Peripheral Airways Of Patients Research Articles

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases.

Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16INK4a, respectively, leading to activation of p21CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype, leading to low-grade chronic inflammation, which further drives senescence. Loss of key antiaging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN (phosphatase tensin homolog), thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a (miR-34a), which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6, and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing senescence-associated secretory phenotype, and reversing cell cycle arrest in epithelial cells from peripheral airways of patients with COPD. miR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 mitogen-activated protein kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but also outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs, or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

Aerosol Deposition of Inhaled Corticosteroids/Long-Acting β2-Agonists in the Peripheral Airways of Patients with Asthma Using Functional Respiratory Imaging, a Novel Imaging Technology

Drug deposition in the peripheral airways has been reported to differ between pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). This study was conducted to determine the drug deposition fraction from three inhaled corticosteroids/long-acting β2-agonists (ICS/LABA) combination products for inhalation in the peripheral airways. An airway deposition model was constructed using computed tomography (CT) images obtained in patients with asthma. Functional respiratory imaging was used to determine the airway deposition of Flutiform® (Kyorin Pharmaceutical), Symbicort® (AstraZeneca and Astellas Pharma), and Relvar® (GlaxoSmithKline K.K.) without actual drug inhalation based on airway images from CT and computational fluid dynamics using drug particle size. The mean drug deposition fractions and standard deviations (SDs) in the peripheral airways for Flutiform, Symbicort, and Relvar were 30.33% ± 1.89%, 18.95% ± 2.03%, and 6.58% ± 0.98% for ICS, and 29.17% ± 1.81%, 17.24% ± 1.87%, and 11.30% ± 1.42% for LABA, respectively, showing that significantly higher proportions of ICS and LABA were deposited to the peripheral airways from Flutiform than from Symbicort and Relvar (p < 0.001). The mean drug deposition fractions and SDs in the entire lung for Flutiform, Symbicort, and Relvar were 46.18% ± 1.29%, 28.85% ± 0.78%, and 13.01% ± 0.66% for ICS, and 44.34% ± 1.23%, 26.32% ± 0.71%, and 20.02% ± 0.80% for LABA, respectively, showing that significantly higher proportions of ICS and LABA were deposited to the lung from Flutiform than from Symbicort and Relvar (p < 0.001). Flutiform (pMDI) was shown to provide significantly higher drug deposition fraction to the central/peripheral airways than Symbicort (DPI) and Relvar (DPI). It is suggested that Flutiform may provide a potent therapeutic option for various asthma patients, including those who have difficulty using DPIs. UMI22840. Kyorin Pharmaceutical Co., Ltd.

Pharmacological effects of lysozyme on COPD and bronchial asthma with sputum: A randomized, placebo-controlled, small cohort, cross-over study

BackgroundMucolytic agents are often used in Japan to ease excessive mucus production in patients with chronic obstructive pulmonary disease (COPD) or bronchial asthma (BA); the treatment ameliorates dyspnea and improves quality of life (QOL). AimEfficacy and safety of lysozyme hydrochloride (LYS), an oral mucolytic enzyme preparation, for patients with COPD or BA were investigated. Patients and methodsThis study was a placebo-controlled, double-blind, randomized, cross-over design. Twenty-four patients with COPD and twenty-four patients with BA were enrolled. LYS or placebo was administered for 28 days in each treatment period, with a 28-day washout between the first and second treatment periods. The results of spirometry, impulse oscillometry system (IOS) examination, fractional exhaled nitric oxide (FeNO) measurement, as well as the changes in the subjective symptoms, were evaluated after the treatment period. ResultsOn spirometry, airway function (FEV1) improved in patients with COPD after administration of LYS (LYS vs placebo: 0.08 L vs 0.029 L, p = 0.030). Similar trends were also found in %FEV1 in COPD patients. On IOS examination, resistance of the respiratory system at 5 Hz levels was significantly improved only in patients with COPD (LYS vs placebo: −0.455 cm H2O/L/s vs 0.095 cmH2O/L/s, p = 0.012). Similar trends were found in terms of the resistance of the respiratory system at 20 Hz, and of the reactance area. In the COPD assessment test, subjective symptoms also significantly improved in patients with COPD during the LYS treatment period (improvement rates—LYS vs. placebo: 69.6% vs. 39.1%; p = 0.022). A similar effect of LYS was not seen in BA patients. ConclusionLYS, a mucolytic agent, has capability to improve the function of peripheral airways in patients with COPD, which leads to improvements of the patients' symptoms and QOL.

