Tumour necrosis factor-a (TNF-a) and interleukin 1b (IL-1b) have been implicated in the pathogenesis of asthma. The p38 kinase inhibitor, SB 203580 inhibits TNF-a and IL-1b production in vitro and in vivo. In this study the e ect of SB 203580 on allergen-induced airway TNF-a production and in¯ammatory cell recruitment was investigated in sensitized Brown Norway rats. The allergen-induced increase in bronchoalveolar lavage (BAL) TNF-a was inhibited by SB 203580 at every dose tested (10 ± 100 mg kg 71 , p.o.). In contrast, neither ovalbumin-induced eosinophilia or neutrophilia were inhibited by SB 203580 (10 ± 100 mg kg 71 , p.o.). In conclusion, SB 203580 inhibits BAL TNF-a production by 95% without inhibiting either antigen-induced airway eosinophilia or neutrophilia. This data suggests that either the residual TNF-a is su cent to drive allergen-induced in¯ammatory cell recruitment into the lung or that TNF-a is not involved in allergen-induced in¯ammatory cell recruitment.

Opioids reduce the cholinergic responses to electrical field stimulation (EFS) in guinea pig and canine airways by a prejunctional effect. We determined whether a similar effect operates in human airways in vitro. [D-Ala2-NMePhe4-Gly-ol5]enkephalin (DAMGO) (10(-8)-10(-6) M), a selective mu-opioid receptor agonist, inhibited the response to EFS in a dose- and frequency-dependent manner. DAMGO (10(-6) M) produced 86% inhibition at 0.5 Hz and 38% inhibition at 4 Hz, but at 32 Hz there was no significant inhibition. Another selective mu-opioid receptor agonist H-Tyr-D-Arg-Gly-Phe(4-NO2)-Pro-NH2 diacetate (BW 443C) also inhibited responses to EFS, producing 57.7% inhibition at 4 Hz at a concentration of 10(-6) M. The inhibitory effect on EFS was blocked by the opioid receptor antagonist naloxone (10(-5) M), indicating that opioid receptors are involved. DAMGO (10(-6) M) had no effect on the contractile response to exogenous acetylcholine, indicating a prejunctional effect. We conclude that mu-opioid agonists inhibit cholinergic neurotransmission in human airways in vitro, and this could have therapeutic potential in the treatment of airway disease.

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), is a seleno-organic compound which protects tissues against oxidative stress. Furthermore, recent data has suggested that this compound possesses a range of anti-inflammatory properties.In this study the authors have investigated the effects of ebselen on Sephadexinduced lung oedema and bronchoalveolar lavage (BAL) tumour necrosis factor (TNF)-a and endothelin(ET)-1 levels in rats.Sephadex administration induced lung oedema which was accompanied by an increase in BAL TNF-a and ET-1 levels. Ebselen administration (1±30 mg . kg -1 , i.p. at 0, 4 and 12 h post Sephadex) significantly inhibited lung oedema (dose that produced 50% of the maximum inhibition of lung oedema 4.6 mg . kg -1 ) and BAL TNF-a levels in a dose-related manner with no effect on ET-1 levels.These data suggest that ebselen may be a useful therapy in lung pathologies in which bronchiolar inflammation is a feature. The Sephadex model of lung oedema in the rat is a model of acute alveolitis and bronchiolitis leading to inflammatory cell infiltration and interstitial oedema which appears to parallel many of the pathophysiological features associated with human interstitial lung diseases [1]. This model has been used previously to demonstrate the anti-inflammatory properties of compounds such as glucocorticosteroids based upon the modulation of lung oedema [2].Ebselen (2-phenyl-1,2-benzisoselenazol-3 (2H)-one) is a selenium-containing organic compound which has been found to protect tissue against oxidative attack by mimicking glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase [3]. In addition, ebselen possesses a range of anti-inflammatory activities including inhibition of the enzymes 5-lipoxygenase, inducible nitric oxide synthase, reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and inactivation of leukotriene B 4 to its biologically inactive 6-trans isomer [4]. In view of its interesting anti-inflammatory profile in a variety of animal models of inflammation [1,5], the authors investigated its effects in the Sephadex model of lung oedema. In addition, the effect of ebselen was examined on tumour necrosis factor (TNF)-a and endothelin(ET)-1 levels in the bronchoalveolar lavage (BAL) fluid from Sephadex-treated rats since these cytokines have been postulated to have a role in inflammatory lung disease [6±9]. Materials and methods AnimalsMale, Sprague-Dawley rats (350 g) were purchased from Harlan-Olac (Bicester, Oxfordshire, UK) and housed for 1 week before initiating experiments. Food and water were supplied ad libitum. Experiments were performed in accordance with the UK Home Office guidelines for animal welfare based on the Animals (Scientific Procedures) Act 1986 [10] and following approval from the Aventis Pharma Animal Care and Use Committee. MethodsRats were dosed intratracheally (i.t.) with vehicle (saline) or Sephadex beads (5 mg . kg -1 ) in a dose volume of 1 mL . kg -1 under halothane anaesthesia (4% in oxygen for 3 min). Ebselen (1...

We studied the role of histamine H3-receptors on neurogenic microvascular leakage in guinea pig airways by measuring extravasation of Evans blue dye. In guinea pig airways the major component of the neurogenic leakage is nonadrenergic noncholinergic (NANC) mediated, due to release of tachykinins. Anesthetized guinea pigs were pretreated with propranolol and atropine to block the beta-adrenergic and cholinergic responses and with mepyramine and cimetidine to block histamine H1- and H2-receptors, respectively. Vagal stimulation significantly increased leakage of dye in trachea (Tr), main bronchi (MB), and central (cIPA) and peripheral intrapulmonary airways (pIPA). The selective H3-receptor agonist (R)-alpha-methylhistamine (alpha-MeHA, 0.3-3 mg/kg iv) did not alter basal leakage but inhibited NANC-mediated leakage in a dose-dependent manner with a maximal inhibition of 56.9 (Tr, P less than 0.01), 66.7 (MB, P less than 0.01), 67.5 (cIPA, P less than 0.01), and 58.2% (pIPA, P less than 0.05) at 1 mg/kg. Pretreatment with phentolamine (2.5 mg/kg iv) had no effect on the inhibitory response produced by alpha-MeHA, but the H3-receptor antagonist thioperamide (5 mg/kg ip) blocked its effect. Exogenous substance P (1 microgram/kg iv) caused comparable plasma leakage to NANC-mediated response but was not inhibited by alpha-MeHA. We conclude that H3-agonists inhibit neurogenic leakage by prejunctional inhibition of neuropeptide release from airway sensory nerves.

Opioid drugs have been shown to inhibit neurogenic plasma exudation in skin by a presynaptic mechanism. We determined whether a similar inhibitory effect operates in the airways of anesthetized guinea pigs in vivo with the use of Evans blue dye as a marker of plasma leakage. Stimulation of the vagus nerve significantly increased leakage of dye in trachea and main bronchi (by approximately 300 and 600%, respectively). Similar increases in leakage were seen in the presence of atropine and propranolol. Morphine (1-30 mg/kg iv) inhibited leakage in a dose-related manner with complete inhibition in the trachea at a dose of 30 mg/kg. The inhibition was blocked by the opioid receptor-antagonist naloxone (1 mg/kg iv). Intravenous substance P significantly increased leakage but was not inhibited by morphine. We conclude that morphine inhibits neurogenic plasma leakage by presynaptic inhibition of release of neuropeptides from sensory nerve endings. If similar mechanisms are operative in human airways, inhibition of neurogenic plasma leakage by opioid drugs devoid of central effects may be of value in the therapy of asthma.