Introduction: Airway inflammation is the pathological hallmark of chronic inflammatory airway diseases, especially asthma and chronic obstructive pulmonary disease (COPD). Airway epithelium plays an indispensable role in these diseases by secreting inflammatory mediators and cytokines in response to foreign substances, such as lipopolysaccharide (LPS). Previous studies have shown that diarylpentanoid analogues, especially 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD) and 2-benzoyl-6-(3,4-dihydroxybenzylidene)cyclohexen-1-ol (BDHBC), significantly inhibited nitric oxide (NO) production; suggesting their anti-inflammatory property. However, the therapeutic potential of DHHPD and BDHBC in airway inflammation has not been explored. Thus, this study aims to investigate their effects on interleukin (IL)-6 and IL-8 gene expression in LPS-induced Calu-3 cells, a cellular model of human airway epithelium. Methods: MTT cytotoxicity assay was carried out to identify non-cytotoxic concentrations of DHHPD and BDHBC on Calu-3 cells. RT-PCR was done to determine IL-6 and IL-8 gene expression levels. Results: DHHPD and BDHBC were not cytotoxic on Calu-3 cells up to 200µM. Four non-cytotoxic concentrations were chosen – 6.25, 12.5, 25 and 50µM to determine the effect of both compounds on gene expression. All four concentrations of DHHPD and BDHBC significantly inhibited LPS-induced mRNA expression of IL-6 while all concentrations of BDHBC, except 6.25µM, significantly reduced IL-8 mRNA expression. Similar finding was obtained for DHHPD, except that at 50µM, there was no inhibition of IL-8 mRNA expression. Conclusion: Diarylpentanoid analogues, DHHPD and BDHBC, are proven to be effective in suppressing LPS-induced IL-6 and IL-8 gene expression. However, further studies are required to confirm their inhibitory effects on the production of pro-inflammatory cytokines.
Airway inflammation

Severe asthma is characterized by poor asthma control and frequent exacerbation despite high degree of medication. Severe asthma leads to not only increased morbidity and mortality but high socioeconomic burden. To date, several research networks have been organized to understand the clinical and pathophysiological characteristics of severe asthma. These groups organized multicenter registries and collected both clinical and biological information. The results of these groups revealed that severe asthma is a very heterogeneous entity, which could not be defined based on a single feature. Various phenotypes of asthma has been identified based on clinical, inflammatory and immune responses. To understand severe asthma more drastically in consideration of many phenotypes, cluster analysis and endotyping severe asthma have been tried. Although uncontrolled inflammation and airway remodeling underlies the development of severe asthma, much is not known about its pathomechanisms. This review discusses the current understanding of the clinical and pathogenic mechanisms of severe asthma based on the recent publications.
Airway Remodeling ; Asthma ; Inflammation ; Phenotype ; Registries

Variable airway obstruction, increased bronchial hyperresponsiveness, allergic inflammatory reaction and airway remodeling are main characteristics of asthma. Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases(TIMPs) do play important roles to pathogenesis and pathology of asthma via influence on the function and migration of inflammatory cells as well as extracellular matrix(ECM) deposition and degradation. MMP-9 is the predominant MMP in asthma and chronic obstructive pulmonary disease(COPD), and its expression is enhanced when asthma patients have spontaneous exacerbations or in response to local instillation of allergen in the airway. As acute inflammation of asthma resolves, MMP-9 levels return to normal. TIMPs bind MMPs in a 1:1 fashion. Thus, an increase in the molar ratio of MMP/TIMP can favor tissue injury, while the reverse ratio could be associated with increased fibrosis. Glucocorticosteroids could downregulate MMPs and enhance TIMPs. Even though it is clear that stimulated allergic inflammation in airway is associated with increased expression of MMPs, whether specific inhibitors of MMPs could reduce airway structural changes and facilitate orderly healing in asthma is still unknown.
Airway Obstruction ; Airway Remodeling ; Asthma* ; Fibrosis ; Humans ; Inflammation ; Matrix Metalloproteinase 9* ; Matrix Metalloproteinases ; Molar ; Pathology

Chronic obstructive pulmonary disease (COPD) is a slowly progressed disease characterized by chronic irreversible airway obstruction with increased airway resistance and loss of elastic recoil by lung parenchymal destruction. COPD is a leading cause of morbidity and mortality worldwide. COPD is defined as a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Pathological changes characteristic of COPD are found in the proximal airways, peripheral airways, lung parenchyma, and pulmonary vasculature, showing chronic inflammation, and structural changes resulting from repeated injury and repair mostly caused by inhaled cigarette smoke. This pathological changes lead to airway trapping and progressive airway limitation.
Airway Obstruction ; Airway Resistance ; Humans ; Inflammation ; Lung ; Pulmonary Disease, Chronic Obstructive ; Smoke ; Tobacco Products

