Airway Submucosa Research Articles

The Use of Bronchial Rheoplasty in Emphysema Patients Previously Treated with Endoscopic Lung Volume Reduction: A Case Series.

Endoscopic lung volume reduction (ELVR) is an established treatment option for patients with severe emphysema. Not all patients are candidates for this type of intervention, and in the context of significant airway secretions, they may be excluded from treatment. Bronchial Rheoplasty (BR) was developed to treat mucus hypersecretion by delivering nonthermal pulsed electric fields to the airway epithelium and submucosa. The literature to date demonstrates that patients treated with BR in clinical studies have a reduction in airway goblet cell hyperplasia as well as substantive clinical improvement in the setting of chronic bronchitis (CB). In this case series, we present four patients treated at three different institutions who had previously undergone ELVR with beneficial outcome. However, over time, these patients subsequently developed worsening clinical issues, including complaints of increased and thickened mucus, along with exacerbations in the setting of a loss of some ELVR-associated benefits. These patients then underwent exploratory treatment with BR with the intent of reducing their secretion burden and potentially restoring the efficacy associated with the initial placement of the airway valves. All BR procedures were well tolerated, and three of the four patients showed substantial improvement in their symptom burden. Airway examinations during the second of the two BR procedures also revealed what appeared to be less airway mucosal inflammation and a decrease in the quantity of airway secretions. Therefore, treatment with BR may have the potential to improve and restore the initial benefits associated with ELVR, thus enhancing long-term outcomes. Further clinical studies with sufficient follow-up are warranted to assess this in a larger cohort of patients, and to determine whether treatment with BR prior to ELVR may make more patients eligible for this treatment through reduction in their secretions and/or symptoms.

The hydro-ethanolic extract of Scoparia dulcis Linn inhibits allergic airway inflammatory responses in murine asthma models

BackgroundInflammatory responses, including airway inflammation, hyper-responsiveness, mucus hyper-secretion, prostaglandins and Th2 cytokines infiltration in the airway submucosa, frequently occur in allergic respiratory disorders. This study sought to investigate the effects of the hydro-ethanolic extract of Scoparia dulcis (SDE) on allergic airway inflammation, airway hyper-responsiveness, goblet cell hyperplasia, mucus hypersecretion, Th2 cytokines and prostaglandin (PG)-D2 using murine asthma models. MethodsAllergic asthma was induced in healthy guinea-pigs, and mice, by exposing them to ovalbumin (OVA) sensitization and challenge, and treatment with either 2 ml/kg normal saline, 10 mg/kg salbutamol, 10 mg/kg prednisolone, 50, 100, or 250 mg/kg of SDE per os. The percentage protection against pre-convulsive dyspnoea after methacholine challenge in OVA-induced asthmatic guinea-pigs was determined for each treatment regime, and histopathological examinations thereafter conducted on the excised lungs. Periodic acid-Schiff staining was also performed to identify goblet cell hyperplasia and mucus hypersecretion in these lung tissues. Lung tissue homogenates and serum from OVA-induced asthmatic mice were also assayed for PGD2, interleukins (IL)-5 and -13 levels using monoclonal antibody-based mouse ELISA kits. ResultsSDE treatments prolonged the time taken for pre-convulsive dyspnoea to occur after methacholine challenge in OVA-induced asthmatic guinea-pigs; indicative of a positive activity against airway hyper-responsiveness. Histopathological studies also showed that SDE significantly inhibited (p ≤ 0.05) pulmonary infiltration of leukocytes, inflammatory cell accumulation, airway smooth muscle thickening and goblet cell hyperplasia. Serum and lung tissue concentrations of PGD2, IL-5 and IL-13, significantly elevated (p ≤ 0.001) following allergic asthma induction in mice, were significantly reduced (p ≤ 0.01) back to within normal levels after SDE treatments. ConclusionThe plant extract exhibited anti-asthmatic and anti-inflammatory properties, as it reduced the severity of allergic inflammation and hyper-reactivity, as well as PGD2 and Th2 cytokines infiltration in the airway; and these effects could be exploited for future management of asthma.

