INTERLEUKIN-4-DEPENDENT PULMONARY EOSINOPHIL INFILTRATION IN A MURINE MODEL OF ASTHMA

The establishment of animal models of asthma is critical to elucidate the mechanisms involved in the pathogenesis of the disease. In the present study, we have used a parasite antigen from Schistosoma mansoni eggs, which induces a TH2 response, to elicit a pulmonary inflammatory reaction that resolves after 3 to 4 days. Histologic examination of the lungs of soluble egg antigens (SEA) or saline vehicle-challenged mice demonstrated a large influx of cells in the antigen- but not vehicle-challenged mice, thus demonstrating an antigen-specific reaction. A characteristic influx of eosinophils could be detected as early as 8 h, with significant increases at 24 to 72 h after challenge. An assessment of the bronchial alveolar lavage (BAL) fluid demonstrated dominant neutrophil infiltration at 8 h, with a subsequent decrease to background by 48 h. In addition, peak monocyte infiltration occurred at 24 h, and peak eosinophil extravasation into the airway was shown at 48 h. The examination of leukocyte infiltrates in the interstitium in dispersed lung preparations again demonstrated early neutrophil and monocyte infiltration at 8 h after challenge, with increases in lymphocyte and eosinophil infiltrates at 24 h. Examination of interleukin-4 (IL-4) production in the BAL fluid demonstrated the presence of IL-4 early in the response, with levels peaking between 8 and 24 h after antigen challenge, with no detectable IL-4 in the saline vehicle-challenged mice. Mice treated with anti-IL-4 antibodies demonstrated a tenfold decrease in BAL eosinophil influx at 48 h after challenge and a reduction in total pulmonary leukocyte cellularity. The data presented define a murine model of airway inflammation comparable with that found in human asthma. In addition, these studies demonstrate an IL-4-dependent mechanism for the induction of eosinophil recruitment. This model will aid in assessing cellular, molecular, and cytokine responses in asthmatic inflammation.