Imaging of Small Airways Disease.

Bronchiolitis refers to a small airways disease and may be classified by etiology and histologic features. In cellular bronchiolitis inflammatory cells involve the small airway wall and peribronchiolar alveoli and manifest on CT as centrilobular nodules of solid or ground glass attenuation. Constrictive bronchiolitis refers to luminal narrowing by concentric fibrosis. Direct CT signs of small airway disease include centrilobular nodules and branching tree-in-bud opacities. An indirect sign is mosaic attenuation that may be exaggerated on expiratory CT and represent air trapping. Imaging findings can be combined with clinical and pathologic data to facilitate a more accurate diagnosis.

Efficacy of nebulized hypertonic saline versus normal saline in the treatment of acute bronchiolitis in inpatient infants.

Aim Compare the efficacy of nebulized hypertonic saline and normal saline in the treatment of infants hospitalized for bronchiolitis. Methods This retrospective study was conducted at the Department of Pulmonology, Paediatric Clinic, Clinical Centre University of Sarajevo, covering the period from January 2015 to December 2019 and comprising 380 children aged between 1 and 12 months having bronchiolitis. One group received nebulized hypertonic saline (NHS, 3% NaCl)), and another group received nebulized normal saline (NNS, 0.9% NaCl). The control group did not receive any of these treatment options. Results There was no statistically significant difference between the treatment groups regarding length of hospital stay (LOS) and Clinical Severity Score (CSS) at admission and discharge as well as in oxygen therapy duration and antibiotic use, the duration of symptoms before hospital admission, frequency of nasal discharge, elevated temperature, dyspnoea, cough and dehydration. Conclusion The results of this study are consistent with several recent studies or meta-analyses and support the evidence against the use of NHS in hospitalized infants with mild or moderate bronchiolitis.

Pressure pulsations enhance penetration index in COPD.

This study was done in order to evaluate the effect of a novel pressure pulsation device (Pulsehaler™, Respinova Ltd., Israel) on the deposition pattern of inhaled aerosol in the lungs of COPD patients. Fifteen COPD patients were recruited to undergo spirometry and SPECT-CT lung scan following nebulization of radioactively labeled albuterol in saline solution with a jet nebulizer ("NEB") and with a combined Pulsehaler™/jet nebulizer ("PH + NEB") treatment. Central and peripheral segments of the coronal and transverse SPECT scans were evaluated for total counts and for the ratios between peripheral counts and central counts (penetration Index, "PI"). There was a significant improvement in FEV1 from before to after albuterol treatment in the PH + NEB group (151 ml ± 187, p < 0.008), but not in the NEB only group (66 ml ± 125, p = 0.06). FVC, FEF25-75, FEV1%, FVC%, FEF25, FEF50, and FEF75 also improved significantly in the PH + NEB group but not the NEB group. There were significant improvements seen between treatments for FEF25-75 (PH + NEB > NEB, p = 0.0176), FEF75 (PH + NEB > NEB, p = 0.0028), but not for the other spirometry measures. Borg scores also were improved significantly improved in PH + NEB vs NEB (p = 0.0006). Total lung deposition and total body deposition were lower in the PH + NEB treatments vs the NEB treatments. However, PI values were 3.08 ± 0.67 times greater on average with the PH + NEB (p = 0.026) as compared to NEB only. The magnitude of the increased penetration index observed in this study indicates that pressure pulsations should be further explored as means to improve drug delivery into the distal small airways of the bronchial tree. Effects of the pressure pulsations on small airway patency could be the mechanism by which the effect was achieved.

Small Airway Reduction and Fibrosis Is an Early Pathologic Feature of Idiopathic Pulmonary Fibrosis.