Bronchial Rheoplasty for Chronic Bronchitis: Results from a Canadian Feasibility Study with RheOx®.

Chronic bronchitis (CB), a chronic obstructive pulmonary disease (COPD) phenotype defined by persistent mucus hypersecretion and cough, is associated with poor quality of life, exacerbations, and lung function impairment. Bronchial Rheoplasty (BR) delivers non-thermal pulsed electric fields to airway epithelium and submucosa. Preliminary studies demonstrated reduced airway goblet cell hyperplasia and symptom improvement in response to BR. This study aimed to further assess the safety and clinical feasibility of BR in the setting of CB. This 3-center, single-arm study evaluated the safety and feasibility of BR in Canadian patients. The major inclusion criteria were the sum of CAT first 2 questions (cough and mucus) ≥ 7 out of 10 and FEV1 ≥ 30% predicted. Right-sided airways were treated first; left, 1 month later. Serious adverse events (SAEs) were tabulated through 12 months. Outcomes were evaluated using the SGRQ and CAT. Ten patients with CB were enrolled and followed for 12 months. The BR procedure was successful in all patients (mean age 69 ± 5.8 years, post-BD FEV1 77.1 ± 28.3, SGRQ 56.2 ± 8.8, CAT 25.4 ± 4.7). Only one SAE, a COPD exacerbation 13 days following the BR procedure, was considered device related. No additional SAEs occurred through 12 months, and 90% of the patients were CAT responders (≥ 2-point improvement) at 3 and 6 months. Similar results were observed in SGRQ. BR was safe and well-tolerated. Meaningful symptom improvement was observed through 12 months, suggesting BR may be a viable treatment option for patients with CB.

Bronchial rheoplasty for chronic bronchitis: 2-year results from a US feasibility study with RheOx

IntroductionChronic bronchitis (CB), a phenotype of chronic obstructive pulmonary disease (COPD) characterised by persistent cough and mucus hypersecretion, is associated with poor outcomes despite guideline-based treatment. Bronchial rheoplasty (BR) with...

Leptin-producing monocytes in the airway submucosa may contribute to asthma pathogenesis

BackgroundObesity leads to an increase in the incidence and severity of asthma. Adipokines, such as leptin, secreted by adipocytes induce systemic inflammation, causing airway inflammation. We previously reported that leptin activates both inflammatory and structural cells, including lung fibroblasts. However, little is known about the differential leptin expression and responsiveness to leptin in asthmatic individuals and healthy controls (HC). In this study, we investigated the expression and origin of leptin in asthmatic airways. We also compared the effect of leptin on asthmatic and HC fibroblasts. MethodsLung specimens from asthmatic and non-asthmatic patients were analyzed by immunohistochemical staining using anti-leptin and anti-CD163 antibodies. Leptin mRNA and protein levels in human monocytes were detected by real-time PCR and western blotting and ELISA, respectively. We used flow cytometry to analyze asthmatic and HC lung fibroblasts for leptin receptor (Ob-R) expression. Further, we determined cytokine levels using cytometric bead array and ELISA and intracellular phosphorylation of specific signaling molecules using western blotting. ResultsAsthma specimens displayed accumulation of leptin-positive inflammatory cells, which were also positive for CD163, a high-affinity scavenger receptor expressed by monocytes and macrophages. Leptin expression was observed at both transcript and protein levels in human blood-derived monocytes. No significant differences were observed between asthmatic and HC lung fibroblasts in Ob-R expression, cytokine production, and intracellular phosphorylation of p38 mitogen-activated protein kinase. ConclusionsOur findings reveal similar responsiveness of control and asthmatic fibroblasts to leptin. However, the accumulation of inflammatory leptin-producing monocytes in the airway may contribute to the pathogenesis of asthma.

Vulnerability to acid reflux of the airway epithelium in severe asthma.

