Impairment in Coupled Beta-Adrenergic Receptor and Adenylate Cyclase System during Bleomycin-Induced Lung Fibrosis in Hamsters

Abstract

The purpose of this study was to evaluate the coupled beta-adrenergic receptor (BAR) and adenylate cyclase (AC) system of the lung during the course of the bleomycin-(Bleo) induced pulmonary fibrosis in hamsters. The BAR population, dissociation constants (K_d), AC activity, and its sensitivity to various stimulators were studied at 2, 4, 7, 14, and 21 days after intratracheal administration of either 1 unit of Bleo or an equivalent volume of saline. The BAR population in the lungs of Bleo-treated animals did not differ from control at the early times, but it was significantly reduced to 5.9 × 10³ fmol and 3.6 × 10³ fmol from the control values of 1.1 × 10⁴ fmol and 1.5 × 10⁴ fmol per lung at 14 and 21 days after treatment, respectively. The K_d values for control hamster lung ranged from 2.5 × 10⁻¹¹ M to 3.7 × 10⁻¹¹ M, and for Bleo-treated hamster lung, from 2.7 × 10⁻¹¹ M to 4.8 × 10⁻¹¹ M. The K_d at the earliest time, 2 days after treatment, did not differ significantly from the K_d values at the subsequent times in control, while for Bleo-treated hamster lung, the K_d values at 7, 14, and 21 days were significantly higher than the K_d at 2 days after treatment. The K_d values for Bleo-treated hamster lung were also significantly higher than control at 14 and 21 days. The AC activity of the lung in Bleo-treated hamster was significantly reduced to 67%, 40%, 38%, and 50% of their respective controls in response to H₂O (basal), GTP (10⁻⁴ M), GTP + isoproterenol (10⁻⁴ M each), and NaF (10 mM) at 21 days after treatment. The extent of AC stimulation in Bleo-treated hamster lung in response to various stimulators was generally less than that of saline control. Reductions in the BAR population and increased K_d values in Bleo-treated hamster lung were attributed to its fibrogenic ability and not to nutritional deficiency, which may partly be accountable for decreased AC activity of the lung in these animals. However, there were qualitative differences in the lung AC activity between Bleo-treated and nutritionally deprived hamsters, since the enzyme from the latter group was generally more responsive to stimulators than the enzyme from the former group. It was concluded from the findings of this study that an impairment in the coupled BAR and AC system of the lung may be partly responsible for the fibrogenic ability of bleomycin.