Rationale: To improve disease outcomes in idiopathic pulmonary fibrosis (IPF), it is essential to understand its early pathophysiology so that it can be targeted therapeutically. Objectives: Perform three-dimensional assessment of the IPF lung microstructure using stereology and multiresolution computed tomography (CT) imaging. Methods: Explanted lungs from patients with IPF (n = 8) and donor control subjects (n = 8) were inflated with air and frozen. CT scans were used to assess large airways. Unbiased, systematic uniform random samples (n = 8/lung) were scanned with microCT for stereological assessment of small airways (count number, and measure airway wall and lumen area) and parenchymal fibrosis (volume fraction of tissue, alveolar surface area, and septal wall thickness). Measurements and Main Results: The total number of airways on clinical CT was greater in IPF lungs than control lungs (P < 0.01), owing to an increase in the wall (P < 0.05) and lumen area (P < 0.05) resulting in more visible airways with a lumen larger than 2 mm. In IPF tissue samples without microscopic fibrosis, assessed by the volume fraction of tissue using microCT, there was a reduction in the number of the terminal (P < 0.01) and transitional (P < 0.001) bronchioles, and an increase in terminal bronchiole wall area (P < 0.001) compared with control lungs. In IPF tissue samples with microscopic parenchymal fibrosis, terminal bronchioles had increased airway wall thickness (P < 0.05) and dilated airway lumens (P < 0.001) leading to honeycomb cyst formations. Conclusions: This study has important implications for the current thinking on how the lung tissue is remodeled in IPF and highlights small airways as a potential target to modify IPF outcomes.

Temporospatial characterization of the bronchus associated lymphoid tissue (BALT) of the one humped camel (Camelus dromedarius).

BACKGROUND: Bronchial-associated lymphoid tissue (BALT) is responsible for the local immune response of the lung against airborne infections. The structure of this tissue varies according to species and age. AIM: The aim of this study was to describe the possible age-related structural variation of the BALT of the one humped camel. MATERIAL AND METHODS: Fresh specimens from both lungs of 15 clinically healthy male camels (10 months-12 years) were studied with light and electron microscopes. RESULTS: The BALT in the camel was variable from few lymphocytes to well-organized lymphoid tissue with a clear germinal center. The BALT of the bronchi is a constant lymphoid tissue in young and adult camels which may be of the large size with clear germinal center in response to repeated immune reaction and involutes in old age. The BALT of the bronchioles may be induced and develops mainly due to an immune reaction and showed great morphological variations and observed in different ages. High endothelial venules were associated with BALT in the bronchi but not with that of the bronchioles. The BALT-associated epithelium was tall pseudostratified columnar ciliated epithelium with goblet cells in the extrapulmonary bronchi changed to pseudostratified columnar ciliated epithelium mucous secreting cells in the intrapulmonary bronchi and simple columnar ciliated to simple cuboidal epithelium with Clara cells without goblet cells or mucous secreting cells in the bronchioles. CONCLUSIONS: The BALT of the bronchi is a constant lymphoid tissue in young and adult camels and involutes in old age. The BALT of the bronchioles may be induced and develops mainly due to an immune reaction and observed in different ages.

Evodiamine protects against airway remodelling and inflammation in asthmatic rats by modulating the HMGB1/NF-κB/TLR-4 signalling pathway.

CONTEXT: Evodiamine, which is isolated from Evodia rutaecarpa (Rutaceae), possess strong anti-inflammatory, immunomodulatory, and antibacterial properties. OBJECTIVE: The protective effects of evodiamine in asthma were evaluated. MATERIALS AND METHODS: Thirty-two Sprague-Dawley (SD) rats were used, asthma was induced by injecting intraperitoneally with a mixture of Al(OH)3 (100 mg) and ovalbumin (OA; 1 mg/kg), further exposing them to a 2% OA aerosol for 1 week. All animals were divided into four groups: control, asthma, and evodiamine 40 and 80 mg/kg p.o. treated group. Serum levels of inflammatory cytokines, interferon gamma (IFN-γ), and immunoglobulin E (IgE) and infiltrations of inflammatory cells in the bronchoalveolar lavage fluid (BALF) of the animals were determined. The thickness of the smooth muscle layer and airway wall in the intact small bronchioles of asthmatic rats was examined as well. RESULTS: Cytokine levels in the serum and BALF were lower in the evodiamine-treated group than in the asthma group. Evodiamine treatment reduced IgE and IFN-γ levels as well as the inflammatory cell infiltrate in the lung tissue of asthmatic rats. The thickness of the smooth muscle layer and airway wall of intact small bronchioles was less in the evodiamine-treated group than in the asthma group. Lower levels of TLR-4, MyD88, NF-κB, and HMGB1 mRNA in lung tissue were measured in the evodiamine-treated group than in the asthma group. DISCUSSION AND CONCLUSION: The effect of evodiamine treatment protects the asthma, as evodiamine reduces airway inflammation and remodelling in the lung tissue by downregulating the HMGB1/NF-κB/TLR-4 pathway in asthma.