Severe asthma is associated with multiple comorbidities, including gastro-oesophageal reflux disease (GORD), which can contribute to exacerbation frequency and poor quality of life. Since epithelial dysfunction is an important feature in asthma, we hypothesised that in severe asthma the bronchial epithelium is more susceptible to the effects of acid reflux. We developed an in vitro model of GORD using differentiated bronchial epithelial cells (BECs) from normal or severe asthmatic donors exposed to a combination of pepsin, acid pH and bile acids using a multiple challenge protocol (MCP-PAB). In addition, we analysed bronchial biopsies and undertook RNA sequencing of bronchial brushings from controls and severe asthmatics without or with GORD. Exposure of BECs to the MCP-PAB caused structural disruption, increased permeability, interleukin (IL)-33 expression, inflammatory mediator release and changes in gene expression for multiple biological processes. Cultures from severe asthmatics were significantly more affected than those from healthy donors. Analysis of bronchial biopsies confirmed increased IL-33 expression in severe asthmatics with GORD. RNA sequencing of bronchial brushings from this group identified 15 of the top 37 dysregulated genes found in MCP-PAB treated BECs, including genes involved in oxidative stress responses. By affecting epithelial permeability, GORD may increase exposure of the airway submucosa to allergens and pathogens, resulting in increased risk of inflammation and exacerbations. These results suggest the need for research into alternative therapeutic management of GORD in severe asthma.

Acute iron oxide nanoparticles exposure induced murine eosinophilic airway inflammation via TLR2 and TLR4 signaling.

Iron oxide nanoparticles (Fe2 O3 NPs) is the main component of air pollution particles in urban rail transit environment. People are more exposed to Fe2 O3 NPs, however, the studies on relationship between Fe2 O3 NPs and respiratory health are limited. In the present study, acute airway inflammation caused by Fe2 O3 NPs and its possible mechanism were investigated. BALB/c mice were intratracheally challenged with different concentrations of Fe2 O3 NPs. Fe2 O3 NPs induced bronchial epithelial barrier function damage, infiltration of neutrophils and lymphocytes into the airway submucosa, secretion of mucus in the airway epithelium and elevated expression of eosinophil major basic protein (EMBP) in lungs. Compared with the control group, Fe2 O3 NPs increased eosinophils by 20 times in bronchoalveolar lavage fluid (BALF), and markedly increased eosinophils related cytokines and chemokines, including interleukin (IL) -5, IL-33, thymic stromal lymphopoietin (TSLP), monocyte chemotactic protein (MCP)-3, eotaxin, tumor necrosis factor (TNF)-α, keratinocyte chemoattractant (KC). Furthermore, Fe2 O3 NPs up-regulated levels of IL-5, MCP-3, eotaxin, and KC in serum. In vitro studies showed that Fe2 O3 NPs increased the genes and proteins expression of Toll-like receptors (TLR)-2, TLR4, TNF receptor associated factor 6 (TRAF6), myeloid differentiation factor 88 (MyD88), nuclear factor (NF)-κB, and TNF-α in RAW267.4 cells. The downstream inflammatory cytokine protein expression and release such as TNF-α was significantly decreased after using TLR2/TLR4 inhibitor OxPAPC, but not MyD88 inhibitor ST2825. These results suggest that TLR2 and TLR4 played important role in Fe2 O3 NPs inducing acute eosinophilic airway inflammation in the murine lung.

Airway Remodeling in Asthma.

Asthma is an inflammatory disease of the airways that may result from exposure to allergens or other environmental irritants, resulting in bronchoconstriction, wheezing, and shortness of breath. The structural changes of the airways associated with asthma, broadly referred to as airway remodeling, is a pathological feature of chronic asthma that contributes to the clinical manifestations of the disease. Airway remodeling in asthma constitutes cellular and extracellular matrix changes in the large and small airways, epithelial cell apoptosis, airway smooth muscle cell proliferation, and fibroblast activation. These pathological changes in the airway are orchestrated by crosstalk of different cell types within the airway wall and submucosa. Environmental exposures to dust, chemicals, and cigarette smoke can initiate the cascade of pro-inflammatory responses that trigger airway remodeling through paracrine signaling and mechanostimulatory cues that drive airway remodeling. In this review, we explore three integrated and dynamic processes in airway remodeling: (1) initiation by epithelial cells; (2) amplification by immune cells; and (3) mesenchymal effector functions. Furthermore, we explore the role of inflammaging in the dysregulated and persistent inflammatory response that perpetuates airway remodeling in elderly asthmatics.

