Reversal of Methylprednisolone Effects in Allergen-Exposed Female Balb/c Mice

Abstract

A high percentage of asthma is associated with aeroallergen exposures. Glucocorticoids such as methylprednisolone represent a major method for managing chronic asthma. However, studies suggested that corticosteroid therapy might have the potential to stimulate rather than inhibit adaptive immune inflammatory reactions, raising concerns about possible adverse reactions due to excessive repeated methylprednisolone treatment. Therefore, a murine model of allergen-induced inflammation was characterized and used to investigate the effects of repeated intraperitoneal (ip) and transnasal treatments with methylprednisolone (0–20 mg/kg body weight) and cyclosporin A (20 mg/kg body weight). Sensitized BALB/c female mice were exposed daily to ovalbumin (OVA) aerosols for up to 5 d with 24-h postexposure analyses for airway responses to methacholine aerosols and inflammatory cell recoveries by bronchoalveolar lavage (BAL) and tissue collagenase dispersion. Although increased tissue neutrophils, lymphocytes, monocytes, and macrophages reached maximal levels after 2 daily OVA exposures, recoverable eosinophil numbers continued to rise over the 5-d period. Daily ip treatments with a 5-mg/kg body weight dose of methylprednisolone diminished both OVA-induced airway responses to methacholine and inflammatory-cell accumulations to levels comparable to those observed with cyclosporin A. However, treatments with higher doses of methylprednisolone reversed this anti-inflammatory effect, indicated by a return to untreated levels of OVA-induced eosinophil recovery. A similar biphasic response in eosinophil recoveries was observed using daily transnasal methylprednisolone treatments that correlated with a concomitant fall and rise in BAL interleukin-13. These results supported the hypothesis that repeated high-steroid treatments might activate rather than suppress allergen-induced immune responses.

This study was supported by the Children's Research Center of Michigan and a grant from the National Institute of Child Health and Human Development (5U01HD37261-04).

Permanent affiliation for Janet Kerr is Merck Research Laboratories, West Point, PA, USA.