Once-daily administration of fluticasone propionate does not worsen controlled airway hyperresponsiveness in patients with asthma.

BACKGROUND: Inhaled steroids are currently the most important drugs for asthma patients, but compliance tends to be low. Compliance could be improved by reducing the number of daily administrations. OBJECTIVES: In the present study, we compared once- and twice-daily administration of fluticasone propionate (FP) to determine the differences in efficacy. METHODS: Subjects were 40 patients diagnosed with bronchial asthma with stable symptoms and pulmonary functions who were on twice-daily FP administration of 100 microg. There were 14 men and 26 women ranging from 29 to 72 years of age. After a 4-week observation period, subjects were randomized into two administration groups by the envelope method and followed for 8 weeks: group A, once-daily administration (200 microg of FP at night), and group B, twice-daily administration (100 microg of FP in the morning and at night). Clinical symptoms, pulmonary functions and airway responsiveness were compared between these two groups. RESULTS: No significant deterioration in clinical symptoms, pulmonary functions and airway responsiveness were observed in group A compared with group B. CONCLUSIONS: These results demonstrate that once-daily FP administration is as effective as twice-daily administration, and that it may improve the compliance for inhaled steroids.

Effect of suplatast tosilate on airway hyperresponsiveness and inflammation in asthma patients.

Because eosinophilic airway inflammation is a characteristic of bronchial asthma, the treatment of such inflammation is important in the management of this disease. Suplatast tosilate is a novel anti-asthma drug that suppresses eosinophil proliferation and infiltration through selective inhibition of Th2 cytokine synthesis. We investigated the effect of oral suplatast tosilate therapy in patients with mild and moderate asthma. Twenty-eight asthma patients were randomized into two groups with or without suplatast tosilate treatment (100 mg t.i.d. for 28 days). We examined the blood eosinophil counts, eosinophilic cationic protein level, sputum eosinophil count, exhaled nitric oxide level, and airway responsiveness before and after treatment. In patients treated with suplatast tosilate, the eosinophil count in the blood and sputum was significantly decreased after treatment, while there was no such change in the patients without suplatast treatment. The exhaled nitric oxide level and airway responsiveness (measured using an Astograph) were also decreased after treatment with suplatast tosilate, while there were no significant changes in patients without suplatast tosilate. These results strongly suggest that oral administration of suplatast tosilate suppresses airway hyperresponsiveness in asthma patients by reducing eosinophilic inflammation in the airways.

Ozone exposure may enhance airway smooth muscle contraction by increasing Ca(2+) refilling of sarcoplasmic reticulum in guinea pig.

Ozone induces airway hyperresponsiveness, but there is controversy about effects of ozone on smooth muscle per se. We therefore investigated effects of in vivo ozone exposure on intracellular calcium mobilization in relation to tracheal smooth muscle contractility in the guinea pig in vitro. Guinea pigs underwent ozone exposure or sham exposure (3 ppm, 2 h). Then, a tracheal smooth muscle strip was mounted in an organ bath to record isometric tension. Effects of ozone exposure on acetylcholine-induced contraction of smooth muscle were as follows. Contraction was not altered in normal Krebs solution, but was increased in Ca(2+)-free solution in ozone-exposed animals. Decline of tension on repetitive application of acetylcholine in Ca(2+)-free solution was reduced, while the tension decline rate while acetylcholine was washed out with Ca(2+)-free solution was facilitated in ozone-exposed animals. Tension decline during the continuous administration of acetylcholine in Ca(2+)-free solution was slowed. Contraction occurred more quickly in Ca(2+)-free solution in ozone-exposed animals. Results suggest that ozone has a direct action on airway smooth muscle by changing Ca(2+) mobilization; Ca(2+) refilling via a Ca(2+) pump and Ca(2+) release via Ca(2+) channels in the sarcoplasmic reticulum were increased, while Ca(2+) extrusion via the plasma membrane Ca(2+) pump was unchanged.

Asymptomatic atresia of the lobar bronchus of the lung: a case report.