BronchoX: bronchoscopy exploration software for biopsy intervention planning.

Virtual bronchoscopy (VB) is a non-invasive exploration tool for intervention planning and navigation of possible pulmonary lesions (PLs). A VB software involves the location of a PL and the calculation of a route, starting from the trachea, to reach it. The selection of a VB software might be a complex process, and there is no consensus in the community of medical software developers in which is the best-suited system to use or framework to choose. The authors present Bronchoscopy Exploration (BronchoX), a VB software to plan biopsy interventions that generate physician-readable instructions to reach the PLs. The authors' solution is open source, multiplatform, and extensible for future functionalities, designed by their multidisciplinary research and development group. BronchoX is a compound of different algorithms for segmentation, visualisation, and navigation of the respiratory tract. Performed results are a focus on the test the effectiveness of their proposal as an exploration software, also to measure its accuracy as a guiding system to reach PLs. Then, 40 different virtual planning paths were created to guide physicians until distal bronchioles. These results provide a functional software for BronchoX and demonstrate how following simple instructions is possible to reach distal lesions from the trachea.

Small airway inflammation and extrafine inhaled corticosteroids plus long-acting beta2-agonists formulations in chronic obstructive pulmonary disease.

OBJECTIVES: To summarize the evidence of small airways involvement in chronic obstructive pulmonary disease (COPD) pathophysiology, and to evaluate the efficacy of extrafine formulations of inhaled corticosteroids (ICS) in combination with long-acting beta2-agonists (LABAs) in the treatment of COPD. DATA SOURCE: A search of the PubMed database was conducted using the keywords "COPD", "small airways", "inflammation" and "extrafine formulation." The search was limited to entries published in English before August 2016. Only studies conducted in humans were considered. STUDY SELECTION: Publications were included on the basis of relevance. RESULTS: COPD is a common preventable and treatable disease, characterized by persistent and progressive airflow limitation. With improved understanding of COPD pathophysiology, small airways (internal diameter <2 mm), a well-known major site of COPD-associated inflammation and remodeling, have emerged as a potential target for COPD pharmacologic therapies. The ability of extrafine formulations of ICS in combination with LABAs to achieve central and peripheral lung deposition, and the implications of the enhanced efficacy that this may bring, are discussed by examining findings from the development trials plan of the extrafine formulation of beclometasone dipropionate/formoterol fumarate (Foster®, Chiesi Farmaceutici, Italy) in patients with COPD. CONCLUSION: There is an urgent need for improved and reliable techniques for small airways assessment in order to detect early damage, disease progression and response to treatment. Evidence from randomized clinical trials supports the benefits of extrafine ICS/LABA formulations in COPD, real world studies are necessary to confirm this.

