8-Epi-prostaglandin F2alpha (8-epi-PGF2alpha) is an F2-isoprostane formed mainly via noncyclooxygenase pathways in vivo. We investigated whether 8-epi-PGF2alpha has any effect on airflow obstruction and plasma exudation in vivo. Airflow obstruction was quantified by measuring lung resistance (RL) in anesthetized and ventilated guinea pigs, and plasma exudation was quantified by the Evans Blue dye method (20 mg/kg intravenously). Intratracheal instillation of 8-epi-PGF2alpha (1 nmol or 10 nmol) caused dose-related increases in RL. Furthermore, the higher dose of 8-epi-PGF2alpha produced Evans Blue dye extravasation in main bronchi and intrapulmonary airways. A prostanoid TP-receptor antagonist, BAY u3405 (1 mg/kg intravenously), abolished the airway effects of 8-epi-PGF2alpha (10 nmol). A thromboxane A2 (TxA2) synthase inhibitor, OKY-406 (30 mg/kg intravenously), significantly attenuated these effects of 8-epi-PGF2alpha (10 nmol). The level of TxB2, a stable TxA2 metabolite, increased in bronchoalveolar lavage fluid (BALF) after 8-epi-PGF2alpha instillation. We conclude that 8-epi-PGF2alpha causes airflow obstruction and plasma exudation in vivo. This effect may be mediated primarily via prostanoid TP-receptors, and a secondary generation of TxA2 may be involved in part of the airway responses in 8-epi-PGF2alpha in the guinea pig.

Prolonged exposure to allergen has been proposed to be important for the development of bronchial hyperresponsiveness and airway remodelling in asthma. The present study was designed to examine the effect of chronic allergen exposure on bronchial responsiveness, eosinophil infiltration, and airway remodelling. We sensitized brown Norway rats with the occupational allergen trimellitic anhydride (TMA) and exposed the animals to TMA conjugated to rat serum albumin (TMA-RSA) on 5 consecutive days each week for 9 weeks, starting 4 weeks after sensitization. IgE and IgG anti-TMA antibodies in serum and bronchial responsiveness to acetylcholine were evaluated before and at weeks 3, 6, and 9 of allergen exposure. Thickness of the airway wall, airway luminal narrowing, and the number of goblet cells and eosinophils in the airway wall were evaluated with an image analysis system in lungs resected after the last assessment of bronchial responsiveness, at the end of the 9-week allergen exposure. All rats developed IgE and IgG anti-TMA antibodies after sensitization. The levels of antibodies increased with allergen exposure until week 6, and then declined. Bronchial hyperresponsiveness to acetylcholine was induced in allergen-exposed rats without ongoing airway eosinophilia. Bronchial hyperresponsiveness induced by chronic allergen exposure via inhalation was accompanied by significantly increased thickness of smooth muscle and airway narrowing in the small airways, and goblet cell hyperplasia in the large airways. We conclude that chronic exposure to allergen can induce bronchial hyperresponsiveness and airway wall remodelling. Airway wall remodelling may contribute to bronchial hyperresponsiveness.

Reduced late asthmatic response by repeated low-dose allergen exposure. M. Palmqvist, Z-H. Cui, M. Sjöstrand, A. Lindén, J.Lötvall. #ERS Journals Ltd 2001. ABSTRACT: Allergic asthmatic individuals are often exposed to low-doses of allergen in their everyday life. Extended exposure to allergen has lead to down-regulation of the allergic process in cell systems and in animal models. The aim of this study was to evaluate whether any such inhibitory mechanism of allergic responses can be seen in man in vivo.Patients with mild asthma were repeatedly and double-blindly exposed to 25% of the individual dose of allergen that caused an early (EAR) and late asthmatic reaction (LAR). One day after the low-dose allergen or placebo exposure periods, the same individual was given a high-dose allergen challenge. Sputum and blood were collected for the evaluation of eosinophils.Exposure to repeated low doses of allergen induced increased bronchial methacholine responsiveness 6 h after the final allergen exposure (p~0.018), and an increase in the number of eosinophils in sputum. By contrast, the late asthmatic response after challenge with a high dose of allergen was significantly attenuated by y30% at 24 h after the final low-dose allergen exposure (p~0.03).In summary, repeated low doses of allergen given directly to the airways, attenuate the high-dose allergen-induced late response, despite enhanced bronchial hyperresponsiveness to methacholine and elevated sputum eosinophils prior to allergen challenge.

Plasma exudation in the airways is mainly dependent on microvascular permeability of the tracheobronchial circulation and may be affected by local blood flow. Aortic blood pressure provides the major inflow pressure to tracheobronchial circulation. Therefore, systemically administered vasoconstrictors, in doses enough to increase systemic blood pressure, may theoretically increase the blood flow in the tracheobronchial circulation by enhancing inflow pressure. Consequently, this may influence plasma exudation induced by inflammatory mediators in the airways. To test this hypothesis, we used guinea-pigs to study: (1) the effects of i.v. vasoconstrictors (methoxamine and angiotensin II) on blood flow in the tracheal mucosa and in the leg skeletal muscle (Laser-Doppler flowmetry); (2) the effects of i.v. vasoconstrictors on plasma exudation induced by tracheal administration of the inflammatory mediator bradykinin (150 nmol). We found that i.v. methoxamine and angiotensin II significantly increase tracheal mucosa blood flow and systemic blood pressure. The increase in tracheal mucosa blood flow was, in the case of angiotensin II, found to be significantly related to the increase in systemic blood pressure. In separate experiments, pre-treatment with i.v. methoxamine and angiotensin II significantly potentiates Evan's Blue dye exudation induced by bradykinin in the trachea and main bronchi. We conclude that i.v. methoxamine and angiotensin II potentiate bradykinin-induced plasma exudation in the guinea-pig airways, possibly by increasing the local blood flow. The increase in the local blood flow is most likely induced by enhanced systemic blood pressure (inflow pressure), owing to a redistribution of the total body blood flow.

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