A 64-year old woman presented with an asymptomatic occlusion of the intermediate bronchus associated with a peripheral mass occupying the entire middle and lower lobes. As malignancy was suspected, inferior bilobectomy was done. There was a complete atelectasis of both lobes, with massive parenchymal necrosis. Pathological examinations suggested a tuberculous granuloma in the bronchus and parenchyma although tuberculous bacilli were not found. This case was unusual as congenital anomaly, and was suspected as bronchial tuberculosis.

Acute interstitial pneumonia induced by ONO-1078 (pranlukast), a leukotriene receptor antagonist.

A 62-year-old woman treated with pranlukast for 2 months developed interstitial pneumonitis with a high fever. A lymphocyte stimulation test was reactive to pranlukast. Her clinical symptoms improved with discontinuation of pranlukast and administration of systemic corticosteroid. To our knowledge, this is the first reported case of drug-induced lung disease involving a leukotriene. The steps that can be taken to promptly reach a diagnosis and to successfully treat this life-threatening condition are described.

PAF mediates cigarette smoke-induced goblet cell metaplasia in guinea pig airways.

Goblet cell metaplasia is an important morphological feature in the airways of patients with chronic airway diseases; however, the precise mechanisms that cause this feature are unknown. We investigated the role of endogenous platelet-activating factor (PAF) in airway goblet cell metaplasia induced by cigarette smoke in vivo. Guinea pigs were exposed repeatedly to cigarette smoke for 14 consecutive days. The number of goblet cells in each trachea was determined with Alcian blue-periodic acid-Schiff staining. Differential cell counts and PAF levels in bronchoalveolar lavage fluid were also evaluated. Cigarette smoke exposure significantly increased the number of goblet cells. Eosinophils, neutrophils, and PAF levels in bronchoalveolar lavage fluid were also significantly increased after cigarette smoke. Treatment with a specific PAF receptor antagonist, E-6123, significantly attenuated the increases in the number of airway goblet cells, eosinophils, and neutrophils observed after cigarette smoke exposure. These results suggest that endogenous PAF may play a key role in goblet cell metaplasia induced by cigarette smoke and that potential roles exist for inhibitors of PAF receptor in the treatment of hypersecretory airway diseases.

[A case of inflammatory endotracheal polyps in an asthmatic subject].

A 60-year-old asthmatic woman was admitted to our department because of bloody sputum and pneumonia. She had been treated with inhaled becromethasone dipropionate (800 micrograms/day) on an outpatient basis for 3 years. Fiberoptic bronchoscopy revealed polypoid lesions in the trachea, most of which were removed with forceps during the procedure. Numerous lymphocytes were observed in the biopsy specimen. Because immunohistochemical staining denied a monoclonal origin for the accumulated lymphocytes, the lesion was diagnosed as an inflammatory polyp. The patient was treated successfully with antibiotics for her pneumonia, and on a follow-up bronchoscopy 6 months later, only a small remnant of the lesion was noted. This is the fourth report about inflammatory polyps in asthmatics. In the previous 3 cases, however, marked eosinophil infiltration was consistently reported. The lymphocyte predominance in the present case therefore suggests a distinct etiology rather than asthmatic airway inflammation.

[An autopsy case of idiopathic interstitial pneumonia with diffuse alveolar hemorrhage due to acute exacerbation].

There has hitherto been no report describing idiopathic interstitial pneumonia associated with diffuse alveolar hemorrhage, but we herein report one such rare case. A 75-year-old man who had received a diagnosis of idiopathic interstitial pneumonia had been followed in our hospital since 1995, and had been treated with cyclophosphamide since September 1999. He discontinued taking cyclophosphamide without informing us, and two months later he was admitted to our hospital with deterioration of dyspnea on September 13, 2000. Since chest radiography and CT findings demonstrated alveolar infiltrates in the right middle lung field, he was treated with antibiotic agents. Although no deterioration of symptoms occurred, on September 14 he began to suffer rapidly progressive dyspnea accompanied with production of bloody sputum, which eventually developed into full-blown hemoptysis in the evening of September 15. He died of respiratory failure early the next morning. The autopsy findings demonstrated diffuse alveolar hemorrhage, diffuse alveolar damage, interstitial pneumonia, and pulmonary fibrosis.

