OBJECTIVE: To identify the underlying mechanism by which quercetin (Que) alleviates sepsis-related acute respiratory distress syndrome (ARDS). METHODS: In vivo, C57BL/6 mice were assigned to sham, cecal ligation and puncture (CLP), and CLP+Que (50 mg/kg) groups (n=15 per group) by using a random number table. The sepsisrelated ARDS mouse model was established using the CLP method. In vitro, the murine alveolar macrophages (MH-S) cells were classified into control, lipopolysaccharide (LPS), LPS+Que (10 μmol/L), and LPS+Que+acetylcysteine (NAC, 5 mmol/L) groups. The effect of Que on oxidative stress, inflammation, and apoptosis in mice lungs and MH-S cells was determined, and the mechanism with reactive oxygen species (ROS)/p38 mitogen-activated protein kinase (MAPK) pathway was also explored both in vivo and in vitro. RESULTS: Que alleviated lung injury in mice, as reflected by a reversal of pulmonary histopathologic changes as well as a reduction in lung wet/dry weight ratio and neutrophil infiltration (P<0.05 or P<0.01). Additionally, Que improved the survival rate and relieved gas exchange impairment in mice (P<0.01). Que treatment also remarkedly reduced malondialdehyde formation, superoxide dismutase and catalase depletion, and cell apoptosis both in vivo and in vitro (P<0.05 or P<0.01). Moreover, Que treatment diminished the release of inflammatory factors interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 both in vivo and in vitro (P<0.05 or P<0.01). Mechanistic investigation clarifified that Que administration led to a decline in the phosphorylation of p38 MAPK in addition to the suppression of ROS expression (P<0.01). Furthermore, in LPS-induced MH-S cells, ROS inhibitor NAC further inhibited ROS/p38 MAPK pathway, as well as oxidative stress, inflammation, and cell apoptosis on the basis of Que treatment (P<0.05 or P<0.01). CONCLUSION Que was found to exert anti-oxidative, anti-inflammatory, and anti-apoptotic effects by suppressing the ROS/p38 MAPK pathway, thereby conferring protection for mice against sepsis-related ARDS.
Animals ; Sepsis/drug therapy* ; Quercetin/therapeutic use* ; Respiratory Distress Syndrome/enzymology* ; p38 Mitogen-Activated Protein Kinases/metabolism* ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism* ; Apoptosis/drug effects* ; Male ; Oxidative Stress/drug effects* ; MAP Kinase Signaling System/drug effects* ; Lung/drug effects* ; Mice ; Lipopolysaccharides ; Macrophages, Alveolar/pathology* ; Inflammation/pathology* ; Protective Agents/therapeutic use*

Animals ; Humans ; Thymic Stromal Lymphopoietin ; Pyroglyphidae/metabolism* ; Cytokines/metabolism* ; Asthma/metabolism* ; Respiratory System ; Epithelial Cells/metabolism*

Mucociliary clearance system is the primary innate defense mechanism of the lung. It plays a vital role in protecting airways from microbes and irritants infection. Mucociliary clearance system, which is mediated by the actions of airway and submucosal gland epithelial cells, plays a critical role in a multilayered defense system via secreting fluids, electrolytes, antimicrobial and anti-inflammatory proteins, and mucus onto airway surfaces. Changes in environment, drugs or diseases can lead to mucus overproduction and cilia dysfunction, which in turn decrease the rate of mucociliary clearance and enhance mucus gathering. The dysfunction of mucociliary clearance system often occurs in several respiratory diseases, such as primary ciliary dysfunction, cystic fibrosis, asthma and chronic obstructive pulmonary disease, which are characterized by goblet cell metaplasia, submucosal gland cell hypertrophy, mucus hypersecretion, cilia adhesion, lodging and loss, and airway obstruction.
Humans ; Mucociliary Clearance ; Respiratory Tract Diseases ; Pulmonary Disease, Chronic Obstructive/metabolism* ; Mucus/metabolism* ; Lung ; Respiratory System