Fructus mume Protects Against Cigarette Smoke Induced Chronic Cough Guinea Pig.

Fructus mume was recorded in the Chinese Pharmacopoeia and traditional Chinese medical books for chronic cough, but the effect and related constituents are still unknown. Thus, we investigated the protect effects and the relevant constituents of F. mume in a guinea pig model with chronic cough induced by cigarette smoke (CS). The organic acids and polysaccharides in F. mume were detected by high performance liquid chromatography, gel permeation chromatography, and gas chromatography-mass spectrometry. The guinea pigs were orally administrated with vehicle or the water extract of Fructus mume (FW) during the 14 days of CS exposure. Citric acid induced coughs were automatically measured by Buxco system. The differential cells in bronchoalveolar lavage fluid (BALF) and histopathological changes in lung tissue were assessed by hematoxylin and eosin staining. The tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8) levels in lung tissue were detected via enzyme-linked immunosorbent assay. The mucus productions in tracheas were determined with Alcian blue-periodic acid Schiff staining. The results suggested relatively high concentration of citric acid, chlorogenic acid, and neochlorogenic acid in F. mume, and high proportion of galactose and glucose and lower molecular weight of polysaccharides. Administration of FW significantly reduced the cough frequency, decreased inflammatory cells in BALF and lung tissue, and attenuated the thickening of airway epithelium and submucosa compared with CS-exposure group. Moreover, the overproduction of TNF-α and IL-8 in lung tissues, and mucus in central airways of CS-induced guinea pigs was markedly inhibited by FW. The extract could also protect against CS exposure-induced chronic cough in guinea pigs by reducing coughs, airways inflammation, and mucus overproduction.

Indoor PM2.5 from coal combustion aggravates ovalbumin-induced asthma-like airway inflammation in BALB/c mice.

We hypothesized that indoor PM2.5 exposure from coal combustion exaggerates airway inflammation in the lung tissue of asthmatic mice induced with ovalbumin (OVA). Forty BALB/c mice, randomly divided into four groups (n = 10 per group), were intratracheally instilled with normal saline alone, PM2.5 (2.5 mg/ml PM2.5 alone), OVA (15 μg/ml OVA alone), and PM2.5+OVA (2.5 mg/ml PM2.5 and 15 μg/ml OVA), respectively, four times at 2-wk intervals. Daily mean concentration of PM2.5 from indoor coal combustion was 156.95 μg/m3. The highest metal composition in PM2.5 was Zn (34.81 ± 1.8 μg/m3). Exposure to PM2.5+OVA significantly elevated IL-4 and decreased IFN-γ production in mice compared with the control (P < 0.05). Exposure to PM2.5+OVA showed a significant increase in the protein levels of granulocyte-macrophage colony-stimulating factor and IL-8 and a decrease in the protein level of transforming growth factor-β1 in bronchoalveolar lavage fluid of mice compared with the control (P < 0.05). The expression of IL-4 mRNA was significantly increased, whereas the expression of IFN-γ mRNA was decreased in lung tissue of the PM2.5+OVA group (P < 0.05). The expression level of Foxp3 mRNA in the PM2.5+OVA group was significantly lower than that in the control group in lung tissue (P < 0.05). Treatment with PM2.5+OVA promoted a prominent neutrophil sequestration into the lung parenchyma, goblet cell proliferation, and severe inflammatory cell infiltration in the airways. Exposure to PM2.5 from indoor coal combustion might induce airway inflammatory immune responses and exacerbate peribronchiolar inflammation due to infiltration of inflammatory cells into the airway submucosa and airway structural pathological changes.