Observation of clinical effect of montelukast sodium in the treatment of chronic cough with small airway disease / 中国基层医药

Objective To explore the clinical efficacy of montelukast sodium in the treatment of chronic cough with small airway disease.Methods 50 chronic cough patients with small airway disease were selected,and they were randomly divided into montelukast sodium group and control group according to the digital table,25 cases in each group.The control group was given conventional treatment,the montelukast sodium group was treated with montelukast sodium on the basis of routine treatment.At the end of treatment,the clinical effect of the two groups was compared.Results The total effective rate of the montelukast sodium group was 92.0％,which of the control group was 84.0％,the difference was not statistically significant between the two groups (x2 =1.05,P ＞ 0.05).After 3 months of treatment,the pulmonary function of the two groups was significantly improved.Compared with the control group,the FEV1,FVC and FEV1/FVC％ of the montelukast sodium group showed no statistically significant differences(t =0.71,0.64,1.46,all P ＞ 0.05),but the FEF25 ％-75 ％,FEF50％,FEF75 ％ improved significantly with significant differences (t =7.07,2.62,3.83,all P ＜ 0.01).After 6 months of treatment,the difference of FEF75 ％ was statistically significant between the two groups (t =1.92,P ＜ 0.05).Compared with the control group,the level of serum IgE was significantlylower in the montelukast sodium group(t =4.02,P ＜0.01).There were no serious adverse reactions in the two groups,the difference was not statistically significant (x2 =1.42,P ＞ 0.05).Conclusion Montelukast sodium in the treatment of chronic cough with small airway disease has significant effcet,it is conducive to improve small airway disease and reduce serum IgE level,it is safe,effective and worthy of clinical application.

Role of endogenous hydrogen sulfide in nerve-evoked relaxation of pig terminal bronchioles.

Hydrogen sulfide (H2S) is a gasotransmitter employed for intra- and inter-cellular communication in almost all organ systems. This study investigates the role of endogenous H2S in nerve-evoked relaxation of pig terminal bronchioles with 260 µm medium internal lumen diameter. High expression of the H2S synthesis enzyme cystathionine γ-lyase (CSE) in the bronchiolar muscle layer and strong CSE-immunoreactivity within nerve fibers distributed along smooth muscle bundles were observed. Further, endogenous H2S generated in bronchiolar membranes was reduced by CSE inhibition. In contrast, cystathionine ß-synthase expression, another H2S synthesis enzyme, however was not consistently detected in the bronchiolar smooth muscle layer. Electrical field stimulation (EFS) and the H2S donor P-(4-methoxyphenyl)-P-4-morpholinylphosphinodithioic acid (GYY4137) evoked smooth muscle relaxation. Inhibition of CSE, nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and of ATP-dependent K+, transient receptor potential A1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) channels reduced the EFS relaxation but failed to modify the GYY4137 response. Raising extracellular K+ concentration inhibited the GYY4137 relaxation. Large conductance Ca2+-activated K+ channel blockade reduced both EFS and GYY4137 responses. GYY4137 inhibited the contractions induced by histamine and reduced to a lesser extent the histamine-induced increases in intracellular [Ca2+]. These results suggest that relaxation induced by EFS in the pig terminal bronchioles partly involves the H2S/CSE pathway. H2S response is produced via NO/sGC-independent mechanisms involving K+ channels and intracellular Ca2+ desensitization-dependent pathways. Thus, based on our current results H2S donors might be useful as bronchodilator agents for the treatment of lung diseases with persistent airflow limitation, such as asthma and chronic obstructive lung disease.

OX40 ligand newly expressed on bronchiolar progenitors mediates influenza infection and further exacerbates pneumonia.

Influenza virus epidemics potentially cause pneumonia, which is responsible for much of the mortality due to the excessive immune responses. The role of costimulatory OX40-OX40 ligand (OX40L) interactions has been explored in the non-infectious pathology of influenza pneumonia. Here, we describe a critical contribution of OX40L to infectious pathology, with OX40L deficiency, but not OX40 deficiency, resulting in decreased susceptibility to influenza viral infection. Upon infection, bronchiolar progenitors increase in number for repairing the influenza-damaged epithelia. The OX40L expression is induced on the progenitors for the antiviral immunity during the infectious process. However, these defense-like host responses lead to more extensive infection owing to the induced OX40L with α-2,6 sialic acid modification, which augments the interaction with the viral hemagglutinin. In fact, the specific antibody against the sialylated site of OX40L exhibited therapeutic potency in mitigating the OX40L-mediated susceptibility to influenza. Our data illustrate that the influenza-induced expression of OX40L on bronchiolar progenitors has pathogenic value to develop a novel therapeutic approach against influenza.