Concept of asthma has changed from symptom-complex or airway hypersensitivity to airway inflammation and airway remodeling. Based on this concept asthma management guidelines (JGL) has been developed in Japan. Death from asthma has decreased drastically since the publication of the guidelines, although it is still high in elderly population. Further works are expected for "zero-death" from asthma and for tighter control of airway inflammation and resultant airway remodeling.
Aged ; Airway Remodeling ; Asthma ; Humans ; Hypersensitivity ; Inflammation ; Japan ; Publications

OBJECTIVE: To investigate the distribution of airway inflammation phenotype in patients with bronchial asthma (asthma), and to analyze clinical characteristics, inflammatory cytokines, pulmonary small vessels remodeling and small airway wall remodeling in patients with neutrophilic asthma. METHODS: Sixty-three patients with asthma were enrolled from January 2015 to December 2015 in Peking University Third Hospital. Clinical data including gender, age, body mass index (BMI), pulmonary function tests (PFTs), asthma control test (ACT) were recorded. All the patients underwent sputum induction. The cellular composition of the sputum was evaluatedand the concentration of active MMP-9 in the sputum tested. Blood routine tests were done and the concentration of IgE, periostin, and TGF-beta1 levels were measured in serum by enzyme-linked immunosorbent assay (ELISA). Small airway wall remodeling was measured in computed tomography (CT) scans, as the luminal diameter, luminal area, wall thickness and wall area % adjusted by body surface area (BSA) at the end of the 6th generation airway, in which the inner diameter was less than 2 mm. Small vascular alterations were measured by cross-sectional area (CSA), and the total vessel CSA < 5 mm² was calculated using imaging software. RESULTS: The distributions of airway inflammatory phenotypes of the asthmatic patients were as follows: neutrophilic asthma (34.9%, 22/63), eosinophilic asthma (34.9%, 22/63), mixed granulocytic asthma (23.8%, 15/63), and paucigranulocytic asthma (6.3%, 4/63). The neutrophilic subtype patients had a significantly higher active MMP-9 level in sputum compared with the eosinophilic phenotypepatuents, as 179.1 (74.3, 395.5) vs. 50.5 (9.7, 225.8), P<0.05. Sputum neutrophil count was negatively correlated with FEV1%pred (r=-0.304,P<0.05), and positively correlated with active MMP-9 level in sputum (r=-0.304, P<0.05), and positive correlation trend with airway wall thickness (r=0.533, P=0.06). There was a significantly negative correlation of active MMP-9 level in sputum with FEV1%pred (r=-0.281, P<0.05), in positive correlation with small airway wall area (%)(r=0.612, P<0.05), and inpositive correlation trend with airway wall thickness (r=0.612, P=0.06). Neutrophils count in peripheral blood was positively correlated with neutrophil counts in sputum. CONCLUSION Neutrophil count in airway is related to lung function in asthmatic patients. Neutrophils may accelerate small airway wall remodeling through the release of active MMP-9. Neutrophil count in peripheral blood is related to neutrophils count in sputum, which may be used as a substitute for evaluating inflammatory phenotype.
Airway Remodeling ; Asthma/physiopathology* ; Eosinophils ; Humans ; Inflammation ; Sputum

BACKGROUND: Airway remodeling of the asthmatic airway, the result of persistent inflammation in the bronchial wall, is associated with irreversible airway obstruction and the severity of asthma. Previous reports had represented that adminitering CpG-oligodeoxynucleotides (CpG-ODN) before sensitization or challenge by allergens inhibits the development of eosinophilic airway inflammation in a murine model of asthma, but the effects of CpG-ODNs on chronic inflammation and airway remodeling had not been characterized. To investigate the influence of CpG-ODNs on chronic inflammation and remodeling of the airway, we performed studies using a murine model of chronic allergen-induced asthma. METHODS: Balb/C mice were sensitized to ovalbumin(OVA) and subsequently exposed to nebulized OVA by means of inhalation twice weekly for 7 weeks. CpG-ODNs(30 microgram) was administered intraperitoneally at sensitization. After final inhalation, mice were evaluated for airway hyperresponsiveness, chronic airway inflammation and remodeling. RESULTS: The mice exposed to chronic and recurrent airway challenge with OVA had persistent airway hyperresponsiveness, chronic inflammation and airway remodeling. Mice treated with CpG-ODNs exhibited decreased bronchial hyperresponsiveness, OVA-specific IgE, chronic inflammation and evidence of airway remodeling, including goblet cell hyperplasia and subepithelial fibrosis. CONCLUSION: CpG-ODNs was thought to prevent chronic inflammation and remodeling changes in a murine model of chronic asthma.
Airway Obstruction ; Airway Remodeling ; Allergens ; Animals ; Asthma* ; Eosinophils ; Fibrosis ; Goblet Cells ; Hyperplasia ; Immunoglobulin E ; Inflammation* ; Inhalation ; Mice ; Ovum

