Small Airway Wall Research Articles

Differences of CT pulmonary function indexes in asbestosis patients engaged in different types of work

Objective To evaluate the changes and characteristics of pulmonary function in asbestosis patients engaged in different types of work by multi-slice spiral CT imaging. Methods Total 30 asbestosis patients were equally divided into three groups, who engaged in the work of raw asbestos processing, fiber combing and pressure molding, respectively. The pulmonary volume, pulmonary density and pulmonary small airway indexes were measured by a whole lung scanning at maximum inspiratory and maximum expiratory efforts. The pulmonary volume indexes include maximum inspiratory volume, maximum expiratory volume, pulmonary volume difference and pulmonary volume ratio. The mean pulmonary density indexes include the mean pulmonary densities after inspiratory and expiratory activities, pulmonary density difference and pulmonary density ratio. The small airway indexes include the diameter ratios of the wall after inspiratory and expiratory activities and the percentage of bronchial wall area after inspiratory activity. Results The differences of the gender, age, stage, and contact history of the patients are not statistically significant for all the groups (all P>0.05). The differences of the mean pulmonary densities after expiratory activity, the left and right pulmonary densities after expiratory activities, pulmonary density ratio, diameter ratios of the wall after inspiratory and expiratory activities, and the percentage of bronchial wall area after inspiratory activity are statistically significant among the three groups (all P 0.05). The differences among the three groups in other indexes are not statistically significant (all P>0.05). Conclusions The emphysema with fibrous thickening in the alveolar septum and small airway wall is more severe in the workers who engaged in asbestos fiber combing comparing with in raw asbestos processing and asbestos pressure molding. Therefore, the medical protection of these groups of patients should be strengthened. Key words: Asbestosis; Respiratory dysfunction; Occupation

Evaluation of respiratory dysfunction in patients with asbestos lung based on pulmonary function indexes utilizing CT

Objective To evaluate the changes and characteristics of respiratory function and pulmonary function in patients with asbestosis by multi-slice spiral CT imaging. Methods 61 asbestosis patents and 30 healthy subjects were enrolled and divided into normal respiratory function group, mild injury group and moderate/severe injury group according to forced vital capacity and forced expiratory volume in one second. The lungs were scanned at the end of inspiratory and expiratory phase, and the lung volume, lung density and small airway index were measured. Results There were significant differences in lung volume (inspiratory and expiratory volume, volume difference, and volume ratio) among the normal group, the mild injury group and the moderate/severe injury group (all P<0.05). There were statistically significant differences in the mean lung density (lung density at the end of inspiratory and expiratory phase, lung density difference, lung density ratio) among the three groups (all P<0.05). There were significant differences in the small airway indexes (tracheal wall thickness ratio at the end of inspiratory and expiratory phase, bronchial wall area ratio) among the three groups (all P<0.05). Conclusions CT lung function imaging techniques can be used to assess the degree of respiratory dysfunction in asbestosis patients. With the development of pulmonary respiratory dysfunction, the total lung volume decreased, the amount of lungs gradually increased, emphysema gradually increased, and the thickness of small airway wall and alveolar fibrous hypertrophy gradually increased. Key words: Asbestosis; Pulmonary respiratory dysfunction; Pulmonary function

Involvement of c-Jun N-Terminal Kinase in TNF-α-Driven Remodeling.

Lung tissue remodeling in chronic obstructive pulmonary disease (COPD) is characterized by airway wall thickening and/or emphysema. Although the bronchial and alveolar compartments are functionally independent entities, we recently showed comparable alterations in matrix composition comprised of decreased elastin content and increased collagen and hyaluronan contents of alveolar and small airway walls. Out of several animal models tested, surfactant protein C (SPC)-TNF-α mice showed remodeling in alveolar and airway walls similar to what we observed in patients with COPD. Epithelial cells are able to undergo a phenotypic shift, gaining mesenchymal properties, a process in which c-Jun N-terminal kinase (JNK) signaling is involved. Therefore, we hypothesized that TNF-α induces JNK-dependent epithelial plasticity, which contributes to lung matrix remodeling. To this end, the ability of TNF-α to induce a phenotypic shift was assessed in A549, BEAS2B, and primary bronchial epithelial cells, and phenotypic markers were studied in SPC-TNF-α mice. Phenotypic markers of mesenchymal cells were elevated both in vitro and in vivo, as shown by the expression of vimentin, plasminogen activator inhibitor-1, collagen, and matrix metalloproteinases. Concurrently, the expression of the epithelial markers, E-cadherin and keratin 7 and 18, was attenuated. A pharmacological inhibitor of JNK attenuated this phenotypic shift in vitro, demonstrating involvement of JNK signaling in this process. Interestingly, activation of JNK signaling was also clearly present in lungs of SPC-TNF-α mice and patients with COPD. Together, these data show a role for TNF-α in the induction of a phenotypic shift in vitro, resulting in increased collagen production and the expression of elastin-degrading matrix metalloproteinases, and provide evidence for involvement of the TNF-α-JNK axis in extracellular matrix remodeling.

