Contribution of Lung Fibroblast Migration in the Fibrotic Process of Airway Remodeling in Asthma

ABSTRACTBackgroundThe fibrotic process in airway remodeling of asthma may be characterized by an exaggerated deposition of extracellular matrix (ECM) components such as fibronectin and type I, III and IV collagen. In the present study, we established airway remodeling model mice and examined the mechanism of fibrotic change by measuring chemotactic activity of lung fibroblasts and quantifying collagen content in lung tissues.MethodsAirway remodeling model mice were made by ovalbumin (OA) sensitization and inhalation. Bronchoalveolar lavage (BAL) and bronchial biopsy were performed. Cell migration was assessed by the Boyden's chamber technique. The collagen content of lung tissue was measured using ELISA.ResultsThe chemotactic activity in lung fibroblasts toward the mouse BAL fluid (BALF) was significantly increased in OA-inhaled mice. Total soluble collagen content was significantly increased in OA-inhaled mice. We observed markedly increased collagen deposition around the airway wall in OA-inhaled mice, which was not shown in saline-inhaled mice. Furthermore, fibronectin in the BALF of OA-inhaled mice was significantly higher than that in the control mice.ConclusionsThe total soluble collagen content increased during the fibrotic change of airway remodeling in asthma. Furthermore, migration of fibroblasts may play a key role in this remodeling process, and fibronectin and type I and IV collagen seem to be chemotactic factors for the fibroblasts

Three Cases of Tsutsugamushi Disease successfully treated with Clarithromycin.

Three cases of tsutsugamushi disease were successfully treated with clarithromycin, a new macrolide antibiotic. This is the first report describing tsutsugamushi disease in Hirado area and the clinical application of clarithromycin to this rickettsial disease

Capsaicin Provocation Test as a Diagnostic Method for Determining Multiple Chemical Sensitivity

Background: Multiple chemical sensitivity (MCS) is characterized by chemically induced symptoms from multiple organs. These symptoms occur in response to demonstrable exposure to chemically unrelated compounds at doses far below those known to cause harmful effects in the general population. Although the mechanism of this action remains unclear and no acceptable and well-documented treatment for MCS has yet been established, regarding neurogenic inflammation, it has been hypothesized that an increased density of C-fiber neurons is found in symptomatic tissues. Methods: Using capsaicin, we examined the sensitivity of the cough reflex in patients with MCS and chronic cough (CC) and compared the findings with those in control subjects. Fifteen patients (four males, 11 females; mean (± SD) age 38.3±16.3 years) suffering from MCS and 29 patients (10 males, 19 females; mean age 46.4±15.9 years) who had cough symptoms lasting 4 weeks or longer and normal chest radiograph findings (CC) were enrolled in the present study. Twenty-nine healthy subjects (14 males, 15 females; mean age 37.9±9.5 years) who had no history of coughing during the previous 6 months and no chronic respiratory diseases were enrolled as controls. Subjects inhaled stepwise incremental concentrations of capsaicin (0.122-62.5 |imol/L) for 15 s. Inhalation was performed at 45 s intervals and the number of coughs per minute was counted. The provocation was terminated when the subject coughed five or more times. Ventilatory functions (forced vital capacity (FVC), forced expiratory volume in 1 s and the expiratory flow rate at 50 and 75% FVC (V50 and V25, respectively)) were also measured. Results: No significant differences were observed in ventilatory function test findings between the three groups. The log concentration of capsaicin causing five or more coughs (C5) was 0.150±0.630, 0.611±0.691 and 1.120±0.612 | mol/L in MCS, CC and control subjects, respectively. The log C5 in MCS subjects was significantly lower than that in CC and control subjects. Conclusions: Capsaicin is a cough-inducing agent in humans that possibly acts on non-myelinated C-fiber endings. The findings of the present study indicate that the mechanisms underlying MCS may originate in the sensory nervous system

Lung sound analysis can be an index of the control of bronchial asthma

Background: We assessed whether lung sound analysis (LSA) is a valid measure of airway obstruction and inflammation in patients with bronchial asthma during treatment with inhaled corticosteroids (ICSs). Methods: 63 good adherence patients with bronchial asthma and 18 poor adherence patients were examined by LSA, spirometry, fractional exhaled nitric oxide (FeNO), and induced sputum. The expiration-to-inspiration lung sound power ratio at low frequencies between 100 and 200 Hz (E/I LF) obtained by LSA was compared between healthy volunteers and bronchial asthma patients. Next, post-ICS treatment changes were compared in bronchial asthma patients between the good adherence patients and the poor adherence patients. Results: E/I LF was significantly higher in bronchial asthma patients (0.62 ± 0.21) than in healthy volunteers (0.44 ± 0.12, p < 0.001). The good adherence patients demonstrated a significant reduction in E/I LF from pre-treatment to post-treatment (0.55 ± 0.21 to 0.46 ± 0.16, p = 0.002), whereas the poor adherence patients did not show a significant change. The decrease of E/I LF correlated with the improvement of FEV1/FVC ratio during the ICS treatment (r = −0.26, p = 0.04). The subjects with higher pre-treatment E/I LF values had significantly lower FEV1/FVC and V50,%pred (p < 0.001), and significantly higher FeNO and sputum eosinophil percentages (p = 0.008 and p < 0.001, respectively). Conclusions: The E/I LF measurement obtained by LSA is useful as an indicator of changes in airway obstruction and inflammation and can be used for monitoring the therapeutic course of bronchial asthma patients

