Fang He

Exposure to Ambient Particulate Matter Induced COPD in a Rat Model and a Description of the Underlying Mechanism

While the health effects of air pollution have been an international public health concern since at least the 1950s, recent research has focused on two broad sources of air pollution, namely, biomass fuel (BMF) and motor vehicle exhaust (MVE). Many studies have shown associations between air pollution PM and exacerbations of pre-existing COPD, but the role of air pollution PM in the development and progression of COPD is still uncertain. The current study indicates that rats can develop pronounced COPD following chronic exposure to air pollution PM (BMF and MVE), as characterized by lung function reduction, mucus metaplasia, lung and systemic inflammation, emphysema, and small airway remodeling. Comparative analyses demonstrate that both BMF and MVE activate similar pathogenesis that are linked to the development of COPD. These findings also show that some differences are found in the lungs of rats exposed to BMF or MVE, which might result in different phenotypes of COPD.

Upregulation of Gelatinases and Epithelial–Mesenchymal Transition in Small Airway Remodeling Associated with Chronic Exposure to Wood Smoke

Background Peribronchiolar fibrosis is an important feature of small airway remodeling (SAR) in cigarette smoke-induced COPD. The aim of this study was to investigate the role of gelatinases (MMP9, MMP2) and epithelial-mesenchymal transition (EMT) in SAR related to wood smoke (WS) exposure in a rat model. Methods Forty-eight female Sprague-Dawley rats were randomly divided into the WS group, the cigarette smoke (CS) group and the clean air control group. After 4 to 7 months of smoke exposure, lung tissues were examined with morphometric measurements, immunohistochemistry and Western blotting. Serum MMP9 and TIMP1 concentrations were detected by ELISA. In vitro, primary rat tracheal epithelial cells were stimulated with wood smoke condensate for 7 days. Results The COPD-like pathological alterations in rats exposed chronically to WS were similar to those exposed to CS; the area of collagen deposition was significantly increased in the small airway walls of those exposed to WS or CS for 7 months. The expression of gelatinases in rats induced by WS or CS exposure was markedly increased in whole lung tissue, and immunohistochemistry showed that MMP9, MMP2 and TIMP1 were primarily expressed in the airway epithelium. The serum levels of MMP9 and TIMP1 were significantly higher in rats secondary to WS or CS exposure. Few cells that double immunostained for E-cadherin and vimentin were observed in the airway subepithelium of rats exposed to WS for 7 months (only 3 of these 8 rats). In vitro, the expression of MMP9 and MMP2 proteins was upregulated in primary rat tracheal epithelial cells following exposure to wood smoke condensate for 7 days by Western blotting; positive immunofluorescent staining for vimentin and type I collagen was also observed. Conclusions These findings suggest that the upregulation of gelatinases and EMT might play a role in SAR in COPD associated with chronic exposure to wood smoke.

Surgical Management of Urolithiasis in Patients after Urinary Diversion

Objective To present our experience in surgical management of urolithiasis in patients after urinary diversion. Patients and Methods Twenty patients with urolithiasis after urinary diversion received intervention. Percutaneous nephrolithotomy, percutaneous based antegrade ureteroscopy with semi-rigid or flexible ureteroscope, transurethral reservoir lithotripsy, percutaneous pouch lithotripsy and open operation were performed in 8, 3, 2, 6, and 1 patients, respectively. The operative finding and complications were retrospectively collected and analyzed. Results The mean stone size was 4.5±3.1 (range 1.5–11.2) cm. The mean operation time was 82.0±11.5 (range 55–120) min. Eighteen patients were rendered stone free with a clearance of 90%. Complications occurred in 3 patients (15%). Two patients (10%) had postoperative fever greater than 38.5°C, and one patient (5%) suffered urine extravasations from percutaneous tract. Conclusions The percutaneous based procedures, including percutaneous nephrolithotomy, antegrade ureteroscopy with semi-rigid ureteroscope or flexible ureteroscope from percutaneous tract, and percutaneous pouch lithotripsy, provides a direct and safe access to the target stones in patients after urinary diversion, and with high stone free rate and minor complications. The surgical management of urolithiasis in patients after urinary diversion requires comprehensive evaluation and individualized consideration depending upon the urinary diversion type, stone location, stone burden, available resource and surgeon experience.