The aim of this study was to investigate the inhibitory effect and the underlying mechanism of ethacrynic acid (EA) on the contraction in mice. BL-420S force measuring system was used to measure the tension of mouse tracheal rings. The whole cell patch clamp technique was utilized to record the channel currents of airway smooth muscle (ASM) cells. The calcium imaging system was used to determine the intracellular Ca concentration ([Ca]) in ASM cells. The results showed that EA significantly inhibited the high K (80 mmol/L) and acetylcholine (ACh, 100 µmol/L)-induced contraction of mouse tracheal rings in a dose-dependent manner. The maximal relaxation percentages were (97.02 ± 1.56)% and (85.21 ± 0.03)%, and the median effective concentrations were (40.28 ± 2.20) μmol/L and (56.22 ± 7.62) μmol/L, respectively. EA decreased the K and ACh-induced elevation of [Ca] from 0.40 ± 0.04 to 0.16 ± 0.01 and from 0.50 ± 0.01 to 0.39 ± 0.01, respectively. In addition, EA inhibited L-type voltage-dependent calcium channel (LVDCC) and store-operated calcium channel (SOCC) currents in ASM cells, and Ca influx. Moreover, EA decreased the resistance of the respiratory system (Rrs) in vivo in mice. These results indicated that EA inhibits LVDCC and SOCC, which results in termination of Ca influx and decreases of [Ca], leading to relaxation of ASM. Taken together, EA might be a potential bronchodilator.
Animals ; Calcium ; metabolism ; Calcium Channels, L-Type ; Enzyme Inhibitors ; pharmacology ; Ethacrynic Acid ; pharmacology ; Mice ; Muscle Contraction ; drug effects ; Muscle, Smooth ; drug effects ; Respiratory System ; cytology ; drug effects

OBJECTIVE: To compare adverse event reporting patterns between ethical-the-counter and over-the-counter drugs from community pharmacies and outpatient settings. METHODS: We conducted a descriptive study using the adverse event reporting database, wherein data were collected from the regional pharmacovigilance centers of the Korean Pharmaceutical Association between January 1, 2016 and December 31, 2016. The reported drugs were classified into either ethical-the-counter or over-thecounter drugs, and we compared the distribution of patient age and gender, frequent adverse events and medications, serious adverse events, and causality assessment results, where causality assessments were performed according to the World Health Organization-The Uppsala Monitoring Centre's system. RESULTS: We included 17,570 reports (75,451 drug-adverse event pairs). Ethical-the-counter and over-the-counter drugs accounted for 81.4% and 18.6% of the total adverse event reports, respectively. The use of over-the-counter drugs was higher in females and patients aged <18 years, whereas the use of ethical-the-counter drugs was higher in those aged >65 years. Alimentary tract and metabolism drugs, and respiratory system drugs were the most frequent ethical-the-counter and over-the-counter drugs, respectively. From causality assessment results, “possible” (75.4%) was the most commonly assigned category for ethical-the-counter drugs, while “possible” (44.0%) and “unlikely” (47.7%) were the most common categories for over-the-counter drugs. The distribution of serious adverse events were similar for both ethical-thecounter and over-the-counter drugs. CONCLUSION: Differences were observed in age, gender, reported medications, and symptoms for both ethical-the-counter and over-the-counter drugs. Further pharmacovigilance activities considering the adverse event characteristics of over-the-counter drugs, which are comparable to ethical-the-counter drugs, should be performed.
Female ; Global Health ; Humans ; Metabolism ; Nonprescription Drugs* ; Outpatients ; Pharmacies* ; Pharmacovigilance ; Prescription Drugs ; Respiratory System

PURPOSE: High-sensitivity assays enabled the identification of C-reactive protein (hs-CRP) at levels that were previously undetectable. We aimed to determine if hs-CRP could reflect airway inflammation in children, by comparing hs-CRP with spirometry and impulse oscillometry (IOS) parameters and symptomatic severities. MATERIALS AND METHODS: A total of 276 asthmatic children who visited Severance Children's Hospital from 2012-2014 were enrolled. Serum hs-CRP and pulmonary function tests were performed on the same day. Patients were divided into hs-CRP positive and negative groups (cut-off value, 3.0 mg/L). RESULTS: Of the 276 asthmatic children [median age 7.5 (5.9/10.1) years, 171 boys (62%)], 39 were hs-CRP positive and 237 were negative. Regarding spirometry parameters, we observed significant differences in maximum mid-expiratory flow, % predicted (FEF25-75) (p=0.010) between hs-CRP positive and negative groups, and a negative correlation between FEF25-75 and hs-CRP. There were significant differences in the reactance area (AX) (p=0.046), difference between resistance at 5 Hz and 20 Hz (R5-R20) (p=0.027), resistance at 5 Hz, % predicted (R5) (p=0.027), and reactance at 5 Hz, % predicted (X5) (p=0.041) between hs-CRP positive and negative groups. There were significant positive correlations between hs-CRP and R5 (r=0.163, p=0.008), and X5 (r=0.164, p=0.007). Spirometry and IOS parameters had more relevance in patients with higher blood neutrophil levels in comparison to hs-CRP. CONCLUSION: Hs-CRP showed significant correlation with FEF25-75, R5, and X5. It can reflect small airway obstruction in childhood asthma, and it is more prominent in neutrophil dominant inflammation.
Airway Obstruction/*diagnosis/etiology ; Asthma/*diagnosis/physiopathology ; C-Reactive Protein/*analysis ; Child ; Child, Preschool ; Female ; Forced Expiratory Volume ; Humans ; Inflammation/*etiology ; Male ; Neutrophils/metabolism ; Oscillometry/*methods ; Respiratory Function Tests/*methods ; Respiratory System ; Sensitivity and Specificity ; *Spirometry

