Airway reversibility and inflammation in stable pre- to late-adolescent asthmatics without long-term control medications.

Objective: Pulmonary function and airway inflammation were investigated in stable pre- to late-adolescent asthmatics without long-term control medications and compared with those in currently medicated asthmatics.Methods: Subjects comprised 34 well-controlled asthmatic children (aged 8.1-18.0 years; group without medication). Flow volume curves before and after inhaling a ß2 agonist, a bronchodilator (BD), were compared and fractional exhaled nitric oxide (FENO) concentrations were measured. All patients were attack-free for at least 12 months prior to testing without the use of asthma medications for at least three months. Fifty-one age-matched stable asthmatics with medications at the time of the present study (group with current medication) underwent the same examinations.Results: The rate of children whose respiratory function after BD improved by 20% or more in both the central and peripheral airways (High responder at total airways subtype: HTA) was significantly higher in the group without medication than in that with current medication (17.6 and 2.0%, respectively; p < 0.01). Furthermore, FEV1.0% pred after BD was significantly lower for HTA than for the low responder subtype in the same group (94.8 ± 3.5 and 104.1 ± 1.5% respectively, p < 0.05). FENO concentrations in the group without medication were high, but not significantly different from those in the group with current medication.Conclusions: Stable asthmatic children without medication include a certain percentage of those with irreversible airflow limitation possibly due to airway remodeling. The control of daily asthma symptoms with long-term control medications may effectively prevent airway remodeling.

Optimal step-down approach for pediatric asthma controlled by salmeterol/fluticasone: A randomized, controlled trial (OSCAR study).

BACKGROUND: Several guidelines, including the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL), recommend salmeterol/fluticasone combination therapy (SFC) as step 3 to 4 treatment for moderate to severe asthma. However, the optimal step-down approach to SFC remains unclear. In the current study, we examined step-down approaches in asthmatic children whose symptoms had been stabilized by SFC 100/200 µg/day. METHODS: This randomized, multicenter, open-label, parallel-group study was conducted over 12 weeks. For step-down therapy, subjects aged 5-15 years were randomly assigned to an SFC group (25/50 µg b.i.d.) or an FP group (100 µg b.i.d.), and treated for 12 weeks. Childhood Asthma Control Test (C-ACT) scores, lung function, and exhaled nitric oxide (FeNO) levels were monitored. RESULTS: Of 131 enrolled subjects, 128 completed the study and were included in the analysis. Decreases in % peak expiratory flow rate and % forced expiratory flow at 50% of vital capacity (V50) were observed in the FP group at each time point. There was a significant difference between the two groups for the change in %V50 from its previous value at each time point. There were no significant changes in FeNO levels (range 15-20 ppb) or C-ACT scores (∼26 points) within or between groups. CONCLUSIONS: A high level of asthma control was maintained with both approaches. The use of SFC step-down resulted in somewhat better respiratory function, with no worsening of airway inflammation. However, halving the dose of SFC and switching to FP alone are both optimal step-down approaches.

Effect of disodium cromoglycate on airway mucus secretion during antigen-induced late asthmatic responses in a murine model of asthma.

BACKGROUND: Disodium cromoglycate (DSCG) is known to inhibit both immediate and late asthmatic responses (IAR and LAR). However, its effect on mucus hypersecretion is unknown. Using a murine model of asthma, we aimed to determine whether mucus secretion increased during IAR and LAR. We also studied the potency of DSCG in inhibiting mucus secretion and on airway eosinophilia. METHODS: Mice were subjected to initial intraperitoneal sensitization and airway challenge to ovalbumin (OVA) and then provoked by additional exposure to OVA. Some mice were pretreated with aerosolized DSCG (20 mg/ml) 1 h before the provocation with OVA. After serial measurements of enhanced pause (Penh), an indicator of airflow obstruction, serum samples and bronchoalveolar lavage fluids (BALF) were collected. Then, the lungs were excised and a morphometric analysis for mucus hypersecretion was performed. RESULTS: A biphasic increase in Penh (IAR and LAR) was observed in sensitized animals after provocation with OVA. Airway eosinophilia was observed during both responses. Intraluminal mucus significantly increased during LAR, but not during IAR. DSCG significantly attenuated both IAR and LAR, and significantly inhibited the increase in intraluminal mucus during LAR, but had no effect on eosinophilia in BALF. CONCLUSION: Our results suggest that airway hypersecretion may be involved as a component of airflow obstruction during LAR, and that this is unlikely during IAR. DSCG may be effective in reducing excessive airway mucus caused by exposure to allergens.