Exon sequencing identifies a novel CHRNA3-CHRNA5-CHRNB4 variant that increases the risk for chronic obstructive pulmonary disease.

Recent genome‐wide association studies have established that single nucleotide polymorphisms in the CHRNA3‐CHRNA5‐CHRNB4 genes are susceptibility loci for chronic obstructive pulmonary disease COPD. However, further effort is still required to reveal their genetic contribution to COPD, considering the existence of ‘missing heritability’, which may be mediated by variants that are of a low frequency or rare. Here we aimed to identify genetic variants in the coding regions of the CHRNA3‐CHRNA5‐CHRNB4 genes and determine their associations with COPD risk in Chinese.

Positive feedback of the amphiregulin-EGFR-ERK pathway mediates PM2.5 from wood smoke-induced MUC5AC expression in epithelial cells

Biomass fuel smoke is thought to contribute to chronic obstructive pulmonary disease, which is characterized by mucous cell metaplasia and enhanced mucus secretion. We investigated the effect of particulate matter (PM) with a diameter <2.5 μm (PM2.5) from wood smoke (WSPM2.5) on the expression of the most prominent secreted mucin, MUC5AC. Wood smoke was able to induce MUC5AC expression in the rat respiratory tract after 3 months of exposure. WSPM2.5 could induce MUC5AC production in both primary human airway epithelial cells and the NCI-H292 cell line. This induction process was mediated by activation of epithelial growth factor receptor (EGFR)-extracellular signal-regulated kinase (ERK) signaling through an EGFR ligand-dependent mechanism. Amphiregulin (AR) was identified as the major ligand responsible for EGFR-ERK signaling activation and MUC5AC expression. In turn, EGFR-ERK pathway activation was found to contribute to the de novo synthesis of AR. This positive feedback loop might play an important role in a sustained mucus hypersecretion response.

The pro-proliferative effects of nicotine and its underlying mechanism on rat airway smooth muscle cells.

Recent studies have shown that nicotine, a major component of cigarette smoke, can stimulate the proliferation of non-neuronal cells. Cigarette smoking can promote a variety of pulmonary and cardiovascular diseases, such as chronic obstructive pulmonary disease (COPD), atherosclerosis, and cancer. A predominant feature of COPD is airway remodeling, which includes increased airway smooth muscle (ASM) mass. The mechanisms underlying ASM remodeling in COPD have not yet been fully elucidated. Here, we show that nicotine induces a profound and time-dependent increase in DNA synthesis in rat airway smooth muscle cells (RASMCs) in vitro. Nicotine also significantly increased the number of RASMCs, which was associated with the increased expression of Cyclin D1, phosphorylation of the retinoblastoma protein (RB) and was dependent on the activation of Akt. The activation of Akt by nicotine occurred within minutes and depended upon the nicotinic acetylcholine receptors (nAchRs). Activated Akt increased the phosphorylation of downstream substrates such as GSK3β. Our data suggest that the binding of nicotine to the nAchRs on RASMCs can regulate cellular proliferation by activating the Akt pathway.

Small airway disease: A different phenotype of early stage COPD associated with biomass smoke exposure

Chronic exposure to biomass smoke (BS) can significantly compromise pulmonary function and lead to chronic obstructive pulmonary disease (COPD). To determine whether BS exposure induces a unique phenotype of COPD from an early stage, with different physiopathological features compared with COPD associated with smoking (cigarette‐smoke (CS) COPD), we assessed the physiopathology of early COPD associated with BS exposure (BS COPD) by incorporating spirometry, high‐resolution computed tomography (HRCT) imaging, bronchoscopy and pathological examinations.