Changes in the respiratory system caused by aging generally include structural changes in the thoracic cage and lung parenchyma, abnormal findings on lung function tests, ventilation and gas exchange abnormalities, decreased exercise capacity, and reduced respiratory muscle strength. Decreased respiratory system compliance caused by reduced elastic recoil of the lung parenchymaand thoracic cage is related to decreased energy expenditure by the respiratory system. Lung function, as measured by 1-second forced expiratory volume and forced vital capacity (FVC), decreases with age, whereas total lung capacity remains unchanged. FVC decreases because of increased residual volume and diffusion capacity also decreases. Increased physiological dead space and ventilation/perfusion imbalance may reduce blood oxygen levels and increase the alveolar-arterial oxygen difference. More than 20% decrease in diaphragmstrength is thought to beassociated withaging-related muscle atrophy. Ventilation per minute remains unchanged, and blood carbon dioxide concentration does not increase with aging. However, responses to hypoxia and hypercapnia are decreased. Exercise capacity also decreases, and maximum oxygen consumption decreases by >1%/year. Consequence of these changes, many respiratory diseases occur with aging. Thus, it is important to recognize these aging-related respiratory system changes.
Aging* ; Anoxia ; Carbon Dioxide ; Compliance ; Diffusion ; Energy Metabolism ; Forced Expiratory Volume ; Hypercapnia ; Lung ; Muscular Atrophy ; Oxygen ; Oxygen Consumption ; Residual Volume ; Respiratory Function Tests ; Respiratory Muscles ; Respiratory System* ; Total Lung Capacity ; Ventilation ; Vital Capacity

Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways. Its main pathological manifestations include airway inflammation, mucus hypersecretion, oxidative stress and apoptotic epithelial cells. Recent research suggests that MAP kinases and Keap1-Nrf2-ARE signaling pathway are involved in the pathological process of inflammation and oxidative stress. This review explores the potential role of the cross talk of these signaling pathways in airway inflammation, mucus hypersecretion, oxidative stress and apoptotic epithelial cells. To clarify the roles of cross talk between MAP kinases and Keap1-Nrf2-ARE signaling pathway, we also focus on the drugs related to that in the treatment of COPD, and it provides ideas for more drug research in the treatment of COPD.
Apoptosis ; Epithelial Cells ; cytology ; Humans ; Inflammation ; Intracellular Signaling Peptides and Proteins ; Kelch-Like ECH-Associated Protein 1 ; Mitogen-Activated Protein Kinases ; NF-E2-Related Factor 2 ; Oxidative Stress ; Pulmonary Disease, Chronic Obstructive ; metabolism ; Respiratory System ; Signal Transduction

OBJECTIVETo explore the effect of miR-20b in inhibiting airway inflammation in a mouse model of asthma.

METHODSFemale BALB/c mouse models of asthma, established by sensitizing and challenging the mice with a mixture of ovalbumin and aluminum hydroxide, were subjected to intranasal instillation of 20 µg miR-20b mimics or a miR-20b scramble every 3 days. On day 49, bronchoalveolar lavage fluid (BALF) was collected from the mice to examine the counts of total cells and different cell populations; HE staining was used to observe the pathological changes of the lung tissue, and the concentration of vascular endothelial growth factor (VEGF) in BALF was detected by ELISA.

