mci-826 and Asthma

Allergic airway eosinophilia is suppressed by cysteinyl leukotriene (CysLT) receptor (CysLT1 receptor) antagonists in several species including humans and guinea-pigs, suggesting that CysLTs are directly or indirectly involved in induction of the response.. We examined the effect of CysLT antagonists (pranlukast and MCI-826) on antigen inhalation-induced eosinophilia in peripheral blood and lung, and on IL-5 activity in serum during late increase of airway resistance (late asthmatic response, LAR) in sensitized guinea-pigs.. Guinea-pigs inhaled ovalbumin (OVA) + Al(OH)3 and OVA mists alternately for sensitization and challenge, respectively, once every 2 weeks. At the fifth challenge, the effects of CysLT antagonists and an anti-IL-5 antibody (TRFK-5) on the occurrence of LAR, and blood and lung eosinophilia, which appeared at 5 h after challenge, were examined. The time-course of IL-5 activity in the serum after the challenge was evaluated by measuring in vitro 'eosinophil survival prolongation activity'. The influence of CysLT antagonists on IL-5 activity was assessed.. CysLT antagonists and TRFK-5 completely abolished blood and lung eosinophilia. LAR was suppressed by both MCI-826 and TRFK-5 by 40-50%. Sera obtained from sensitized, challenged animals 3 h and 4 h after challenge induced an obvious prolongation of eosinophil survival. The activity of the sera was completely neutralized by prior exposure to TRFK-5, suggesting that it reflected IL-5 activity. Increased IL-5 activity in the serum was inhibited by both pranlukast and MCI-826 by over 90%.. CysLTs produced after antigen provocation sequentially induced IL-5 production from some immune component cells via CysLT1 receptor activation. Thus, it is likely that CysLTs indirectly cause antigen-induced eosinophilia through IL-5 production.

Topics: Animals; Asthma; Cell Survival; Chromones; Cysteine; Eosinophilia; Guinea Pigs; Interleukin-5; Kinetics; Leukotriene Antagonists; Leukotrienes; Male; Membrane Proteins; Ovalbumin; Pulmonary Eosinophilia; Receptors, Leukotriene; Thiazoles

We developed an animal model of late asthmatic response (LAR) in guinea pigs and examined the effects of anti-asthmatic drugs and peptide leukotriene antagonist, MCI-826, on this model. Bronchial challenge of DNP-As (Dinitrophenylated-Ascaris suum extract)-sensitized guinea pigs induced a biphasic increase in pulmonary resistance (RL) with the maximal increase being observed immediately (IAR, immediate asthmatic response) and 3 to 5 hr after antigen inhalation (LAR). Twelve of 22 guinea pigs showed both IAR and LAR. The average increases in RL for all 22 guinea pigs at IAR and LAR, were 168 +/- 13 and 207 +/- 16 (% of baseline value), respectively. Bronchoalveolar lavage (BAL) fluid of guinea pigs that received antigen, revealed increases in the numbers of eosinophils (7.3-fold compared to animals receiving saline) and neutrophils (5.3-fold compared to animals receiving saline) 4 hr after antigen inhalation. When DSCG (disodium cromoglycate) was administered (10 mg/kg, i.v.) before antigen challenge, DSCG significantly inhibited IAR (p less than 0.05) and slightly inhibited LAR (p less than 0.2). Theophylline (30 mg/kg, p.o.) administered before antigen, slightly inhibited both IAR and LAR (p less than 0.2). Salbutamol (3 mg/kg, i.p.) administered before antigen, significantly inhibited IAR (p less than 0.05), but did not affect LAR. These results were correlated with clinical trials. Moreover, peptide leukotriene antagonist, MCI-826, (E)-2,2-Diethyl-3'-[2-[2-(4- isopropyl)thiazolyl] ethenyl]succinanilic acid (0.1 mg/kg, p.o.) administered 1 hr before antigen challenge, significantly inhibited both IAR and LAR (p less than 0.05). MCI-826 (0.1 mg/kg, p.o.) administered 1.5 hr after antigen inhalation, also inhibited LAR (p less than 0.05). Analysis of BAL fluid revealed that DSCG and MCI-826 significantly inhibited the increase in eosinophils (p less than 0.05). These data suggest that leukotriene plays an important role in the development of the pathogenesis of LAR, and that our model is an useful experimental model for investigating the mechanisms of LAR and examining the effects of several anti-asthmatic drugs on LAR.

Topics: Albuterol; Allergens; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cromolyn Sodium; Cytodiagnosis; Disease Models, Animal; Guinea Pigs; Immunization; Male; Respiratory Mechanics; Theophylline; Thiazoles; Time Factors