The effects of imiquimod on the level of BALF IL-12, IL-13 and sera IgE in asthmatic murine

Objective To observe the effects of aerosol imiquimod on the level of Interleukin-12(IL-12) and interleukin-13(IL-13) in bronchial alveolar lavage fluid(BALF) and serum immunoglobulin E( IgE ) level in mouse asthma models. Methods Thirty BALB/c mice were divided into 3 groups, control group, asthma group and imiquimod group, ten in each group.The asthma group and imiquimod group were established by sensitization and challenge with ovalbumin (OVA), imiquimod group was interfered with aerosol imiquimod 30 min before challenge.Serum in each group was collected by excising eyeball 24 h after the last challenge.The level of IgE in serum was measured by ELISA.Bronchoalveolar lavage fluid (BALF) was performed, and total cell counts, cell differential were examined.The level of IL-12 and IL-13 in BALF was measured by ELISA and total cell counts, cell differential were examined in BALF.The inflammation changes of lung was observed by HE staining. Results (1)By hematoxylin-eosin(HE) staining, the result of asthma mice were small airway wall thickening, secretion increased, epithelial cells fall off, arranging disorderly, and submucosal had plenty of inflammatory cells infiltration, mainly with lymphocytes.But imquimod group attenuated the airway inflammation of asthmatic mice.(2)Total cell counts and all kinds of inflammatory cells of asthma group were increased greatly compared with normal group; Eosinophil and lymphocyte cells were much lower in imquimod group than those in asthma group (P<0.05). (3) The level of IL-13 in BALF and the level of IgE in serum in imiquimod group was obviously higher than that in control group, IL-13 level were positively correlated with IgE level(r=0.774, P<0.05), but imiquimod group was greatly decreased compared with control group and increased in comparison with that in group A; The level of IL-12 in asthma group was reduced and the level of IgE was increased compared with normal group.IL-12 level in imiquimod group was evidently higher and IgE level was lower than that in asthma group.IL-12 level negatively correlated with IgE level(r=-0.802, P<0.05). Conclusion Imiquimod aerosol inhalation may up-regulate the level of Th1 chemokine IL-12, down-regulates the level of Th2 chemokine IL-13 and decrease the level of IgE in serum so that it may suppress antigen-induced airway inflammation. Key words: Asthma; IgE; Imiquimod

Therapeutic effects of LASSBio-596 in an elastase-induced mouse model of emphysema.

Emphysema is an intractable pulmonary disease characterized by an inflammatory process of the airways and lung parenchyma and ongoing remodeling process in an attempt to restore lung structure. There is no effective drug therapy that regenerates lung tissue or prevents the progression of emphysema; current treatment is aimed at symptomatic relief. We hypothesized that LASSBio-596, a molecule with potent anti-inflammatory and immunomodulatory effects, might reduce pulmonary inflammation and remodeling and thus improve lung function in experimental emphysema. Emphysema was induced in BALB/c mice by intratracheal administration of porcine pancreatic elastase (0.1 IU) once weekly during 4 weeks. A control group received saline using the same protocol. After the last instillation of saline or elastase, dimethyl sulfoxide, or LASSBio-596 were administered intraperitoneally, once daily for 8 days. After 24 h, in elastase-induced emphysema animals, LASSBio-596 yielded: (1) decreased mean linear intercept, hyperinflation and collagen fiber content, (2) increased elastic fiber content, (3) reduced number of M1 macrophages, (4) decreased tumor necrosis factor-α, interleukin-1β, interleukin-6, and transforming growth factor-β protein levels in lung tissue, and increased vascular endothelial growth factor. These changes resulted in increased static lung elastance. In conclusion, LASSBio-596 therapy reduced lung inflammation, airspace enlargement, and small airway wall remodeling, thus improving lung function, in this animal model of elastase-induced emphysema.