Effect of dimethylthiourea, a hydroxyl radical scavenger, on cigarette smoke-induced bronchoconstriction in guinea pigs.

Cigarette smoke exposure causes bronchoconstriction in guinea pigs by stimulating cholinergic and excitatory nonadrenergic, noncholinergic (eNANC)-nerves in vagus system. The aim of this study is to elucidate the role of hydroxyl radical (OH(-)), contained in cigarette smoke, in bronchoconstriction. Anaesthetized animals were exposed to 80 puffs of smoke for 4 min. Pretreatment with dimethylthiourea, a OH(-) scavenger, significantly inhibited cigarette smoke-induced bronchoconstriction. To investigate its site of action, effects of dimethylthiourea were examined on vagally mediated bronchcoconstriction by electrical stimulation and on the bronchoconstriction by intravenous acetylcholine and neurokinin-A. Dimethylthiourea did not inhibit bronchoconstriction evoked by vagal stimulation, acetylcholine or neurokinin-A. These results suggest that dimethylthiourea inhibits cigarette smoke-induced bronchoconstriction by scavenging the smoke-derived OH(-), but not by inhibiting airway nerve function.

Neutrophil elastase inhibitor, ONO-5046 suppresses ozone-induced airway mucus hypersecretion in guinea pigs.

To investigate the role of neutrophil elastase in ozone-induced airway hypersecretion, we measured goblet cell secretion by using a semiquantitative morphometric technique in guinea pigs. The magnitude of mucus discharge was estimated from the mucus score, which is inversely related to the degree of mucus discharge in histological sections of trachea stained for mucus glycoprotein with periodic acid Schiff/Alcian blue. Mucus hypersecretion of goblet cells was induced by ozone exposure and persisted for up to 5 h after exposure. Pretreatment with N-[2-¿4-(2,2-dimethyl-propionyloxy) phenyl-sulfonylamino¿ benzoyl] aminoacetic acid (ONO-5046), a specific neutrophil elastase inhibitor (200 mg/kg, intraperitoneally), significantly inhibited goblet cell hypersecretion both just after and 5 h after ozone-exposure, but the latter inhibition was not complete. In bronchoalveolar lavage fluid, ozone exposure significantly increased the number of neutrophils just after and 5 h after exposure, while ONO-5046 significantly inhibited the increase in neutrophils only 5 h after ozone-exposure. These results indicate that neutrophil elastase may play an important role in the ozone-induced tracheal goblet cell hypersecretion and influx of neutrophils.

[A case of latex allergy with bronchial asthma].

A 26-year-old nurse consulted our department because of shortness of breath, wheezing and skin eruption after eating lunch several days before. At the consultation, the symptoms had disappeared, pulmonary function showed no abnormality, and there were no abnormal findings on chest auscultation. Latex allergy was suspected because of a history of wheezing and skin eruption after wearing latex gloves and an elevated serum IgE level specific to latex antigen. After a usage test of medical latex gloves, wheezing, skin eruption, and a decrease of FEV1.0 on pulmonary function testing were observed. The case was therefore diagnosed as latex allergy with bronchial asthma. Her symptoms were not observed after polymer coated gloves were substituted. Latex allergy is apt to complicate food allergy, an initial symptom of the present case. Specific IgE for several kinds of food was also elevated.

Role of neutrophil elastase in ozone-induced airway responses in guinea-pigs.