PURPOSE: While asthma has been considered to be a completely reversible obstructive airway disease, many asthmatics have evidences of residual airway obstruction. Therefore, with the recent attention to the cells participating in inflammation, the definition of asthma was modified based on pathophysiologic observations including the inflammation of the airways. Airway inflammation, demonstrable in most of the asthmatics, is already present in the airways of patients with very mild asthma and is increased with the severity of the disease. It also has been associated with the development of airway hyperresponsiveness. However, the mechanisms by which the airway inflammation leads to airway hyperresponsiveness may result from various factors including the evidences of airway remodeling. These findings indicate that asthma is a disease with important airway remodeling which may leads to permanent tissue destruction. High-resolution computed tomography (HRCT) provides a high degree of anatomic details and can indirectly confirm airways remodeling in asthmatics, such as bronchial thickening, mucoid impaction, bronchial dilatation and bronchiectasis. METHODS: Twenty children with asymptomatic chronic moderate to severe asthma, who have visited pediatric allergy clinic in Soonchunhyang University, were performed HRCT to find out the airway changes in comparison with the asthma severity and the duration of asthma history. RESULTS: High resolution computed tomography revealed various findings, such as bronchial wall thickening, mosaic perfusion, atelectasis and bronchiectasis. The results indicate no positive correlation with the asthma severity and the duration of asthma history. CONCLUSION: Therefore, early intervention for diagnosis and treatment of asthma is very important to prevent the permenant chronic airway obstruction and airway remodeling in childhood asthma.
Airway Obstruction ; Airway Remodeling ; Asthma* ; Bronchiectasis ; Child ; Diagnosis ; Dilatation ; Early Intervention (Education) ; Humans ; Hypersensitivity ; Inflammation ; Perfusion ; Pulmonary Atelectasis

Asthma is characterized by airway inflammation, hyperresponsiveness, and remodeling, which are responsible for the variable airway obstruction and respiratory symptoms. Although a number of anti-asthma drugs have been developed, none has succeeded in managing symptoms and underlying airway inflammation as effectively as corticosteroids. However, systemic effects of the drugs were a major obstacle to use them in asthma therapy. A significant breakthrough in asthma therapy occurred when corticosteroids became available as inhaled preparations, reducing the potential for systemic effects while achieving excellent therapeutic efficacy. The first inhaled corticosteroid (ICS) having such characteristics was beclomethasone-17alpha, 21-dipropionate, which was introduced in the early 1970s. With growing information on their efficacy and the recognition of chronic inflammation as a fundamental component of asthma, ICSs have become the cornerstone of asthma therapy since the early 1990s. The potent anti-inflammatory effect of ICSs seems to be resulted mainly from the reduction of the number and activation of inflammatory cells in the bronchial mucosa and through their inhibitory effects on the synthesis of various mediators and cytokines. In addition, the airway selectivity is thought to come from a high hepatic first-pass inactivation rate of the drugs. A number of ICSs are currently on the market, and some drugs are available as the combination of an ICS and a long-acting beta2 agonist in a single inhaler. The present paper comprises a short background behind the development of ICSs, their pharmacologic and clinical profiles, and the current positions in asthma treatment.
Adrenal Cortex Hormones* ; Airway Obstruction ; Asthma* ; Cytokines ; Inflammation ; Mucous Membrane ; Nebulizers and Vaporizers

PURPOSE: Fractional exhaled nitric oxide (FeNO) is considered an indirect marker of airway inflammation, and forced expiratory flow between 25% and 75% of vital capacity (FEF25%-75%) is widely used as a sensitive indicator of small airway obstruction in asthma. The aim of this study was to investigate relationships between FeNO and FEF25%-75% in children with asthma. METHODS: A total of 118 children with asthma underwent spirometry and measurement of eosinophil markers. FeNO levels were measured, and skin prick tests to 13 common allergens were done. Study subjects were divided into 2 groups according to FEF25%-75% values (group 1, normal FEF25%-75%> or =65%pred, n=90; group 2, impaired FEF25%-75%<65%pred, n=28). RESULTS: The mean (+/-standard deviation, SD) age was not significantly different between groups 1 and 2 (10.3+/-2.8 years vs. 11.1+/-3.4 years), and the sex ratio was also not significantly different between 2 groups. The geometric mean (range of 1 SD) concentration of FeNO was significantly higher in group 2 than in group 1 (25.8 ppb [14.2-46.9 ppb] vs. 37.2 ppb [24.2-57.2 ppb], P=0.008). A significant inverse correlation between FeNO and FEF25%-75% was observed in group 2 (r=-0.493, P=0.038), but not in group 1 (r=-0.037, P=0.749) after adjustment for confounders, such as atopy, age, sex, weight, and height. CONCLUSION: FeNO levels were higher in group of asthmatic children with impaired FEF25%-75% level. FeNO levels were inversely correlated with FEF 25%-75% only in impaired small-airway obstruction group after adjustment for atopy. These results suggest that small-airway obstruction may relate more closely to airway inflammation in asthmatic children with impaired small-airway function.
Airway Obstruction ; Allergens ; Asthma* ; Child* ; Eosinophils ; Humans ; Inflammation ; Nitric Oxide* ; Sex Ratio ; Skin ; Spirometry ; Vital Capacity