CYTOKINE AND EOSINOPHIL RESPONSES IN THE LUNG, PERIPHERAL-BLOOD, AND BONE-MARROW COMPARTMENTS IN A MURINE MODEL OF ALLERGEN-INDUCED AIRWAYSINFLAMMATION

Selective accumulation of eosinophils and activated CD4+ cells is now considered a central event in the pathogenesis of asthma, and this pro cess is thought to be mediated by a number of cytokines including tumo r necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-sti mulating factor (GM-CSF), and the Type 2 cytokines interleukin-4 (IL-4 ) and IL-5. To carry out a detailed time-course analysis of cellular c hanges in the bronchoalveolar lavage fluid (BAL), peripheral blood (PB ), and bone marrow (BM), and of changes in the aforementioned cytokine s in BAL and serum, Balb/c mice were sensitized by intraperitoneal inj ection with ovalbumin (OVA) adsorbed to aluminum hydroxide on two occa sions 5 days apart, and were subjected to an OVA aerosol challenge 12 days after the second sensitization. This resulted in an airways infla mmatory response characterized by early transient neutrophilia, marked eosinophilia, and, to a lesser extent, lymphocytosis in the BAL. Infl ammatory events were first observed 3 h and 24 h after antigen challen ge in the lung tissue and BAL, respectively, and lasted for 21 days. I n the BM, we detected a 1.5- and 5-fold increase in the total number o f cells and eosinophils, respectively, 4 days after the second sensiti zation. This was followed by a decrease, although BM eosinophilia rema ined clearly present at the time of antigen challenge. A second eosino poietic event was observed in the BM shortly after challenge and reach ed a peak at day 3. BM cellularity returned to normal at day 21 after challenge. Serum OVA-specific IgE was first detected 3 days following the second sensitization (150 ng/ml). IgE levels then decreased but re mained at the 75 ng/ml range at the time of the aerosol challenge. Dur ing the sensitization period, TNF-alpha (approximate to 25 pg/ml), IL- 4 (approximate to 40 pg/ml), and IL-5 (approximate to 250 pg/ml) were detected in serum, but not in the BAL fluid (BALE) and returned to bac kground levels at the time of the antigen challenge. After antigen cha llenge, TNF-alpha, IL-4, IL-5, and GM-CSF were detected in serum. Peak levels were observed at 3 h (approximate to 40 pg/ml), 3 h (approxima te to 120 pg/ml), 12 h (approximate to 350 pg/ml), and 3 h (approximat e to 10 pg/ml), respectively, and returned to background levels 24 h a fter challenge. In the BALE we detected peak levels of TNF-cr, IL-4, I L-5, and GM-CSF at 6 h (approximate to 250 pg/ml), 24 h (approximate t o 140 pg/ml), 24 h (350 pg/ml), and 3 h (approximate to 10 pg/ml), res pectively, with a return to background levels 5 days after challenge. No IL-10 could be detected at any time point during sensitization or a fter challenge in either serum or BAL. We also detected approximately 40 pg/ml of interferon-gamma (IFN-gamma) in the serum of normal untrea ted mice. Serum IFN-gamma levels fluctuated during sensitization and a fter challenge, but never exceeded those observed in untreated mice. T hus, the cytokine profile observed in this experimental model of aller gic inflammation is characterized by IL-4 and IL-5 dominance, with an apparently minor TNF-alpha and GM-CSF contribution and relatively low or undetectable levels of IFN-gamma and IL-10.