Use of Volumetric Capnography in Submaximal Exercise Test: What Did We Learn?

Tools that assess the response of the body to exercise activities have been sought in numerous clinical situations. Chronic obstructive pulmonary diseases such as cystic fibrosis (CF) may lead to reduction or limitation in exercise performance by ventilator factors. Consequently, a reduction in lung function can be observed, characterized by decreased respiratory reserve and dynamic hyperinflation during exercise. Various instruments have been developed and studied in thepediatricpopulation in order to evaluate the functional capacity during exercise, being grouped into maximal tests and submaximal tests. The difference between maximal and submaximal tests depends on whether the test is performed in an open area or laboratory, with ergometers or not. In the maximal test, the individual performs the activity to achieve voluntary exhaustion, leading the participant to the fullest of their oxygen uptake and/or estimated (more than 90%) heart rate (HR). In the submaximal tests, the HR is located around 75% to 90% of the maximum estimated HR. In the study, we used a reproducible exercise test protocol in accordance with the pediatric age group. We used the VCap, as an evaluation feature for lung function in children and adolescents with CF and with various degrees of severity of lung disease. We have identified the inhomogeneity of distribution of ventilation in the peripheral airways of patients with normal spirometry. Our findings collaborate with the idea that the VCap is a respiratory assessment tool that is practical, inexpensive and easy to use. The VCap provides information on the pulmonary involvement by the indices and is considered an assessment tool of the degree of regional heterogeneity of the lung for gas exchange. Thus, the VCap is a tool that can be used for analysis of ventilatory efficiency during exercise, providing evidence that the cardiorespiratory response that can be measured non-invasively during exercise testing.

Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: A systematic review

Traditionally, asthma has been considered a disease that predominantly involves the large airways. Today, this concept is being challenged, and increasing evidence has become available showing that abnormalities in the small airways also contribute to the clinical expression of asthma. The small airways can be affected by inflammation, remodeling, and changes in the surrounding tissue, all contributing to small-airways dysfunction. In this article we have performed a systematic review of the literature on the association between small-airways dysfunction and clinical signs and symptoms of asthma. This review shows that small-airways dysfunction associates with worse control of asthma, higher numbers of exacerbations, the presence of nocturnal asthma, more severe bronchial hyperresponsiveness, exercise-induced asthma, and the late-phase allergic response. Importantly, small-airways dysfunction can already be present in patients with mild asthma. Our review provides suggestive evidence that a better response of the small airways to inhaled steroids or montelukast associates with better asthma control. For this reason, an early recognition of small-airways dysfunction is important because it enables the physician to start timely treatment to target the small airways. It is important to develop simpler and more reliable tools (eg, questionnaires or bronchial provocation tests with small-particle stimuli) to assess the presence and extent of small-airways dysfunction in daily clinical practice.

Increased levels ofNε-(carboxymethyl)lysine in epithelial lining fluid from peripheral airways in patients with chronic obstructive pulmonary disease: a pilot study

It has been reported that small airway inflammation is closely associated with the severity of airflow limitation in COPD (chronic obstructive pulmonary disease). We tested a new method of measurement of biochemical constituents in ELF (epithelial lining fluid) obtained separately from the central or peripheral airways using a bronchoscopic microsampling technique. The present study was designed to determine the validity of measuring CML [N(epsilon)-(carboxymethyl)lysine] levels in ELF for the assessment of small airway inflammation in COPD. Ten non-smokers, ten current smokers and 16 COPD patients were included in the present study. Concentrations of CML, 8-isoprostane and IL-8 (interleukin-8) were measured in ELF separately from the central or peripheral airways. CML levels in central airways did not differ significantly, but were markedly higher in peripheral than in central airways in the three groups. However, CML levels in peripheral airways of COPD patients were significantly higher than those in non-smokers and current smokers. In COPD patients, the CML level in peripheral airways was significantly correlated with FEV1 (forced expiratory volume in 1 s) (r=-0.82, P=0.002) and FEV1/FVC (forced vital capacity) (r=-0.57, P=0.03). Moreover, CML levels in peripheral airways were significantly correlated with levels of both 8-isoprostane (r=0.76, P=0.003) and IL-8 (r=0.67, P=0.01). In conclusion, these findings suggest that elevated levels of CML in ELF from peripheral airways were observed in COPD patients, and this parameter was correlated with the severity of airflow limitation.