RESULTSTreatment of the asthmatic mice with miR-20b mimics decreased not only the counts of the total leukocytes, neutrophils and eosinophils in the BALF but also mucus secretion in the airway and inflammatory cell infiltration around the bronchus, and lessened thickening of the airway mucosa. Instillation with miR-20b mimics significantly reduced the concentration of VEGF in BALF from 28.55±3.42 pg/mL in the asthma model group to 18.19±3.67 pg/mL (P<0.01).

CONCLUSIONMiR-20b can inhibit airway inflammation in asthmatic mice possibly by reducing the expression of VEGF.

Animals ; Asthma ; physiopathology ; therapy ; Bronchi ; Bronchoalveolar Lavage Fluid ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Eosinophils ; Female ; Inflammation ; physiopathology ; therapy ; Leukocyte Count ; Lung ; Mice ; Mice, Inbred BALB C ; MicroRNAs ; pharmacology ; Neutrophils ; Ovalbumin ; Respiratory System ; physiopathology ; Vascular Endothelial Growth Factor A ; metabolism

BACKGROUNDAerobic exercise can improve symptoms, reduce airway inflammation, and even ameliorate airway remodeling in asthmatic animals and patients. However, previous studies have focused mainly on the effect of aerobic exercise on steroid-sensitive asthma (SSA). The goals of this study were to determine the effect of low-intensity aerobic exercise training on airway hyperresponsiveness, inflammation, and remodeling in a rat model of steroid-resistant asthma (SRA) and to identify the potential mechanisms underlying these effects.

METHODSEndotoxin-free ovalbumin with or without lipopolysaccharide were applied to establish rat models of SRA and SSA, respectively. Airway hyperresponsiveness, inflammation, remodeling, expression of interleukin (IL)-25, IL-33, thymic stromal lymphopoietin (TSLP), high mobility group box-1 (HMGB1), and IL-17 in bronchoalveolar lavage fluid (BALF), and the role of dexamethasone (DXM) were compared between these two asthmatic rat models. The effect of low-intensity aerobic exercise training and anti-HMGB1 treatment on airway hyperresponsiveness, inflammation, and remodeling in SRA rats also was evaluated.

RESULTSSRA rats developed neutrophil-dominated airway inflammation ((29.5±4.1)% of the total cell numbers in BALF), whereas SSA rats developed eosinophil-dominated airway inflammation ((24.0±6.1)% of the total cell numbers in BALF). Compared with SSA rats, SRA rats had more severe airway hyperresponsiveness, lower levels of IL-25 ((33.6±10.3) vs. (104.8±24.9) pg/ml), IL-33 ((87.5±25.0) vs. (226.6±40.7) pg/ml), and TSLP ((1 933.2±899.5) vs. (7 224.0±992.1) pg/ml), and higher levels of HMGB1 ((21.2±4.5) vs. (5.4±1.6) ng/ml) and IL-17 ((780.5±261.7) vs. (291.4±76.4) pg/ml) in BALF (all P < 0.05). However, there was no significant difference in goblet cell hyperplasia, subepithelial collagen thickness, and airway smooth muscle remodeling between the two groups. Compared with control SSA rats, airway hyperresponsiveness, inflammation, and remodeling in SRA rats were less sensitive to DXM treatment. Anti-HMGB1 treatment attenuated airway hyperresponsiveness, inflammation, and remodeling in SRA rats to a certain extent and was accompanied by lower levels of IL-17 ((369.2±126.7) vs. (780.5±261.7) pg/ml in control SRA rats) in BALF (P < 0.05). Low-intensity aerobic exercise training decreased the expression of both HMGB1 ((14.1±2.9) vs. (21.2±4.5) ng/ml in control SRA rats) and IL-17 ((545.3±148.6) vs. (780.5±261.7) pg/ml in control SRA rats) in BALF (all P < 0.05) and was accompanied by improved airway hyperresponsiveness, inflammation, and remodeling in SRA rats (all P < 0.05).

CONCLUSIONSLow-intensity aerobic exercise training attenuated airway hyperresponsiveness, inflammation, and remodeling in a rat model of SRA. Decreased HMGB1 and IL-17 levels in BALF by aerobic exercise training at least partly contributed to the improvements of SRA.

Airway Remodeling ; physiology ; Animals ; Asthma ; drug therapy ; metabolism ; therapy ; HMGB1 Protein ; metabolism ; Male ; Physical Conditioning, Animal ; methods ; Rats ; Rats, Sprague-Dawley ; Respiratory System ; physiopathology