Timing of administration of anti-VLA-4 differentiates airway hyperresponsiveness in the central and peripheral airways in mice

The development of airway hyperresponsiveness (AHR) is correlated with the infiltration into the lungs of activated eosinophils and T lymphocytes. In large part, influx of eosinophils into the lung is dependent on very late a ctivating antigen-4 (VLA-4) expression. However, the kinetics of eosinophil recruitment and the development of AHR are not fully delineated. Airway fu nction was monitored by changes in lung resistance (RL) and dynamic complia nce (Cdyn) to methacholine (MCh) inhalation after anti-VLA-4. After ovalbum in (OVA) sensitization and airway challenge of BALB/c mice, AHR increased a s did the number of lung inflammatory cells. Administration of anti-VLA-4 t o sensitized mice 2 h before the first (of three) OVA airway challenges sig nificantly prevented changes in RL. Moreover, injection of the antibody fro m 2 h before the first challenge to 42 h after the last challenge significa ntly prevented the increases in RL, as well as eosinophil and lymphocyte nu mbers in the bronchoalveolar lavage fluid (BALF); interleukin-5 (IL-5) and leukotriene concentrations in BALF were also significantly inhibited. Inter estingly, treatment with anti-VLA-4 only prevented changes in Cdyn and gobl et cell hyperplasia when administered 2 h before the first challenge. These studies demonstrate that the timing of anti-VLA-4 administration can selec tively affect pathologic processes that contribute to altered airway functi on in the central and peripheral airways after allergen challenge.