Urban PM2.5 exacerbates allergic inflammation in the murine lung via a TLR2/TLR4/MyD88-signaling pathway

Nevertheless its mechanism has not been well explained yet, PM2.5 is recognized to exacerbate asthma. In the present study, the roles of toll-like receptor (TLR) 2, TLR4 and MyD88, in exacerbation of allergen-induced lung eosinophilia caused by urban PM2.5 was investigated. TLR2-, TLR4-, MyD88-deficient and WT BALB/c mice were intratracheally challenged with PM2.5 +/− ovalbumin (OVA) four times at 2-week intervals. PM2.5 increased neutrophil numbers and KC in bronchoalveolar lavage fluid and caused slight peribronchiolar inflammation in WT mice. However, these changes were attenuated, but not completely suppressed in gene-deficient mice, especially in MyD88−/− mice. In WT mice, PM2.5 + OVA exacerbated OVA-related lung eosinophilia. This exacerbation includes increase of IL-5, IL-13, eotaxin and MCP-3; infiltration of eosinophils into the airway submucosa; proliferation of goblet cells in the airway epithelium; and the production of antigen-specific IgE and IgG1 in serum. All these effects were stronger in TLR2−/− mice than in TLR4−/− mice. In MyD88−/− mice, this pro-inflammatory mediator-inducing ability was considerably weak and lung pathology was negligible. These results suggest that urban PM2.5 may exacerbate allergic inflammation in the murine lung via a TLR2/TLR4/MyD88-signaling pathway. PM2.5-bound trace microbial elements, such as lipopolysaccharide may be a strong candidate for exacerbation of murine lung eosinophilia.

Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions.

Hyaluronan (HA) has been used in treatment of cystic fibrosis (CF) via a nebulizer and has demonstrated success in clinical outcomes. HA is an important glycosaminoglycan that is cross-linked by heavy chains (HCs) from inter-α-inhibitor during inflammation. HC cross-linked HA (HC-HA) becomes significantly more adhesive for leukocytes than non-cross-linked HA, which can enhance inflammation. Our studies tested the hypothesis that HC-HA is present in CF airways and that altered ratios of HC-HA to its degradation into relatively lower molecular weight HA contribute to the pathophysiology of chronic inflammation in CF. We evaluated the distribution, levels, and size of HC-HA within CF, healthy, and diseased control lung, bronchus, and sputum tissues by histological and biochemical approaches. HC-HA was significantly elevated in CF, with deposits around the pulmonary vasculature, airway submucosa, and in the stroma of the submucosal glands. The increased infiltration of leukocyte populations correlated with the distribution of HC-HA matrices in the airways. Elevated lung tissue HC-HA correlated with decreased HA levels in CF mucus and sputum compared with controls, suggesting that aberrant degradation and cross-linking of HA in lung tissue is a unique feature of CF. The accumulation and degradation of proinflammatory HC-HA in CF lung tissue suggests that aberrant HA catabolism and cross-linking may contribute to chronic inflammation in airway tissues and affect mucus viscosity in CF airways.

Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation.

Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell-associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol. Airway hyperresponsiveness to inhaled mannitol was measured in 23 non-smoking, corticosteroid-free asthmatic individuals and 10 healthy controls. Mast cells and eosinophils were identified in mucosal biopsies from all participants. Mast cells were divided into phenotypes based on the presence of chymase. mRNA expression of mast cell-associated genes was measured by real-time PCR. The proportion of submucosal MCTC was higher in asthmatic individuals with AHR to mannitol compared with asthmatic individuals without AHR (median: 40.3% vs. 18.7%, P=0.03). Increased submucosal MCTC numbers were associated with increased levels of mRNA for thymic stromal lymphopoietin (TSLP) and CPA3 in asthmatics. Reactivity to mannitol correlated significantly with eosinophils in submucosa (r(s): 0.56, P=0.01). Airway hyperresponsiveness to inhaled mannitol is associated with an altered submucosal mast cell profile in asthmatic individuals. This mast cell profile is associated with increased levels of TSLP and CPA3. The degree of AHR to mannitol is correlated with the degree of eosinophilic inflammation in the airway submucosa.

The Rise and Fall of Hyaluronan in Respiratory Diseases.