SU-F-207-04: Noise-Robust and Accurate Measurement Method of Small Airway Wall Thickness in Low-Dose CT Scan: A COPDgene Phantom Study

Purpose: We present a novel method, attenuation profile matching (APM) technique, which provides accurate determination the wall thickness of small airways as well as superior robustness to noise and reconstruction kernel variation. Methods: Point spread functions (PSF) of a commercial CT (Sensation 16, Siemens) were acquired by using a wire phantom for various reconstruction kernels (B10s ∼ B80s). Sets of COPDgene phantom CT data were created for varying exposure (25 to 200 mAs) and FOVs, and with different reconstruction kernels. Line profiles were obtained across the airway walls with varying sizes (0.6–1.5mm), and compared with synthetic line profiles which were generated by taking convolution of the PSF with a the numerical airway wall phantoms derived from the variation of COPDgene phantom design data. Wall thickness of a given airway was determined as that of the numerical model yielding minimum error. The performance of APM method was compared with that of two other methods (FWHM, IBM) for varying exposure conditions and with different reconstruction kernels. Results: Measurement error the APM method ranged from 0.01 to 0.15 (± 0.012) mm, whereas that of the FWHM and IBM method was from 0.07 to 0.88 (± 0.015) mm and 0.08 to 0.72 (± 0.015) mm, respectively, for varying range of wall thickness and different reconstruction kernels. Average error of APM method was markedly lower (p<0.01) than that of FWHM and IBM methods. Conclusion: Our proposed APM technique could determine the airway wall thickness accurately even for the small airways less than 1mm. Our technique may allow detection of early change of airway wall thickening in early diagnosis, patient sub-typing, and therapeutic monitoring in the management of COPD disease.

Follicular Bronchiolitis: A Literature Review.

Follicular bronchiolitis (FB) also known as hyperplasia of the bronchial associated lymphoid tissue (BALT), or bronchiolar nodular lymphoid hyperplasia, is an entity characterized by the development of lymphoid follicles with germinal centers in the walls of small airways. FB is thought to be caused by antigenic stimulation of BALT, followed by a polyclonal lymphoid hyperplasia. It is currently classified as one of the reactive pulmonary lymphoid disorders in a group known as the lymphoproliferative pulmonary diseases (LPDs). FB is a pathological diagnosis that can be seen in several clinical settings, including connective tissue diseases, immunodeficiency states, autoimmune diseases, infections, obstructive airway diseases, as well as several types of interstitial lung diseases (ILDs). Its characteristics need to be carefully identified and differentiated from other closely related diseases in the group of LPDs due to significant differences in treatment and prognosis.

Upregulation of gelatinases and epithelial-mesenchymal transition in small airway remodeling associated with chronic exposure to wood smoke.

BackgroundPeribronchiolar 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.MethodsForty-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.ResultsThe 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.ConclusionsThese findings suggest that the upregulation of gelatinases and EMT might play a role in SAR in COPD associated with chronic exposure to wood smoke.

A Multi-Step Algorithm for Measuring Airway Luminal Diameter and Wall Thickness in Lung CT Images.

Accurate measurements of airway diameter and wall thickness are important parameters in understanding numerous pulmonary diseases. Here, we describe an automated method of measuring small airway luminal diameter and wall thickness over numerous contiguous computed tomography (CT) images. Using CT lung images from 22 patients and an airway phantom, a seeded region-growing algorithm was first applied to identify the lumen of the airway. The result was applied as an initial region for boundary determination using the level set method. Once found, subsequent algorithmic expansion of the luminal border was used to calculate airway wall thickness. This algorithm automatically evaluates neighboring slices of the airway and measures the airway luminal diameter and wall thickness. This approach also detects airway bifurcations. Our new procedure provides rapid, automated, accurate, and clinically important lung airway measurements that would be useful to radiologists who use CT images for pulmonary disease assessment.

Personalized management of chronic obstructive pulmonary disease via transcriptomic profiling of the airway and lung.

Chronic obstructive pulmonary disease (COPD) is a clinically heterogeneous disease composed of variable degrees of airflow obstruction, emphysematous destruction, and small airway wall thickening. The natural history of this disease, although generally characterized by continued decline in lung function, is also highly variable. Novel transcriptomic approaches to study the airway and lung tissue in COPD hold the potential to improve our understanding of the molecular mechanisms underlying this heterogeneity and identify molecular subtypes of disease that have similar clinical manifestations. This new understanding can be leveraged to develop targeted COPD therapies and ultimately personalize treatment of COPD based on each patient's specific molecular subphenotype.