Airway responsiveness and airway remodeling after chronic exposure to procaterol and fenoterol in guinea pigs in vivo.

BACKGROUND: Chronic exposure to fenoterol (FEN), a beta(2)-adrenergic receptor (beta(2)-AR) agonist, was shown to induce both airway hyperresponsiveness and airway remodeling in experimental animals. OBJECTIVE: We wanted to know the effects of chronic exposure to procaterol (PRO), a beta(2)-AR agonist, on airway function and structure, because this agent is widely used as a bronchodilator in Japan. For comparison, the effects of FEN were also examined. METHODS: Aerosolized PRO (0.1 or 1 mg/ml), FEN (1 mg/ml) or vehicle (0.9% NaCl) was given to guinea pigs 3 times a day for 6 weeks. Sublaryngeal deposition of these agents was calculated using radioisotopes. At 72 h after the last inhalation of PRO, FEN or vehicle, the dose-response relationship between lung resistance (R(L)) and intravenously administered acetylcholine (ACh) was measured. After measuring R(L), histological changes in noncartilaginous airway dimensions were evaluated. RESULTS: The amount of sublaryngeal deposition of 0.1 mg/ml PRO in the present study was speculated to be 100 times larger than that of therapeutic dose. ACh concentrations causing 2-fold, 10-fold and maximal increases in R(L) were not different in 4 groups tested. In the smaller membranous airways (<0.4 mm in diameter), but not the larger ones, thickening of adventitial areas was significantly greater in animals treated with beta(2)-AR agonists than in control animals (23 and 25, and 96% higher in animals treated with 0.1 and 1 mg/ml PRO or 1 mg/ml FEN, respectively). The degree of the increase was significantly less in PRO-treated animals than in FEN-treated animals (p < 0.01). CONCLUSION: Our results did not provide any evidence that regular inhalation of PRO at the therapeutic dose might induce bronchial hyperresponsiveness. In addition, huge amounts of PRO only caused a mild thickening of the adventitial areas, suggesting that PRO may be a weak inducer of airway remodeling compared with FEN.

Maturational changes in airway remodeling after chronic exposure to ovalbumin in sensitized guinea pigs: role of cell renewal of airway resident cells.

We wanted to know whether airway remodeling caused by chronic exposures to antigen differed depending on the degree of maturation of animals. We sensitized guinea pigs at different stages of maturation: juvenile (approximately 200 g in body weight), adult (400 g), and old animals (800 g). Then, animals were repeatedly challenged with inhaled ovalbumin (0.3% or 3%) or vehicle twice a week for 6 wk. After the final challenge, the lungs were excised for the histologic evaluation of changes in the thickness of the inner wall area (Ti), the smooth muscle area (Tm), and the outer wall area (To) in noncartilaginous airway dimensions. To clarify whether or not the observed changes were due to renewal of airway cells, we stained the samples with labeled nucleotide 5'-bromo-2'-deoxyuridine (BrdU), which we injected repeatedly during the challenge periods. Chronic exposures to antigen induced airway wall thickening regardless of their stages of maturation. However, prominent areas of thickening differed between the three groups. Ti increased more remarkably in juvenile and adult animals than in old ones. By contrast, Tm significantly increased only in old animals. BrdU staining revealed more renewal of epithelial cells in juvenile and adult animals than in old ones (juvenile >or=adult > old), suggesting that increased renewal of epithelial cells contributed to the thickening of Ti in juvenile and adult animals. By contrast, only a slight increase in smooth muscle cell renewal was found even in old animals, indicating that an increase in Tm was due to factors such as hypertrophy. These results show that the development of antigen-induced airway remodeling is partly modified by the degree of maturation of animals in vivo.

