suggested to play an important role in a group of asthma patients. We hypothesized that there is a subgroup of patients with asthma characterized by systemic inflammation. In this study, we aimed to discriminate asthma subtypes based on circulating biomarkers and to determine whether a systemic inflammatory endotype of asthma could be identified. In the present cross-sectional study, 50 patients with untreated asthma were prospectively recruited from a single academic outpatient clinic, and characterized with respect to clinical, functional, and inflammatory parameters. The expression profiles of 20 serum cytokines were assessed by anti-human cytokine antibody array. Then, hierarchical clustering analysis was performed based on principal component analysis (PCA)-transformed data to classify the clinical groups. PCA showed that 6 independent components accounted for 80.113% of the variance, and PCA-based hierarchical clustering identified 3 endotypes. One of the endotypes was evidenced by elevated systemic inflammation markers such as leptin, vascular endothelial growth factor (VEGF), and reduced levels of soluble receptor for advanced glycation end products (sRAGE), an anti-inflammatory molecule. More female patients were included, with higher circulating neutrophil counts and more severe symptoms. In conclusion, we identified an endotype of asthma characterized by systemic inflammation and severe symptoms. Increased levels of VEGF, leptin and decreased level of sRAGE may contribute to the systemic inflammation of this asthma endotype.

Clinical Management of Acute Interstitial Pneumonia: A Case Report

We describe a 51-year-old woman who was admitted to hospital because of cough and expectoration accompanied with general fatigue and progressive dyspnea. Chest HRCT scan showed areas of ground glass attenuation, consolidation, and traction bronchiectasis in bilateral bases of lungs. BAL fluid test and transbronchial lung biopsy failed to offer insightful evidence for diagnosis. She was clinically diagnosed with acute interstitial pneumonia (AIP). Treatment with mechanical ventilation and intravenous application of methylprednisolone (80 mg/day) showed poor clinical response and thus was followed by steroid pulse therapy (500 mg/day, 3 days). However, she died of respiratory dysfunction eventually. Autopsy showed diffuse alveolar damage associated with hyaline membrane formation, pulmonary interstitial, immature collagen edema, and focal type II pneumocyte hyperplasia.