Nicotine reduces the levels of surfactant proteins A and D via Wnt/β-catenin and PKC signaling in human airway epithelial cells

A deficiency of surfactant proteins A and D has been proposed as a mechanism in airway remodeling, which is one characteristic of chronic obstructive pulmonary disease (COPD). We recently showed that in vitro nicotine exposure induces Wnt3a/β-catenin activation, which is a pathway that has also been implicated in altering levels of SP-A and SP-D. Nicotine induced activation of protein kinase C(PKC), and the involvement of PKC in mediating Wnt signaling has been demonstrated previously. The main aim of this study was to investigate whether human bronchial epithelial cells reduce levels of SP-A and SP-D in vitro following nicotine stimulation via the Wnt3a/β-catenin and PKC signaling pathway. We showed that nicotine activated the Wnt3a/β-catenin and PKC signaling pathway, and this activation was accompanied by a decrease in SP-A and SP-D expression. Knockdown of Wnt3a with small interfering RNA (siRNA) prevented translocation of β-catenin into the nucleus and reduction levels of SP-A and SP-D. Furthermore, a PKC inhibitor partially prevented these effects,which suggests in HBECs, Wnt3a/β-catenin and PKC pathways interact during nicotine-reduced levels of SP-A and SP-D. These results suggest that HBECs reduce the levels of surfactant proteins A and D in vitro via the Wnt3a/β-catenin and PKC signaling pathway upon nicotine stimulation.

Exposure to ambient particulate matter alters the microbial composition and induces immune changes in rat lung

BackgroundAmbient particulate matter exposure has been shown to increase the risks of respiratory diseases. However, the role of the lung microbiome and the immune response to inhaled particulate matter are largely unexplored. We studied the influence of biomass fuel and motor vehicle exhaust particles on the lung microbiome and pulmonary immunologic homeostasis in rats.MethodsFifty-seven Sprague–Dawley rats were randomly divided into clean air (CON), biomass fuel (BMF), and motor vehicle exhaust (MVE) groups. After a 4-week exposure, the microbial composition of the lung was assessed by 16S rRNA pyrosequencing, the structure of the lung tissue was assessed with histological analysis, the phagocytic response of alveolar macrophages to bacteria was determined by flow cytometry, and immunoglobulin concentrations were measured with commercial ELISA kits.ResultsThere was no significant difference in lung morphology between the groups. However, the BMF and MVE groups displayed greater bacterial abundance and diversity. Proteobacteria were present in higher proportions in the MVE group, and 12 bacterial families differed in their relative abundances between the three groups. In addition, particulate matter exposure significantly increased the capacity of alveolar macrophages to phagocytose bacteria and induced changes in immunoglobulin levels.ConclusionWe demonstrated that particulate matter exposure can alter the microbial composition and change the pulmonary immunologic homeostasis in the rat lung.

PM2.5 Induced the Expression of Fibrogenic Mediators via HMGB1-RAGE Signaling in Human Airway Epithelial Cells

Background The aim of the present study was to test whether fine particulate matter (PM2.5) induces the expression of platelet-derived growth factor-AB (PDGF-AB), PDGF-BB, and transforming growth factor-β1 (TGF-β1) in human bronchial epithelial cells (HBECs) in vitro via high-mobility group box 1 (HMGB1) receptor for advanced glycation end products (RAGE) signaling. Methods Sprague-Dawley rats were exposed to motor vehicle exhaust (MVE) or clean air. HBECs were either transfected with a small interfering RNA (siRNA) targeting HMGB1 or incubated with anti-RAGE antibodies and subsequently stimulated with PM2.5. Results The expression of HMGB1 and RAGE was elevated in MVE-treated rats compared with untreated rats, and PM2.5 increased the secretion of HMGB1 and upregulated RAGE expression and the translocation of nuclear factor κB (NF-κB) into the nucleus of HBECs. This activation was accompanied by an increase in the expression of PDGF-AB, PDGF-BB, and TGF-β1. The HMGB1 siRNA prevented these effects. Anti-RAGE antibodies attenuated the activation of NF-κB and decreased the secretion of TGF-β1, PDGF-AB, and PDGF-BB from HBECs. Conclusion PM2.5 induces the expression of TGF-β1, PDGF-AB, and PDGF-BB in vitro via HMGB1-RAGE signaling, suggesting that this pathway may contribute to the airway remodeling observed in patients with COPD.