EFFECT OF CHRONIC ANTIGEN AND BETA(2) AGONIST EXPOSURE ON AIRWAY REMODELING IN GUINEA-PIGS

We recently reported that chronic exposure to fenoterol (FEN) in guine a pigs increases in vivo and in vitro airway responsiveness to a deg r ee similar to that induced by chronic antigen (ovalbumin [OA]) exposur e. We hypothesized that these changes were due to airway inflammation and airway remodeling. To trace newly recruited granulocytes as a mark er of inflammation and to detect DNA replication in resident airway wa ll cells, the nucleotide 5'-bromo-2'-deoxyuridine (BrdU) was administe red intermittently over the six-wk period of chronic FEN and/or OA exp osure. Noncartilaginous airway dimensions were measured and the area f raction of Brd U-immunoreactive and total nuclei in adventitia, smooth muscle, and epithelium was determined by immunohistochemistry and poi nt counting. The proliferation index was defined as the ratio of the t wo area fractions in each wall area. The adventitial areas of FEN- and OA-treated airways were respectively 62 and 88% greater than those of control airways (p < 0.05). The inner wall areas were not increased. The smooth muscle cell and epithelial cell proliferation index was inc reased after OA (smooth muscle index: control, 2.7 +/- 1.1% [SEM]; OA 23.0 +/- 3.7%; p < 0.02) but not after FEN exposure, and there was an increased number of BrdU-immunoreactive granulocytes in the adventitia and epithelium after OA but not after FEN exposure. The increased in vive airways responsiveness produced by chronic OA or FEN exposure may be attributable to adventitial thickening and increased in vitro musc le contractility, but the cellular mechanisms underlying these and oth er airway wall responses are different. That is, OA but not FEN exposu re was associated with an inflammatory cell infiltrate and smooth musc le proliferation. The increased outer wall area induced by both FEN an d OA may have contributed to the excessive airway narrowing observed b y altering airway-parenchymal interdependence.