A possible role for CD8+ and non‐CD8+ cell granzyme B in early small airway wall remodelling in centrilobular emphysema

CD8(+) cell infiltration and apoptosis of airway epithelial cells are increased in chronic obstructive pulmonary disease (COPD). CD8(+) T cells induce apoptosis by releasing granzymes, which can also cause extracellular matrix degradation and remodelling. Granzyme B levels and T cells expressing granzyme B are increased in bronchoalveolar lavage fluid of COPD patients, which suggests that granzyme B may contribute to the pathogenesis of COPD. This study provides quantitation of granzyme B-positive cells in relation to CD8(+) cells in the small airway walls of emphysema. Antibodies against CD8 and granzyme B were used to identify CD8(+) and granzyme B(+) cells. Volume fraction (Vv) of CD8(+) and granzyme B(+) cells were quantitated by the point counting method in the small airways of 13 non-smoker control subjects and 46 emphysema patients (14 panlobular emphysema (PLE) and 32 centrilobular emphysema (CLE) lungs). Immunohistochemical detection of macrophage scavenger receptor was also performed in randomly selected cases. The Vv of CD8(+) and granzyme B(+) cells in CLE was greater than those in control and PLE (both P < 0.001) subjects. The Vv of granzyme B(+) cells was greater than that of CD8(+) cells (P = 0.006), and not all CD8(+) cells were positive for granzyme B in CLE subjects. Monocytes expressing both granzyme B and macrophage scavenger receptor and granulocytes expressing granzyme B were identified. Upregulation of granzyme B in CD8(+) and non-CD8(+) cells is an early phenomenon of small airway wall remodelling in centrilobular emphysema and suggests its possible role in the pathogenesis of COPD.

The small airways in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is caused by a mixture of small airway disease (obstructive bronchitis) and parenchymal lung tissue destruction (emphysema). The relative contributions of these two pathologic states vary from person to person. Having the ability to phenotype patients into predominately small airways disease or emphysema may affect the clinical management. Pathologic studies have shown that the progression of COPD from Global Initiative for Chronic Obstructive Lung Disease stages 0 to 4 is most strongly associated with small airway wall thickening as a result of lung repair or remodeling. The narrowing and loss of small airways occurs prior to emphysematous destruction. There is an increase in the amount of neutrophils and CD8⁺ T lymphocytes (cells that induce apoptosis and necrosis) in the small airways in COPD. Small airways disease can be identified on pulmonary function testing, using multiple nitrogen breath washout testing, indirectly through high-resolution chest computed tomography (CT) imaging or MRI, or directly by using microCT of resected lung tissue. There may be increased mortality in advanced COPD and concomitant small airway disease. There are newer methods to deliver respiratory therapies to reach the small airways. The current techniques utilized to assess patients for small airway disease need to be improved, so clinicians can more effectively phenotype patients with COPD and small airways disease. This will allow new therapies that target the small airways to be developed and tested, and positively impact on the natural progression of COPD.

Expression of acute-phase cytokines, surfactant proteins, and epithelial apoptosis in small airways of human acute respiratory distress syndrome

PurposeRecent studies suggest a role for distal airway injury in acute respiratory distress syndrome (ARDS). The epithelium lining the small airways secretes a large number of molecules such as surfactant components and inflammatory mediators. There is little information on how these small airway secretory functions are altered in ARDS. Materials and MethodsWe studied the lungs of 31 patients with ARDS (Pao2/fraction of inspired oxygen ≤200, 45 ± 14 years, 16 men) and 11 controls (52 ± 16 years, 7 men) submitted to autopsy and quantified the expression of interleukin (IL) 6, IL-8, surfactant proteins (SP) A and SP-B in the epithelium of small airways using immunohistochemistry and image analysis. In addition, an index of airway epithelial apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine-triphosphatase nick-end labeling assay, caspase 3, and Fas/Fas ligand expression. The density of inflammatory cells expressing IL-6 and IL-8 within the small airway walls was also quantified. ResultsAcute respiratory distress syndrome airways showed an increase in the epithelial expression of IL-8 (P = .006) and an increased density of inflammatory cells expressing IL-6 (P = .004) and IL-8 (P < .001) compared with controls. There were no differences in SP-A and SP-B epithelium expression or in epithelial apoptosis index between ARDS and controls. ConclusionDistal airways are involved in ARDS lung inflammation and show a high expression of proinflammatory interleukins in both airway epithelial and inflammatory cells. Apoptosis may not be a major mechanism of airway epithelial cell death in ARDS.

