15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Pulmonary-Eosinophilia

This chapter describes the use of bilateral vagotomy as a tool for determining autonomic regulation of airway responses to the exogenous bronchoconstrictor thromboxane mimetic U46619 in an acute model of asthma in the mouse. Mice receive a sensitization of ovalbumin (OVA) and adjuvant followed by 3 days of OVA aerosol to induce allergic airway disease characterized by bronchoalveolar lavage (BAL) eosinophilia, increased mucus production, and elevated IgE and IL-13. Using a small animal ventilator (Flexi-vent) and the forced oscillatory technique fit to the constant phase model of the lung, a variety of features associated with human asthma can be evaluated in mouse models. For example, this protocol describes the methods to evaluate central and peripheral airway mechanics, airway resistance (R aw) and tissue damping (G), and tissue elastance (H) in response to U46619. The contribution of autonomic nerves in this response is determined by severing both the left and right vagus nerves prior to aerosol challenge.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Allergens; Animals; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Humans; Mice; Pulmonary Eosinophilia; Vagotomy

Antigen-stimulated contraction and release of chemical mediators were examined in saline- or Sephadex-treated rat lung parenchymal strips. Sephadex treatment caused eosinophilia in the blood and the lung tissue. Antigen challenge of the isolated parenchymal strips in Sephadex-treated rat was followed by passive sensitization, resulted in an augmented contraction and elevated releases of thromboxane (TX) B2 and peptide-leukotrienes (p-LTs) in bath fluid compared with those of saline-treated control. Although 5-hydroxytryptamine (5-HT) and histamine were significantly released after antigen challenge, the levels were not different between saline- and Sephadex-treated groups. DP-1904, a selective thromboxane synthetase inhibitor, and methysergide but not atropine significantly reduced the augmented contraction and inhibited the elevated TXB2 release in the Sephadex-treated group. Similar increased contraction and the elevated TXB2 release above were observed when Sephadex-treated rat lung strips were stimulated by exogenous 5-HT and LTD4. These augmented contractions were closely correlated with the increase in TXB2 level (r = 0.83; p < 0.01). In addition, contraction to U-46619, a thromboxane mimetic, was significantly greater in Sephadex-treated rat lung strips. Our results indicate that the ability of Sephadex-treated rat lung tissue to synthesize newly generated mediators such as TXA2 and p-LTs is increased, and the spasmogenic susceptibility of the lung tissue to TXA2 itself is modified by Sephadex treatment, suggesting these are due to the augmented contraction in an established hyperresponsiveness state induced by Sephadex.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Atropine; Bronchial Hyperreactivity; Dextrans; Dose-Response Relationship, Drug; Imidazoles; Leukotriene D4; Lung; Male; Methysergide; Prostaglandin Endoperoxides, Synthetic; Pulmonary Eosinophilia; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes; Thromboxane A2; Vasoconstrictor Agents