Elimination of IL-13 reverses goblet cell metaplasia into ciliated epithelia in vitro, and transition of goblet cells to other phenotypes, especially ciliated cells, may be involved in this phenomenon. IL-13 inhibition may be a therapeutic strategy of established goblet cell metaplasia in asthma.

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1 Ginsenoside, an extract of Panax ginseng, is an essential constituent of anti-asthmatic Chinese herbal medicine. To elucidate whether ginsenoside a ects airway smooth muscle tone and, if so, what the mechanism of action is, we studied relaxant responses of human bronchial strips under isometric condition in vitro, and directly measured the release of nitric oxide (NO) by an amperometric sensor for this molecule. 2 Addition of ginsenoside relaxed the tissues precontracted with acetylcholine in a dose-dependent manner, the maximal relaxation and the ginsenoside concentration required to produce 50% relaxation being 67+8% and 210+29 mg ml 71 , respectively. 3 The relaxant responses to ginsenoside were inhibited by N G -nitro-L-arginine methylester (L-NAME) and removal of the epithelium, but not by N G -nitro-D-arginine methylester (D-NAME) or tetrodotoxin. This inhibitory e ect of L-NAME was reversed by L-arginine but not by D-arginine. 4 Addition of ginsenoside to the medium containing bronchial tissues dose-dependently increased NO-selective electrical current, and this e ect was greatly attenuated by the epithelial removal or Ca 2+ -free medium. 5 Ginsenoside also increased tissue cyclic GMP contents, an e ect that was abolished in the presence of L-NAME. 6 It is concluded that ginsenoside induces relaxation of human bronchial smooth muscle via stimulation of NO generation predominantly from airway epithelium and cyclic GMP synthesis. This action might account for the anti-asthmatic e ect of Panax ginseng.

Tryptase is a specific marker of mast-cell activation and plays a part in the pathophysiology of various allergic diseases including asthma, but little is known of the spillover of this enzyme into the systemic circulation. Therefore, we measured serum levels of mast-cell-derived tryptase in 21 patients with mild to moderate asthma and 20 healthy, subjects, using a B12 monoclonal antibody-based immunofluoroassay that detects both monomers and tetramers of alpha- and beta-tryptases. There was a good correlation between serum and sputum tryptase levels, and, compared with healthy subjects (1.68 +/- 0.31 ng/ml), asthma patients had higher concentrations of serum tryptase (atopic asthma, 4.18 +/- 0.95 ng/ml, p = 0.022; nonatopic asthma, 3.93 +/- 0.82 ng/ml, p = 0.031). Although serum tryptase levels did not correlate with asthma symptom scores, peak expiratory flow, or forced expiratory volume in 1 s, they positively correlated with mast-cell and eosinophil counts (p = 0.041 and p = 0.025, respectively) and eosinophil cationic protein contents (p = 0.029) in induced sputum. These results suggest that serum tryptase detected with B12 antibody is a marker of allergic airway inflammation in asthma.

Current guidelines for asthma treatment do not recommend daily maintenance therapy in patients with mild intermittent (step 1) asthma. However, because there is increasing evidence that airway inflammation is present even in this patient group, maintenance anti-inflammatory therapy may be considered. We investigated the clinical impact of regular treatment with the inhaled corticosteroid beclomethasone dipropionate and the leukotriene receptor antagonist pranlukast in the patients concerned. The study was a randomized, controlled, parallel-group, multicenter trial. Eighty-five symptomatic patients with newly diagnosed mild intermittent asthma having normal pulmonary function were assigned beclomethasone or pranlukast for 8 weeks. Then, these medications were stopped for the next 16 weeks. Main outcome measures were asthma symptoms, pulmonary function, and airway inflammation. Treatment with beclomethasone and pranlukast significantly increased forced expiratory volume in 1 second and peak expiratory flow from baseline and decreased asthma symptom scores and sputum eosinophil counts and eosinophil cationic protein contents. After discontinuation of the treatment, symptom scores remained unchanged, but pulmonary function and airway inflammation were aggravated and then returned to the baseline levels. Therefore, maintenance therapy with inhaled corticosteroid or leukotriene receptor antagonist can provide further improvements in asthma symptoms, pulmonary function, and airway inflammation, and discontinuation of the therapy causes worsening of asthma, indicating that stopping or interrupting anti-inflammatory therapy may not be advisable in patients with symptomatic mild intermittent asthma.