Ozone-induced airway hyperresponsiveness occurs concurrently with neutrophilic inflammation and epithelial injury in various species including humans. The mechanism of neutrophil-induced airway hyperresponsiveness, however, has not yet been fully clarified. Neutrophil elastase (NE) is a multipotent protease released from activated neutrophils, which may play a role in ozone-induced airway hyperresponsiveness. In order to address this issue, the effects of ONO-5046, a specific NE inhibitor, were investigated in ozone-exposed guinea-pigs. Awake animals were exposed to ozone at 3 parts per million for 2 h, airway responsiveness to acetylcholine (ACh) measured and examination of bronchoalveolar lavage fluid (BALF) performed. Ozone exposure increased airway responsiveness to both inhaled and intravenous ACh, the concentration of NE in BALF and the number of neutrophils and airway epithelial cells in BALF. Although pretreatment with ONO-5046 (200 mg x kg(-1), i.p.) had no effect on these changes immediately after the exposure, it significantly inhibited airway hyperresponsiveness to inhaled ACh, whilst decreasing the number of neutrophils and epithelial cells in BALF 3-5 h after the exposure. In contrast, ONO-5046 showed no significant effect on airway hyperresponsiveness to intravenous ACh at any time. These results suggest that neutrophil elastase contributes to ozone-induced airway hyperresponsiveness developing during the hours after exposure, presumably by means of inducing epithelial injury.

[Diffuse idiopathic skeletal hyperostosis with fibrobullous change in upper lung lobes and dyspnea due to limitation of thoracic cage].

A 48-year-old man was admitted to our hospital because of shortness of breath and abnormal shadows on chest roentgenograms. Although he had been given a diagnosis of ankylosing spondylitis (AS) at the onset of his symptoms, a diagnosis of diffuse idiopathic skeletal hyperostosis (DISH) was made by our orthopedics department on the basis of bone X-ray findings. Spirograms demonstrated a restrictive pattern and residual volume was increased. Total lung capacity and respiratory muscle function were normal, suggesting that the abnormal spirogram findings were due to decreased thoracic cage compliance. Chest roentgenograms and computed tomographic scans showed apical fibrobullous changes in both lungs, similar to those observed in AS. To our knowledge, this is the first case of DISH with pulmonary involvement to be reported to date. The pulmonary manifestations were similar to those of AS, and it was speculated that they were due to limitation of the thoracic cage.

PACAP reverses airway hyperresponsiveness induced by ozone exposure in guinea pigs.

BACKGROUND: We previously demonstrated that pituitary adenylate cyclase activating peptide (PACAP) inhibits airway smooth muscle contraction and plasma extravasation. OBJECTIVE: We thus hypothesized that PACAP may regulate airway responsiveness through these effects and examined the effects of exogenously applied PACAP on the airway hyperresponsiveness induced by ozone exposure. METHODS: Ozone exposure was carried out in awake, spontaneously breathing guinea pigs using 3 ppm for 2 h. Airway responsiveness to histamine was determined before and 30 and 90 min after the termination of ozone exposure for 2 h in anesthetized animals. Extravasation of Evans blue was measured before and 90 min after the termination of ozone exposure. Either PACAP (10(-6) mol/kg) or vehicle was administered intravenously 60 min after exposure. The airway responsiveness was expressed as the concentration of histamine required to produce a 200% increase in total pulmonary resistance (PC(200)). RESULTS: Ozone exposure caused a significant decrease in PC(200) (n = 5, p < 0.05) 30 min after ozone exposure which persisted 90 min thereafter, thus suggesting that ozone caused airway hyperresponsiveness. PACAP significantly suppressed the increase in airway hyperresponsiveness induced by ozone 90 min after exposure (n = 5, p < 0.05). In contrast, this peptide did not have any effect on plasma extravasation. CONCLUSION: We thus conclude that PACAP decreases ozone-induced airway responsiveness, and, therefore, intravenously administered PACAP may be useful in reversing airway hyperresponsiveness.

Repeated allergen exposure of sensitized Brown-Norway rats induces airway cell DNA synthesis and remodelling.

