Enhanced Acute Lung Damage Following Corticosteroid Treatment

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Abstract
The administration of butylated hydroxytoluene (BHT) to mice has been shown to produce diffuse alveolar epithelial cell damage which is largely resolved within 2 wk. Treatment with the corticosteroid prednisolone, 30 mg/kg twice daily during the first 5 days after BHT, greatly exacerbated the initial damage. A severe interstitial pneumonitis was evident histologically 15 days after BHT-treatment. The infiltrate became even more extensive 22 days after BHT with a massive consolidation of the lungs. The pneumonitis was characterized by cellular infiltrates, alveolar thickening and the deposition of fibrillar collagenous material. This massive steroid-induced pneumonitis was virtually gone at 60 days after BHT-treatment. The extent of the fibrotic changes, as quantitated by measuring total lung hydroxyproline levels, was dependent both on the corticosteroid dose and the time when they were administered. Increases in total lung hydroxyproline were seen following the administration of 30 mg/kg prednisolone or methylprednisolone acetate twice daily on Days 1 to 5 after BHT. These biochemical changes were evident 15 days after BHT and, in contrast to the histologic findings, persisted to Day 60. The administration of prednisolone of Days 3 to 7, 6 to 10 or 1 to 10 after BHT, or at lower doses they had no effect on the development of fibrosis. Single 30 mg/kg doses of prednisolone and methylprednisolone acetate inhibited the increased lung DNA synthesis normally seen after BHT. This inhibition was maintained by twice daily doses of prednisolone on Days 1 to 5 after BHT, and was followed by a rebound in DNA synthesis on Day 7. High dose corticosteroid therapy can aggravate acute lung damage if given during the early repair phase. Both dose and timing considerations are important in the ultimate outcome of corticosteroid therapy.