In normal airways, hyaluronan (HA) matrices are primarily located within the airway submucosa, pulmonary vasculature walls, and, to a lesser extent, the alveoli. Following pulmonary injury, elevated levels of HA matrices accumulate in these regions, and in respiratory secretions, correlating with the extent of injury. Animal models have provided important insight into the role of HA in the onset of pulmonary injury and repair, generally indicating that the induction of HA synthesis is an early event typically preceding fibrosis. The HA that accumulates in inflamed airways is of a high molecular weight (>1600 kDa) but can be broken down into smaller fragments (<150 kDa) by inflammatory and disease-related mechanisms that have profound effects on HA pathobiology. During inflammation in the airways, HA is often covalently modified with heavy chains from inter-alpha-inhibitor via the enzyme tumor-necrosis-factor-stimulated-gene-6 (TSG-6) and this modification promotes the interaction of leukocytes with HA matrices at sites of inflammation. The clearance of HA and its return to normal levels is essential for the proper resolution of inflammation. These data portray HA matrices as an important component of normal airway physiology and illustrate its integral roles during tissue injury and repair among a variety of respiratory diseases.

Ovalbumin sensitization of guinea pig at birth prevents the ontogenetic decrease in airway smooth muscle responsiveness.

Airway smooth muscle (ASM) displays a hyperresponsive phenotype at young age and becomes less responsive in adulthood. We hypothesized that allergic sensitization, which causes ASM hyperresponsiveness and typically occurs early in life, prevents the ontogenetic loss of the ASM hyperresponsive phenotype. We therefore studied whether neonatal allergic sensitization, not followed by later allergen challenges, alters the ontogenesis of ASM properties. We neonatally sensitized guinea pigs to ovalbumin and studied them at 1 week, 3 weeks, and 3 months (adult). A Schultz‐Dale response in isolated tracheal rings confirmed sensitization. The occurrence of inflammation was evaluated in the blood and in the submucosa of large airways. We assessed ASM function in tracheal strips as ability to produce force and shortening. ASM content of vimentin was also studied. A Schultz‐Dale response was observed in all 3‐week or older sensitized animals. A mild inflammatory process was characterized by eosinophilia in the blood and in the airway submucosa. Early life sensitization had no effect on ASM force generation, but prevented the ontogenetic decline of shortening velocity and the increase in resistance to shortening. Vimentin increased with age in control but not in sensitized animals. Allergic sensitization at birth without subsequent allergen exposures is sufficient to prevent normal ASM ontogenesis, inducing persistence to adulthood of an ASM hyperresponsive phenotype.

Co-exposure to allergen and diesel exhaust enhance inflammatory responses in human airway submucosa

Background Asthma is a chronic condition described by inflammation of the airways and lungs. Diesel exhaust (DE) is a major contributor to ambient particulate matter (PM) air pollution. There is rising evidence that PM acts as adjuvant on the immune responses and may lead to augmentation of allergic inflammation [1,2]. We aim to elucidate if DE increases allergen-induced inflammation and cellular immune response in the airways of atopic human subjects.

Aggravation of ovalbumin-induced murine asthma by co-exposure to desert-dust and organic chemicals: an animal model study.

BackgroundThe organic chemicals present in Asian sand dust (ASD) might contribute to the aggravation of lung eosinophila. Therefore, the aggravating effects of the Tar fraction from ASD on ovalbumin (OVA)-induced lung eosinophilia were investigated.MethodsThe Tar fraction was extracted from ASD collected from the atmosphere in Fukuoka, Japan. ASD collected from the Gobi desert was heated at 360°C to inactivate toxic organic substances (H-ASD). ICR mice were instilled intratracheally with 12 different test samples prepared with Tar (1 μg and 5 μg), H-ASD, and OVA in a normal saline solution containing 0.02% Tween 80. The lung pathology, cytological profiles in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines/chemokines in BALF and OVA-specific immunoglobulin in serum were investigated.ResultsSeveral kinds of polycyclic aromatic hydrocarbons (PAHs) were detected in the Tar sample. H-ASD + Tar 5 μg induced slight neutrophilic lung inflammation. In the presence of OVA, Tar 5 μg increased the level of eosinophils slightly and induced trace levels of Th2 cytokines IL-5 and IL-13 in BALF. Also mild to moderate goblet cell proliferation and mild infiltration of eosinophils in the submucosa of airway were observed. These pathological changes caused by H-ASD + OVA were relatively small. However, in the presence of OVA and H-ASD, Tar, at as low a level as 1 μg, induced severe eosinophil infiltration and proliferation of goblet cells in the airways and significantly increased Th2 cytokines IL-5 and IL-13 in BALF. The mixture showed an adjuvant effect on OVA-specific IgG1 production.ConclusionsThese results indicate that H-ASD with even low levels of Tar exacerbates OVA-induced lung eosinophilia via increases of Th2-mediated cytokines. These results suggest that ASD-bound PAHs might contribute to the aggravation of lung eosinophila.