Chronic inflammation in asthmatic airways can lead to characteristic airway smooth muscle (ASM) thickening and pathological changes within the airway wall. This study assessed the effect of repeated allergen exposure on ASM and epithelial cell deoxyribonucleic acid (DNA) synthesis, cell recruitment and airway wall pathology. Brown-Norway rats were sensitized and then exposed to ovalbumin or saline aerosol every 3 days on six occasions. After the final exposure, rats were administered twice daily for 7 days with the DNA S-phase marker bromodeoxyuridine (BrdU). Using a triple immunohistochemical staining technique, BrdU incorporation into ASM and epithelium was quantified employing computer-assisted image analysis. There were >3-fold mean increases in BrdU incorporation into ASM from 1.3% of cells (95% confidence interval (CI) 1.0-1.6) in saline controls to 4.7% (95% CI 2.6-6.7) after allergen exposure (p<0.001), and in airway epithelium, from 1.3 (95% CI 0.6-2.0) BrdU-positive cells x mm basement membrane(-1) in saline controls to 4.9 (95% CI 3.0-6.7) after allergen exposure (p<0.001). There was increased subepithelial collagen deposition and mucus secretion along with a significant eosinophil and lymphocyte recruitment to the airways. Increased rates of deoxyribonucleic acid synthesis in both airway smooth muscle and epithelial cells along with changes to the airway wall pathology may precede the establishment of smooth muscle thickening and airway remodelling after repeated allergen exposure in rats. This model seems to be appropriate for studying structural changes within the airways as observed in asthma.

Role of nitric oxide released from iNANC neurons in airway responsiveness in cats.

The precise role of inhibitory nonadrenergic noncholinergic (iNANC) neurons and nitric oxide in airway hyperresponsiveness remains uncertain. The role of NO in the regulation of airway responsiveness was studied in anaesthetized and mechanically ventilated cats. To assess airway responsiveness, the changes in total pulmonary resistance (RL) produced by delivering serotonin aerosol to the airways were measured before and after N(omega)-nitro-L-arginine methyl ester (L-NAME), or a ganglionic blocker, hexamethonium, which has been reported to block iNANC. Serotonin was chosen because it causes bronchoconstriction in part by neural reflex. To further clarify the mechanism(s) involved, the effect of inhaled capsaicin was also determined in animals with sustained bronchoconstriction induced by serotonin after treatment with atropine and propranolol. Inhibition of NO synthase by L-NAME or blockade of iNANC neurons by hexamethonium significantly increased airway responsiveness. However, addition of L-NAME did not further increase airway responsiveness in animals treated with hexamethonium. In the presence of atropine and propranolol, inhaled capsaicin caused a marked bronchodilation during serotonin-induced sustained bronchoconstriction. The bronchodilation induced by capsaicin was significantly suppressed by hexamethonium and by L-NAME. These results suggest that the nitric oxide released from inhibitory nonadrenergic noncholinergic neurons is important in modulating the airway responsiveness of cats in vivo.

Effect of inhaled glucocorticoid on the cellular profile and cytokine levels in induced sputum from asthmatic patients.

Cytokines are considered to play a role in the airway inflammation of bronchial asthma. We examined the cellular profile and cytokine levels in induced sputum samples obtained before and after treatment with beclomethasone dipropionate (BDP, 800 microg/day, for 4 weeks) in 12 mild to moderate asthmatic subjects who had not previously received inhaled glucocorticosteroids. Sputum was induced with a 20-min inhalation of 3% saline by an ultrasonic nebulizer. The freshly expectorated sputum separated from the saliva was analyzed for cell counts, for the concentration of interleukin-8 (IL-8), and for the concentration of granulocyte-macrophage colony-stimulating factor (GM-CSF). The mean percentage of eosinophils in the sputum samples decreased significantly after BDP treatment, but no significant change in the percentage of neutrophils was observed. The mean IL-8 and GM-CSF levels also decreased significantly after treatment. The BDP treatment was associated with an increase in the mean peak expiratory flow (PEF) and with a decrease in the diurnal variation of PEF. These results suggest that inhaled steroids improve airway inflammation and lung function in asthmatics, presumably in part by inhibiting the synthesis of inflammatory cytokines such as IL-8 and GM-CSF.

Effects of thromboxane A2 antagonist on airway hyperresponsiveness, exhaled nitric oxide, and induced sputum eosinophils in asthmatics.