Site of Fluid Secretion in Small Airways.

The secretion and management of readily transportable airway surface liquid (ASL) along the respiratory tract is crucial for the clearance of debris and pathogens from the lungs. In proximal large airways, submucosal glands (SMGs) can produce ASL. However, in distal small airways, SMGs are absent, although the lumens of these airways are, uniquely, highly plicated. Little is known about the production and maintenance of ASL in small airways, but using electrophysiology, we recently found that native porcine small airways simultaneously secrete and absorb. How these airways can concurrently transport ASL in opposite directions is puzzling. Using high expression of the Na-K-2Cl cotransport (NKCC) 1 protein (SLC12a2) as a phenotypic marker for fluid secretory cells, immunofluorescence microscopy of porcine small airways revealed two morphologically separated sets of luminal epithelial cells. NKCC1 was abundantly expressed by most cells in the contraluminal regions of the pleats but highly expressed very infrequently by cells in the luminal folds of the epithelial plications. In larger proximal airways, the acini of SMGs expressed NKCC1 prominently, but cells expressing NKCC1 in the surface epithelium were sparse. Our findings indicate that, in the small airway, cells in the pleats of the epithelium secrete ASL, whereas, in the larger proximal airways, SMGs mainly secrete ASL. We propose a mechanism in which the locations of secretory cells in the base of pleats and of absorptive cells in luminal folds physically help maintain a constant volume of ASL in small airways.

Effects of hydrogen sulphide in smooth muscle.

In recent years, it has become apparent that the gaseous pollutant, hydrogen sulphide (H2S) can be synthesised in the body and has a multitude of biological actions. This review summarizes some of the actions of this 'gasotransmitter' in influencing the smooth muscle that is responsible for controlling muscular activity of hollow organs. In the vasculature, while H2S can cause vasoconstriction by complex interactions with other biologically important gases, such as nitric oxide, the prevailing response is vasorelaxation. While most vasorelaxation responses occur by a direct action of H2S on smooth muscle cells, it has recently been proposed to be an endothelium-derived hyperpolarizing factor. H2S also promotes relaxation in other smooth muscle preparations including bronchioles, the bladder, gastrointestinal tract and myometrium, opening up the opportunity of exploiting the pharmacology of H2S in the treatment of conditions where smooth muscle tone is excessive. The original concept, that H2S caused smooth muscle relaxation by activating ATP-sensitive K(+) channels, has been supplemented with observations that H2S can also modify the activity of other potassium channels, intracellular pH, phosphodiesterase activity and transient receptor potential channels on sensory nerves. While the enzymes responsible for generating endogenous H2S are widely expressed in smooth muscle preparations, it is much less clear what the physiological role of H2S is in determining smooth muscle contractility. Clarification of this requires the development of potent and selective inhibitors of H2S-generating enzymes.

Bronchiolar remodeling in adult mice following neonatal exposure to hyperoxia: relation to growth.

Preterm infants who receive supplemental oxygen for prolonged periods are at increased risk of impaired lung function later in life. This suggests that neonatal hyperoxia induces persistent changes in small conducting airways (bronchioles). Although the effects of neonatal hyperoxia on alveolarization are well documented, little is known about its effects on developing bronchioles. We hypothesized that neonatal hyperoxia would remodel the bronchiolar walls, contributing to altered lung function in adulthood. We studied three groups of mice (C57BL/6J) to postnatal day 56 (P56; adulthood) when they either underwent lung function testing or necropsy for histological analysis of the bronchiolar wall. One group inhaled 65% O2 from birth until P7, after which they breathed room air; this group experienced growth restriction (HE+GR group). We also used a group in which hyperoxia-induced GR was prevented by dam rotation (HE group). A control group inhaled room air from birth. At P56, the bronchiolar epithelium of HE mice contained fewer Clara cells and more ciliated cells, and the bronchiolar wall contained ∼25% less collagen than controls; in HE+GR mice the bronchiolar walls had ∼13% more collagen than controls. Male HE and HE+GR mice had significantly thicker bronchiolar epithelium than control males and altered lung function (HE males: greater dynamic compliance; HE+GR males: lower dynamic compliance). We conclude that neonatal hyperoxia remodels the bronchiolar wall and, in adult males, affects lung function, but effects are altered by concomitant growth restriction. Our findings may partly explain the reports of poor lung function in ex-preterm children and adults.