Effects of STA(2), a thromboxane A(2) mimetic, in inducing airflow obstruction and airway microvascular leakage in guinea pigs.

BACKGROUND: U-46619, a thromboxane A(2) (TXA(2)) mimetic, is shown to cause airway microvascular leakage, although the effects is weak when comparing with that to induce bronchoconstriction in guinea pigs. OBJECTIVE: In order to know the airway effect of TXA(2) more accurately, we have examined the effects of STA(2), a TXA(2) mimetic with higher affinity to TXA(2) (TP) receptors than U-46619, to induce airway microvascular leakage and airflow obstruction. METHODS: Anesthetized and ventilated guinea pigs were i.v. given STA(2) (3-30 nmol/kg) or U-46619 (3-100 nmol/kg) 1 min after i.v. Evans blue dye. STA(2)- and U-46619-induced increases in lung resistance (R(L)) was measured for 6 min. The amount of extravasated Evans blue dye in the lower airways was, then, examined as an index of leakage. In selected animals, specific TP receptor antagonists (10 microg/kg S-1452 or 10 mg/kg ONO-3708) were pretreated i.v. RESULTS: Both STA(2) and U-46619 induced significant increases in leakage and airflow obstruction. However, STA(2) induced a slow and significantly less increase in R(L) but caused a significantly greater increase in extravasation of Evans blue dye compared to U-46619. Specific TP receptor antagonists completely abolished both airway effects induced by STA(2) and U-46619. CONCLUSION: Our present results have supported a possibility that TXA(2) induces microvascular leakage as well as bronchoconstriction in the airways.

Effects of Y-27632, a Rho/Rho kinase inhibitor, on leukotriene D(4)- and histamine-induced airflow obstruction and airway microvascular leakage in guinea pigs in vivo.

Recent in vitro studies have shown that the Rho/Rho kinase pathway is involved in the mechanism of not only airway smooth muscle contraction but also vascular endothelial permeability caused by certain stimuli. This suggests that Rho/Rho kinase inhibitors may become useful agents against asthma via reduction of increased airway microvascular leakage, one of the main features of this disease. Thus, we wanted to know the in vivo effect of Y-27632, a selective Rho kinase inhibitor, on airway microvascular leakage caused by leukotriene D(4) (LTD(4)) and histamine, potent mediators of allergic airway inflammation, by comparing its effect against airflow obstruction. For comparison, the effects of procaterol, a beta(2)-adrenoceptor agonist, on these responses were also studied. Tracheostomized guinea pigs were given either aerosolized Y-27632 (3 or 15 mmol/l), procaterol (6 micromol/l) or vehicle (0.9% NaCl) for 5 min under spontaneous breathing. After being mechanically ventilated, the animals were given intravenous Evans blue dye 15 min after the end of inhalation. One minute later, either 2 nmol/kg LTD(4), 300 nmol/kg histamine or vehicle was administered intravenously. After measurements of lung resistance (R(L)) for 6 min, the lungs of animals were taken out, and the amount of extravasated Evans blue dye was examined as an index of leakage. Inhaled Y-27632 dose-dependently attenuated increases in R(L) caused by LTD(4) and histamine. The degree of inhibition was almost similar between 15 mmol/l Y-27632 and 6 micromol/l procaterol. By contrast, only 15 mmol/l, but not 3 mmol/l, Y-27632 partially reduced LTD(4)-induced leakage. Histamine-induced Evans blue dye extravasation was not inhibited by 15 mmol/l Y-27632. Procaterol significantly inhibited the dye extravasation caused by either LTD(4) or histamine. These results suggest that Y-27632 is not a useful agent in attenuating airway microvascular leakage which is seen in asthma, although it is potent in inhibiting airflow obstruction.