We examined effects of a thromboxane A2 (TXA2) antagonist seratrodast on airway hyperresponsiveness, exhaled nitric oxide (NO), and eosinophils in induced sputum in 14 asthmatics. Subjects were administered 80 mg of seratrodast once a day for 4 weeks. Respiratory conductance (Grs) was measured by the forced oscillation method and airway responsiveness was evaluated as the inhaled dose of methacholine, which induced 35% decrease in Grs. Subjects breathed into a Teflon bag, and NO concentration in the bag was measured by a chemiluminescence analyzer. Induced sputum comprised the entire expectorate produced during a 20 min inhalation of 3% saline, and was analyzed for total and differential cell counts. Airway hyperresponsiveness was significantly decreased by seratrodast. By contrast, no differences in either exhaled NO or percentage of eosinophils in sputum were observed before or after seratrodast. We conclude that seratrodast may attenuate airway hyperresponsiveness, presumably by antagonizing TXA2 released from the inflamed airways.

Eosinophilic airway inflammation induced by repeated exposure to cigarette smoke.

Acute exposure to cigarette smoke causes airway hyperresponsiveness (AHR) in guinea-pigs, which resolves within a few hours. Repeated exposure may have a different effect on the airways. To address this question, guinea-pigs were repeatedly exposed to cigarette smoke (six cigarettes for 1 h x day(-1)) for 14 consecutive days. Airway responsiveness to inhaled histamine and differential cell counts in bronchoalveolar lavage fluid (BALF) were evaluated 1 day after the last exposure. Significant neutrophilia in BALF was observed after 3 days of smoke exposure. Significant eosinophilia in BALF and AHR were observed after 14 days of smoke exposure, but not after 3 or 7 days of smoke exposure. These changes persisted until 3 days after the last exposure and resolved 7 days afterwards. Histologically, the recruited eosinophils were observed predominantly in the airways, but not in the alveoli. Treatment with E-6123, a specific platelet-activating factor receptor antagonist (1 mg x kg(-1) x day(-1) p.o. during smoke exposure) significantly inhibited the eosinophil influx and AHR. Repeated exposure to cigarette smoke may induce prolonged airway inflammation and airway hyperresponsiveness in guinea-pigs. Platelet-activating factor or platelet-activating factor-like lipids may play a key role in airway hyperresponsiveness, presumably by the induction of eosinophilic airway inflammation.

Proliferation of airway epithelium after ozone exposure: effect of apocynin and dexamethasone.

Ozone is an environmental pollutant with potent oxidizing properties. We investigated whether exposure to ozone-induced cell proliferation in the lungs of rats, and determined the effect of an antioxidant and of a glucocorticosteroid in Brown-Norway (BN) rats. Following single ozone exposure (0.5, 1.0, or 3.0 ppm for 6 h), proliferating cell nuclear antigen (PCNA) expression, as determined with immunohistochemistry, was significantly increased in the bronchial epithelium and alveolar epithelium as compared with controls exposed to filtered air with a maximal effect at 24 to 48 h (p < 0.001). Apocynin (5 mg/kg, orally), a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, reduced the PCNA index in bronchial epithelium induced by ozone (3 ppm, 6 h) from 11.5 +/- 1.3% (percent of nuclear cells expressing PCNA) to 4.4 +/- 1.3% (mean +/- SEM; p < 0.05). Dexamethasone (3 mg/kg, intraperitoneally) also reduced the PCNA index in bronchial epithelium, from 19.2 +/- 2.3% to 10.9 +/- 2.6% (p < 0.05). Dexamethasone but not apocynin inhibited ozone-induced neutrophil influx. Rats exposed repeatedly to ozone (3.0 ppm, 3 h, on three occasions 48 h apart) expressed a lower PCNA index in bronchial epithelium than did rats exposed only once at 1.9 +/- 0.7% versus 6.0 +/- 0.9%, respectively (p < 0.05). The proliferative epithelial response following a single exposure to ozone is modulated through oxidative and inflammatory mechanisms probably involving neutrophils.