The aim of the present study was to elucidate whether Chinese traditional herbal drugs, Gorei-San (TJ-17) and Toki-Shakuyaku-San (TJ-23), affect airway smooth muscle tone and, if so, to determine what the mechanism of action is.Rabbit tracheal segments were isolated and the contractile responses to electrical field stimulation and acetylcholine were measured before and after the application of TJ-17 or TJ-23 under isometric conditions in vitro. Ouabain-sensitive rubidium-86 ( 86 Rb) uptake by tissues in response to each drug was also measured.Each herbal medicine attenuated the contractile responses to electrical field stimulation and acetylcholine in a concentration-dependent manner, the maximal inhibition of acetylcholine-induced contraction being 37.5 4.9% for TJ-17 and 42.4 5.3% for TJ-23 (p<0.05 for each). These effects were not altered by mechanical removal of the epithelium, indomethacin, the nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester, the cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor adenosine 3'5'-cyclic monophosphorothiioate (Rp-cAMPS), the cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor KT5823, or the calcium (Ca 2+ )-activated potassium (K + ) channel inhibitor charybdotoxin, but were greatly inhibited in the presence of the sodium (Na + )-K + adenosine triphosphatase (ATPase) inhibitor ouabain. Incubation of tissues with TJ-17 and TJ-23 dose dependently increased ouabain-sensitive 86 Rb uptake.The results of the study suggest that both Gorei-San and Toki-Shakuyaku-San reduce airway smooth muscle tone via a postjunctional mechanism probably through stimulation of the sodium pump and the subsequent hyperpolarization/repolarization of the cell membrane. These effects may contribute to the antiasthmatic properties of these herbal medicines.

Background: The sodium pump (Na⁺-K⁺-ATPase) plays a part in the regulation of smooth muscle contractility, and alterations of enzyme activity by hypoxia could contribute to the mechanism of hypoxic pulmonary vasoconstriction. Objective: To determine the role of Na⁺-K⁺-ATPase in the sodium nitroprusside (SNP)-induced relaxation of pulmonary artery in hypoxia. Methods: Using isolated canine pulmonary arterial rings, we measured the relaxant responses of KCI-contracted tissues to SNP under hyperoxic (95% O₂, 5% O₂) and hypoxic conditions (5% O₂, 5% CO₂, 90% N₂) in vitro. Na⁺-K⁺-ATPase activity was assessed by measuring ouabain-sensitive ⁸⁶Rb uptake. Results: The SNP-induced relaxation was reduced under hypoxia, so that the maximal relaxation decreased from 80.1 ± 8.6 to 57.8 ± 6.8% (p < 0.01) and the concentration of SNP required to produce 50% relaxation increased from 1.9 ± 0.4 × 10^–6 to 2.6 ± 0.6 × 10^–5M (p < 0.01). Addition of ouabain, an Na⁺-K⁺-ATPase inhibitor, attenuated the relaxant response to SNP and this inhibition was still observed under hypoxia. Incubation of endothelium-denuded rings with SNP caused dose-dependent increases in intracellular cGMP levels and ouabain-sensitive ⁸⁶Rb uptake, and these effects were not significantly altered by hypoxia. Conclusion: These results suggest that sarcolemmal Na⁺-K⁺-ATPase activity may be implicated in the mechanism of nitrovasodilator-induced vasodilation of pulmonary artery and may still be functioning under hypoxia.

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