T cell receptor heterodimer (alpha beta/gamma delta) expressions in diffuse panbronchiolitis

Several reports have indicated that T cells bearing gamma delta T cell receptor (TCR) are major effector cells in mucosal immunity of the murine intestinal tract. In humans, abnormal distribution of gamma delta + T cells has also been found in inflammatory bowel diseases. We studied TCR heterodimer expressions in lymphocytes infiltrating the peripheral airways in patients with diffuse panbronchiolitis (DPB), because DPB is histologically characterized by chronic inflammation in bronchioles and could be a model for investigation of the significance of gamma delta + T cells in persistent inflammation of the human respiratory tract. Open lung biopsy specimens were obtained from 7 patients and peripheral blood lymphocytes (PBL) from 9 patients. Immunohistochemically, we detected alpha beta and gamma delta TCR by avidin-biotin complex immunoperoxidase method, utilizing BMA 031 and TCR delta 1 monoclonal antibody, respectively, PBL were analyzed by flow cytometry. Histological analysis revealed that DPB lesions mainly involved the bronchiolar walls with marked infiltration of small round cells. Many T cells were distributed in the submucosal area, although few T cells infiltrated the epithelium. Most of the T cells in the bronchioles expressed alpha beta TCR (98.7%), whereas only 1.3% expressed gamma delta TCR. There was no significant difference in the percentage of gamma delta + T cells in PBL between DPB and age- and sex-matched controls (6.7% vs. 9.1%). These results suggest that the increase of T cells bearing alpha beta TCR played a major role. However, the possibility that the decrease of T cells bearing gamma delta TCR caused reduced mucosal defense against external antigens, leading to persistent inflammation of the lower respiratory tracts in DPB, is not excluded.

Anatomy, pathology, and physiology of the tracheobronchial tree: Emphasis on the distal airways

This article covers the airway tree with respect to anatomy, pathology, and physiology. The anatomic portion discusses various primate groups so as to help investigators understand similarities and differences between animal models. An emphasis is on distal airway findings. The pathology section focuses on the inflammatory responses that occur in proximal and distal airways. The physiologic review brings together the anatomic and pathologic components to the functional state and proposes ways to evaluate the small airways in patients with asthma.

Activation of Nuclear Factor-κB in Airway Epithelial Cells in Patients with Chronic Obstructive Pulmonary Disease

Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation. Nuclear factor-ĸB (NF-ĸB) is a transcription factor that mediates proinflammatory gene expression. NF-ĸB is activated when its inhibitor, IĸBα, is phosphorylated and degraded. Objectives: The aims of this study were to compare the number of phosphorylated IĸBα-immunopositive airway epithelial cells (AECs) in the peripheral airways of patients with COPD, asymptomatic smokers and asymptomatic nonsmokers. Methods: We examined lung tissues obtained from 10 smokers with COPD, 7 asymptomatic smokers and 10 asymptomatic nonsmokers. Paraffin-embedded sections and immunohistochemical techniques were used to assess the number of phosphorylated IĸBα-positive AECs as well as the numbers of tumor necrosis factor (TNF)α-positive, 8-hydroxy-2′-deoxyguanosine (8-OHdG)-positive and 4-hydroxy-2-nonenal (4-HNE)-positive AECs in the peripheral airway specimens. Results: The percentages of phosphorylated IĸBα-positive AECs and TNFα-positive AECs out of the total number of AECs were significantly higher in patients with COPD than in asymptomatic nonsmokers (p < 0.05). The percentage of phosphorylated IĸBα-positive AECs was positively correlated with the percentage of TNFα-positive AECs (r = 0.82, p < 0.01), but not with the percentage of 8-OHdG-positive AECs or the percentage of 4-HNE-positive AECs. Conclusions: The activation of NF-ĸB, which was evaluated by measuring the level of phosphorylated IĸBα, was enhanced in the peripheral airway epithelia of the COPD patients in this study. The activation of NF-ĸB in the peripheral airway epithelium is associated with an elevated level of TNFα and seems to occur through a mechanism independent of oxidative stress.