Peripheral bronchial obstruction evaluation in patients with asthma by lung sound analysis and impulse oscillometry

Background: Computer-aided lung sound analysis (LSA) has been reported to be useful for evaluating airway inflammation and obstruction in asthma patients. We investigated the relation between LSA and impulse oscillometry with the evaluation of peripheral airway obstruction. Methods: A total of 49 inhaled corticosteroid-naive bronchial asthma patients underwent LSA, spirometry, impulse oscillometry, and airway hyperresponsiveness testing. The data were analyzed to assess correlations between the expiration: inspiration lung sound power ratio (dB) at low frequencies between 100 and 195 Hz (E/I LF) and various parameters. Results: E/I LF and X5 were identified as independent factors that affect V˙50,%predicted. E/I LF showed a positive correlation with R5 (r = 0.34, p = 0.017), R20 (r = 0.34, p = 0.018), reactance area (AX, r = 0.40, p = 0.005), and resonant frequency of reactance (Fres, r = 0.32, p = 0.024). A negative correlation was found between E/I LF and X5 (r = −0.47, p = 0.0006). E/I LF showed a negative correlation with FEV1/FVC(%), FEV1,%predicted, V˙50,%predicted, and V˙25,%predicted (r = −0.41, p = 0.003; r = −0.44, p = 0.002; r = −0.49, p = 0.0004; and r = −0.30, p = 0.024, respectively). E/I LF was negatively correlated with log PC20 (r = −0.30, p = 0.024). Log PC20, X5, and past smoking were identified as independent factors that affected E/I LF level. Conclusions: E/I LF as with X5 can be an indicator of central and peripheral airway obstruction in bronchial asthma patients

Airway inflammation phenotype prediction in asthma patients using lung sound analysis with fractional exhaled nitric oxide

Background: We previously reported the results of lung sound analysis in patients with bronchial asthma and demonstrated that the exhalation-to-inhalation sound pressure ratio in the low frequency range between 100 and 200 Hz (E/I LF) was correlated with the presence of airway inflammation and airway obstruction. We classified asthma patients by airway inflammation phenotype using the induced sputum eosinophil and neutrophil ratio and determined whether this phenotype could be predicted using E/I LF and fractional exhaled nitric oxide values. Methods: Steroid-naive bronchial asthma patients were classified into four phenotypes, including “Low inflammation” (35 patients), “Eosinophilic type” (58 patients), “Neutrophilic type” (15 patients), and “Mixed type” (15 patients) based on the results of induced sputum examinations. The E/I LF data and FeNO levels were then evaluated for the four phenotype groups; the prediction powers of these two indices were then analyzed for each phenotype. Results: The median E/I LF value was highest in the “Mixed type” and lowest in the “Low inflammation” group. FeNO differentiated between the “Low inflammation” and “Eosinophilic type” groups, “Low inflammation” and “Neutrophilic type” groups, and “Neutrophilic type” and “Mixed type” (p < 0.0001, p = 0.007, and p = 0.04, respectively). E/I LF differentiated between the “Low inflammation” and “Eosinophilic type” groups (p = 0.006). E/I LF could distinguish the “Mixed type” group from the “Low inflammation” and “Eosinophilic type” groups (p = 0.002). Conclusions: A combination of the E/I LF value and FeNO may be useful for the classification of the airway inflammation phenotype in patients with bronchial asthma

A Study of the Usefulness of Anti-inflammatory Treatment for Mild Intermittent Asthma (Step 1): Budesonide vs. Montelukast

Background: Early intervention in adult asthma has been evaluated mostly with regard to symptoms, respiratory function and airway hyperresponsiveness, and has rarely been evaluated with regard to airway inflammation. Further, no clinical data concerning prevention of remodeling by anti-inflammatory therapy have been reported. The anti-inflammatory activities of an inhaled steroid and a leukotriene receptor antagonist were compared using sputum induced by inhaled hyperosmotic NaCl solution, and the usefulness of anti-inflammatory treatment for mild intermittent asthma (step 1) was investigated. Methods: The subjects of the study were patients with mild intermittent asthma (step 1) who had not received steroid treatment and had only been treated with inhaled β2-stimulants as needed. The subjects were divided into two groups : one group received 400 μg/day of budesonide (BUD group ; n = 15) and the other group received 10 mg/day of montelukast (MK group ; n = 12). The anti-inflammatory activities of BUD and MK were compared by examining respiratory function, exhaled nitric oxide (ENO) concentrations, airway hyperresponsiveness (acetylcholine provocation test) and the sputum induced by inhalation of hyperosmotic NaCl solution at three time points, i.e., before, 1 month after, and 6 months after the start of treatment. Results: It was shown that even in mild intermittent asthma (step 1) the levels of ENO and sputum eosinophil ratio were elevated, indicating that airway inflammation was clearly present and that airway hyperresponsiveness was elevated. The effects of BUD and MK in improving ENO and sputum eosinophil ratio were almost the same. However, airway hyperresponsiveness in both groups were not significantly improved after 1 and 6 months of treatment. Conclusions: Anti-inflammatory treatment is necessary even for mild intermittent asthma (step 1). We believe that early intervention with anti-inflammatory drugs is important for the prevention of airway remodeling, exacerbation of disease and progression to intractable asthma. Either of the two types of drugs, low-dose inhaled steroids or leukotriene receptor antagonists, can be selected as anti-inflammatory drugs for mild intermittent asthma