AZD9668: Pharmacological Characterization of a Novel Oral Inhibitor of Neutrophil Elastase

N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (AZD9668) is a novel, oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms, and disease progression in NE-driven respiratory diseases such as bronchiectasis and chronic obstructive pulmonary disease via its role in the inflammatory process, mucus overproduction, and lung tissue damage. In vitro and in vivo experiments were done to evaluate the binding kinetics, potency, and selectivity of AZD9668, its effects in whole-blood and cell-based assays, and its efficacy in models of lung inflammation and damage. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan-stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells. AZD9668 showed good crossover potency to NE from other species. Oral administration of AZD9668 to mice or rats prevented human NE-induced lung injury, measured by lung hemorrhage, and an increase in matrix protein degradation products in bronchoalveolar lavage (BAL) fluid. In an acute smoke model, AZD9668 reduced the inflammatory response to cigarette smoke as indicated by a reduction in BAL neutrophils and interleukin-1β. Finally, AZD9668 prevented airspace enlargement and small airway wall remodeling in guinea pigs in response to chronic tobacco smoke exposure whether dosed therapeutically or prophylactically. In summary, AZD9668 has the potential to reduce lung inflammation and the associated structural and functional changes in human diseases.

Interleukin-17 expression and significance in normal lung function smokers and chronic obstructive pulmonary disease patients

To study the effect of interleukin 17 (IL-17) with mechanism of pulmonary inflammatory in smokers with normal lung function and chronic obstructive pulmonary disease (COPD) patients. The peripheral lung cancer patients in need of a surgical therapy were divided into normal lung function and non-smoking group (NS group, n = 10), normal lung function and smoking group (S group, n = 13) and smoking with stable COPD group (COPD group, n = 10). The fresh normal lung tissue was harvested from the surgical specimens with a margin of 5 cm away from resection foci. Then the lung tissue levels of IL-17 were detected with enzyme-linked immunosorbent assay. The average alveolar area, the total small airway pathology score and the pulmonary muscular artery (MA) wall thickness were measured by HE and Victoria blue-Van Gieson's stains. The IL-17+ cells and CD4+, CD8+ lymphocytes in alveolar walls, small airways and lung MA were analyzed by immunohistochemistry. The investigators also explored the relationships between IL-17 level, pathological morphology of pulmonary parenchyma, small airway, pulmonary artery reconstruction and pulmonary functions. The IL-17 levels in lung tissue of NS, S and COPD groups were 6.1 (3.7 - 12.4), 9.7 (3.5 - 69.7) and 22.7 (7.0 - 114.4) pg/mg respectively. The S and COPD groups were significantly higher than the NS group (P < 0.05, P < 0.01). The S group was significantly higher than the NS group (P < 0.05). The average alveolar area were (50 708 +/- 14 125), (106 517 +/- 13 851) and (152 344 +/- 43 783) microm(2), the total small airway pathology score (49 +/- 10), (101 +/- 34) and (163 +/- 36), and the MA wall thickness (119 +/- 11), (139 +/- 25) and (172 +/- 28) microm respectively. The S and COPD groups were significantly higher than the NS group (P < 0.05, P < 0.01). And the COPD group was significantly higher than the S group (P < 0.05, P < 0.01). IL-17 was predominantly expressed in lung infiltration of inflammatory cells. IL-17 of alveolar walls, small airway wall and MA wall in the S and COPD groups were significantly higher than the NS group. And the COPD group was significantly higher than NS group (P < 0.05). IL-17+ cells were positively correlated with the average alveolar area in pulmonary parenchyma (r = 0.561, P < 0.01), the pulmonary artery wall thickness in MA (r = 0.682, P < 0.01) and the pathological score in small airways (r = 0.425, P < 0.05). IL-17+ cells of pulmonary parenchyma, small airways and MA were positively correlated with CD4+ and CD8+ lymphocytes in lung (P < 0.05, P < 0.01). The levels of IL-17 in lung homogenate tissue showed a negative correlation with the FEV(1) percentage of predicted value (r = -0.471, P < 0.01). IL-17 is up-regulated in lung tissues of normal lung function smokers and COPD patients. And it has a close correlation with CD4+ and CD8+ lymphocytes in lung, lung parenchyma destruction, pulmonary inflammation, pulmonary artery reconstruction and airflow limitation. All of these suggest that IL-17 plays an important pro-inflammatory role in COPD.