Toxic inhalational injury-associated interstitial lung disease in children.

Interstitial lung disease in children (chILD) is a group of disorders characterized by lung inflammation and interstitial fibrosis. In the past recent years, we noted an outbreak of child in Korea, which is possibly associated with inhalation toxicity. Here, we report a series of cases involving toxic inhalational injury-associated chILD with bronchiolitis obliterans pattern in Korean children. This study included 16 pediatric patients confirmed by lung biopsy and chest computed tomography, between February 2006 and May 2011 at Asan Medical Center Children's Hospital. The most common presenting symptoms were cough and dyspnea. The median age at presentation was 26 months (range: 12-47 months), with high mortality (44%). Histopathological analysis showed bronchiolar destruction and centrilobular distribution of alveolar destruction by inflammatory and fibroproliferative process with subpleural sparing. Chest computed tomography showed ground-glass opacities and consolidation in the early phase and diffuse centrilobular nodular opacity in the late phase. Air leak with severe respiratory difficulty was associated with poor prognosis. Although respiratory chemicals such as humidifier disinfectants were strongly considered as a cause of this disease, further studies are needed to understand the etiology and pathophysiology of the disease to improve the prognosis and allow early diagnosis and treatment.

Toxic Inhalational Injury-Associated Interstitial Lung Disease in Children

Interstitial lung disease in children (chILD) is a group of disorders characterized by lung inflammation and interstitial fibrosis. In the past recent years, we noted an outbreak of child in Korea, which is possibly associated with inhalation toxicity. Here, we report a series of cases involving toxic inhalational injury-associated chILD with bronchiolitis obliterans pattern in Korean children. This study included 16 pediatric patients confirmed by lung biopsy and chest computed tomography, between February 2006 and May 2011 at Asan Medical Center Children's Hospital. The most common presenting symptoms were cough and dyspnea. The median age at presentation was 26 months (range: 12-47 months), with high mortality (44%). Histopathological analysis showed bronchiolar destruction and centrilobular distribution of alveolar destruction by inflammatory and fibroproliferative process with subpleural sparing. Chest computed tomography showed ground-glass opacities and consolidation in the early phase and diffuse centrilobular nodular opacity in the late phase. Air leak with severe respiratory difficulty was associated with poor prognosis. Although respiratory chemicals such as humidifier disinfectants were strongly considered as a cause of this disease, further studies are needed to understand the etiology and pathophysiology of the disease to improve the prognosis and allow early diagnosis and treatment.

The Middle Lobe Cancer Treated with Bronchovascular Resection and Reconstruction / 中国医师杂志

Objective In order to research the operative method for preservation of healthy lung in the middle lobe carcinoma.Methods From June,1994 to August,1999,16 cases lobectomy of middle lobe cancer were performed.12 of 16 cases were received middle lobectomy with bronchial wedge-shaped resection,6 of which were followed by partial pulmonary artery resection,2 of which,with pulmonary artery sleeve resection,3 of 16 were cured by the middle lobe sleeve lobectomy,one of which was done with combined partial pulmonary artery resection.One of 16 received both middle and lower lobectomy,simultaneously,completed upper pulmonary vein and lower pulmonary vein reconstruction.Results 16 cases operation were all successful.The survival rate in 1 and 3 years were 88% and 50%,respectively.Conclusion Bronchovascular resection and reconstruction applied to treat the middle lobe cancer not only could maximal remove the focal lesion,but also reserve the healthy lung fully,and expanded the surgical indication.