Evidence of remodeling in peripheral airways of patients with mild to moderate asthma: Effect of hydrofluoroalkane-flunisolide

We have shown previously that inflammation in asthma is not restricted to central airways but can also be demonstrated in peripheral airways. It is not clear whether inflammation of the peripheral airways is associated with structural changes and whether this remodeling process can be modulated by deposition of inhaled corticosteroids (ICSs). To compare remodeling in peripheral and central airways and to investigate the effects of hydrofluoroalkane (HFA)-ICS on remodeling at these sites. Transbronchial and endobronchial biopsies were obtained from 12 patients with mild to moderate asthma before and after a 6-week course of HFA-ICS (flunisolide). Total collagen deposition, expression of collagen III, TGF-beta, and alpha-smooth muscle actin were examined by using Van Gieson staining and immunocytochemistry, respectively. Total collagen occupied 37.7% of the wall area of peripheral airways, compared with 54.5% of the wall area of central airways (P = .04). There was no significant difference in central versus peripheral airways for collagen III or alpha-smooth muscle actin immunoreactivity and in the number of TGF-beta(+) cells in the submucosa. The only significant effect of HFA-flunisolide was a decrease in alpha-smooth muscle actin area in peripheral airways (13.4% vs 4.6%; P = .01) that correlated with the percentage increase in forced expiratory flow at 25% to 75% of vital capacity (r(s) = -1.00; P = .00). Our data show that there is a considerable degree of airway remodeling in peripheral airways in patients with asthma and confirm the inability of ICS to modulate collagen deposition and TGF-beta expression. Treatment with HFA-flunisolide is associated with a significant decrease in the expression of alpha-smooth muscle actin in peripheral airways, which correlated with improvement in peripheral airway function.

Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease

To study the expression of mucins in peripheral airways in patients with chronic obstructive pulmonary disease (COPD). Peripheral lung sections from smokers with COPD (n = 9) and age-matched controls including smokers (n = 11) and lifelong non-smokers with normal lung function (n = 6) were stained with alcian blue, periodic acid-Schiff (PAS) and by immunohistochemistry of mucins (MUC): MUC2, MUC4, MUC5AC, MUC5B and MUC6. Histochemical staining and immunoreactivity of bronchiolar epithelium were graded and the presence or absence of stained mucus in the bronchiolar lumen was evaluated. There were no differences in alcian blue and PAS epithelial staining between the three groups. Intraluminal PAS staining was significantly more frequent among COPD subjects (P < 0.05). The expression of MUC5AC was significantly higher in the bronchiolar epithelium of patients with COPD (P < 0.05). Within the bronchiolar lumen, the predominant mucin was MUC5B. Intraluminal MUC5B was significantly more frequent among COPD patients (P < 0.05). COPD is specifically associated with increased expression of MUC5B in the bronchiolar lumen and of the mucin MUC5AC in the bronchiolar epithelium. These changes in mucin production in the peripheral airways may contribute to the pathophysiology of COPD.

Characteristic modifications of the peripheral airways in patients with bronchial asthma in areas with air pollution.

Changes in the peripheral airways in patients with bronchial asthma who were living in the Kawasaki industrial zone, region with severe air pollution, were morphologically investigated in order to determine the pathological conditions of such bronchial asthma, in particular ascertaining the effect of air pollution. Studies were made of the morphological characteristics of the peripheral airways in patients with bronchial asthma who had resided for long periods in an area near Tokyo affected by air pollution. The endoscopic findings of the peripheral airways were distinct, consisting of reddening, stenosis, pigmentation, pallor, lustrelessness and hypersecretion. The histological findings also differed from those in usual forms of asthma. The bronchial asthma in the present patients appeared to be a totally different form from a morphological viewpoint, although it was quite similar to known types in its clinicophysiological features.