Tracheobronchopathia osteochondroplastica: a case report and literature review.

Tracheobronchopathia osteochondroplastica (TO) was diagnosed in a 52-year-old male with prolonged dry cough. Computerized tomography (CT) demonstrated that there were multiple calcified nodules in the anterolateral wall of trachea, sparing the posterior tracheal membrane. Fiberoptic bronchoscopy (FOB) showed that submucosal nodules protruded into the airway lumen. Histopathological exam found ossification and cartilage in the submucosa. TO is a scarce benign disorder, characterized by submucosal bony and cartilaginous nodules. The clinical manifestation is undistinguished and treatment is symptomatically dependent. FOB is a definitive diagnostic procedure. The characteristics of FOB finding are described as beaded, spiculate, rock garden, or cobble-stoned like nodules, which projected into the tracheobronchus lumen, sparing the posterior wall. Histopathological exam might re-confirm the diagnosis, finding ossification and cartilage in the submucosa of airway. Awareness of TO is significantly important, especially in chronic cough patients with special CT image, and FOB should be performed to confirm the diagnosis.

Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: I. Effects on lung remodeling and pathology

BackgroundGlycogen synthase kinase-3 (GSK-3) is a constitutively active kinase that regulates multiple signalling proteins and transcription factors involved in a myriad of cellular processes. The kinase acts as a negative regulator in β-catenin signalling and is critically involved in the smad pathway. Activation of both pathways may contribute to pulmonary features of chronic obstructive pulmonary disease (COPD).MethodsIn the present study, we investigated the effect of the selective GSK-3 inhibitor SB216763 on pulmonary pathology in a guinea pig model of lipopolysaccharide (LPS)-induced COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pre-treated with either intranasally instilled SB216763 or corresponding vehicle 30 min prior to each LPS/saline challenge.ResultsRepeated LPS exposures activated β-catenin signalling, primarily in the airway epithelium and submucosa. LPS also induced pulmonary inflammation and tissue remodelling as indicated by inflammatory cell influx, increased pulmonary fibronectin expression and enhanced small airway collagen content. Inhibition of GSK-3 by SB216763 did not affect LPS-induced inflammatory cell influx, but prevented the small airway remodelling and, unexpectedly, inhibited the activation of β-catenin in vivo. LPS or SB216763 treatment had no effect on the airway smooth muscle content and alveolar airspace size. However, GSK-3 inhibition prevented LPS-induced right ventricle hypertrophy.ConclusionsOur findings indicate that GSK-3 inhibition prevents LPS-induced pulmonary pathology in guinea pigs, and that locally reduced LPS-induced β-catenin activation appears in part to underlie this effect.

Tracheobronchial Amyloidosis in a Patient With Sjogren Syndrome

Pulmonary amyloidosis in the setting of Sjogren syndrome is rare. It most commonly presents in form of multinodular disease with or without cysts formation. Amyloid plaques may also deposit in the airway submucosa, causing airway narrowing; the condition referred as "tracheobronchial amyloidosis" (TBA). Patients with this condition most commonly present with postobstructive pneumonia, wheezing, and occasionally hemoptysis. Endoscopic therapies, using flexible forceps with or without laser therapy is crucial to alleviate the obstruction and control the bleeding. Other therapeutic modalities such as external beam radiation has been shown to be promising; however, further data are still needed. To our knowledge, our patient is the first reported case of TBA in a setting of Sjogren syndrome.