The Disruption of the Epithelial Mesenchymal Trophic Unit in COPD

ABSTRACTProgression of COPD is associated with a measurable increase in small airway wall thickness resulting from a repair and remodeling process that involves fibroblasts of the epithelial mesenchymal trophic unit (EMTU). The present study was designed to examine the organization of fibroblasts within the lamina propria of small airways with respect to their contacts with the epithelium and with each other in persons with COPD. Transmission electron microcopy (TEM) and three-dimensional (3D) reconstructions of serial TEM sections were used to estimate the frequency and determine the nature of the contacts between the epithelium and fibroblasts within the EMTU in small airways from 5 controls (smokers with normal lung function), from 6 persons with mild (GOLD-1) and 5 with moderate (GOLD-2) COPD. In airways from control lungs fibroblasts make frequent contact with cytoplasmic extensions of epithelial cells through apertures in the epithelial basal lamina, but the frequency of these fibroblast-epithelial contacts is reduced in both mild and moderate COPD compared to controls (p < 0.01). The 3D reconstructions showed that the cytoplasmic extensions of lamina propria fibroblasts form a reticulum with fibroblast-fibroblast contacts in an airway from a control subject but this reticulum may be reorganized in airways of COPD patients. Development of COPD is associated with significant disruption of the EMTU due to a reduction of contacts between fibroblasts and the epithelium.

Simvastatin attenuates experimental small airway remodelling in rats

The aim of this study was to assess the beneficial effects of simvastatin on cigarette smoke-induced small airway remodeling in rats. Simvastatin was administered at different doses for 16 weeks to rats with cigarette smoke-induced small airway remodelling. Morphological analyses were performed, and collagen deposition, production of growth factors, inflammatory parameters and RhoA, as well as the Smad signalling pathway in the lungs, were examined. Simvastatin attenuated small airway wall thickening and prevented the increase in lung hydroxyproline content and collagen deposition induced in airway walls by cigarette smoking. In addition, simvastatin downregulated transforming growth factor-beta1 and connective tissue growth factor protein and gene expression in the lungs. Furthermore, accumulation of macrophages and neutrophils and increases in tumour necrosis factor-alpha concentration in BAL fluid were inhibited by simvastatin. Simultaneously, the expression of RhoA and the phosphorylation of Smad2 and Smad3 in lungs exposed to cigarette smoke were inhibited during simvastatin administration. However, the increased expression of Smad2 and Smad3 proteins and the decreased level of Smad7 protein in remodelled lungs were not affected by simvastatin. Simvastatin attenuated experimental small airway remodelling, as indicated by decreases in collagen deposition and small airway wall thickening. Simvastatin may inhibit cigarette smoke-induced small airway remodelling by reducing growth factor expression and inflammation. The mechanism of action of simvastatin on small airway remodelling involved RhoA and the Smad signalling pathway. These findings indicate that simvastatin may have potential beneficial effects in the treatment of COPD.

Novel site-specific mast cell subpopulations in the human lung

Background:Lung mast cells are stereotypically divided into connective tissue (MCTC) and mucosal (MCT) mast cells. This study tests the hypothesis that each of these subtypes can be divided further into...

Small airways: an important but neglected target in the treatment of obstructive airway diseases

Changes in the structure and function of the small airways (<2mm diameter) are now recognized to play a major role in airflow limitation in both chronic obstructive pulmonary disease (COPD) and severe asthma. Increased thickness of the small airway wall causes lumenal narrowing, which can be further occluded by mucus and/or inflammatory cell exudate. This leads to increased peripheral resistance, air trapping and shortness of breath on exertion. Studies in animal models and in subjects with COPD have suggested that oxidant-driven transforming growth factor (TGF)-beta1 activation and subsequent increased airway wall collagen synthesis might be central to the changes in small airway structure. However, it remains difficult to measure small airway function in patients, and delivery of inhaled drugs to peripheral airways has not yet been optimised. The increased understanding of the processes underlying the development of small airways disease should facilitate pharmacological intervention targeted at this hitherto neglected compartment.

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1beta, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-beta activation in amplifying SM and driving IL-1beta-dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin alpha(v)beta(8), which is the major mediator of airway fibroblast TGF-beta activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-beta as a potential therapeutic target for COPD.