Effect of MX-68 on airway inflammation and hyperresponsiveness in mice and guinea-pigs

Abstract

MX-68 is a newly synthesized antifolate, which is a derivative of methotrexate (MTX). In this paper, the effect of MX-68 on allergic airway responses in mice and guinea-pigs was studied. In the first experiment, antigen-induced airway inflammation and airway hyperresponsiveness (AHR) to acetylcholine in mice were examined and compared with the effects of classical antifolate methotrexate and prednisolone. Mice were sensitized with ovalbumin as an antigen and challenged with ovalbumin inhalation three times. After the last inhalation, AHR and airway inflammation were observed. An increase in Th2 cytokines (IL-4 and IL-5) and a decrease in a Th1 cytokine (IFN-gamma) in the bronchoalveolar lavage fluid (BALF), as well as an elevation of the immunoglobulin level in serum, were observed in sensitized mice. Oral administration of MX-68 had no effect on changes of body weight, but prednisolone reduced body weight during the experiment. The antigen-induced AHR and increases in the number of eosinophils and lymphocytes in BALF were significantly inhibited by MX-68. MX-68 interfered with the elevation of IL-4 and IL-5 levels in BALF, but had no effect on the decrease in IFN-gamma. Moreover, MX-68 significantly inhibited the elevation of serum IgE and IgG levels. In the guinea-pig model for bronchial asthma, biphasic increases in airway resistance (immediate asthmatic response, IAR, and late asthmatic response, LAR), as well as accumulated inflammatory cells in BALF, were observed after repeated antigen challenge. These asthmatic responses and inflammatory signs were significantly decreased by administration of MX-68. These results suggest that MX-68 obviously has an anti-inflammatory effect in an animal model of asthma and would be useful clinically for the treatment of bronchial asthma.

Two Pharmacological Phases in Antigen-Induced Immediate Airway Response in Rats

“…22) The guinea pig asthmatic model exhibits two phases, IAR over a few minutes and LAR during a few hours after antigen exposure. 23) Regarding guinea pig IAR and the LAR model, it is known that antihistamine suppresses IAR but not LAR, 24) anti-TXA 2 suppress IAR 25) and that anti-LT suppresses both IAR and LAR. 26) In addition, b2-agonists like salbutamol suppress only IAR but not LAR, indicating that IAR is mainly medi- ated by airway smooth muscle contraction.…”

Effects of Schisandra chinensis Turcz. fruit on contact dermatitis induced by dinitrofluorobenzene in mice

“…By contrast, MESC did not affect body weight gains or spleen/ body weight ratios. In a previous study by Nagao et al (20), it was reported that corticosteroid-induced weight loss was the result of adverse reactions. In addition, the spleen mass reduction observed in the DEX group could have reflected general immune suppression, which is one of the major side effects of corticosteroids.…”

Induction of late airway response was involved in serum antigen-specific immunoglobulin G in rats

“…In a mouse asthmatic model, IAR is decreased by repeated antigen exposure [9], consistent with our findings. However, in a guinea pig asthmatic model, IAR and LAR were commonly provoked together after antigen challenge [18]. It is unclear why IAR disappeared or was diminished in some models of LAR.…”