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Enhanced Acute Lung Damage in Mice following Administration of 1,3-Bis(2-chloroethyl)-1-nitrosourea¹

Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712-1074 [J. P. K.], and The University of Texas System Cancer Center, Smithville, Texas 78957 [A. J. P. K-S.]

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), also known as carmustine, is a lipid soluble anticancer drug which produces pulmonary fibrosis in up to 30% of the patients who receive this drug. The major risk factor for this disorder is preexisting lung damage. Animal models of this interaction have not been reported previously. A diffuse alveolar lesion was produced in male BALB/c mice by the administration of butylated hydroxytoluene (BHT). Total lung hydroxyproline levels, an index of fibrosis, were not increased in mice 21 days after single doses of BHT or BCNU. Total lung DNA synthesis, an index of pulmonary damage, was slightly increased after 15 and 18 days in rats and mice treated with BCNU (15 and 35 mg/kg, respectively). This suggested that a single dose of BCNU had only a minimal toxic effect on lung tissue. Combined treatments in mice given BHT (350 or 400 mg/kg), followed on Day 1 by BCNU (35 mg/kg), resulted in the deposition of significantly more hydroxyproline than with either agent alone. This enhancement was not seen following lower doses of BHT and was diminished when the dose of BCNU was decreased. Delaying the administration of BCNU (35 mg/kg) until Day 3 or 5 eliminated increases in hydroxyproline content, but not histological evidence of enhanced lung damage. Additional histological analyses confirmed the presence of an increased fibrotic reaction, especially when high doses of BCNU were administered 1 day after BHT (400 mg/kg). Most of the lungs were totally consolidated with numerous hyperactive fibroblasts and a large number of giant type II cells with atypical nuclei. These effects may be related to the ability of BCNU to inhibit pulmonary glutathione reductase activity and the increased DNA synthesis normally seen after BHT. These data show that BCNU treatment can enhance BHT-induced lung damage resulting in a fibrotic lesion similar to that seen in some human patients. This effect is dependent on the extent of the initial lung lesion as well as the time when BCNU is administered and may represent an animal model of the primary risk factor for the development of pulmonary fibrosis in human patients receiving this drug.

¹ This work was supported by Grant HL 29463 from the National Heart, Lung, and Blood Institute and by Grant CH-263 from the American Cancer Society.

² Recipient of Research Career Development Award HL 01435 from the National Heart, Lung, and Blood Institute. To whom requests for reprints should be addressed.

Received 5/17/85. Revised 8/12/85. Accepted 8/13/85.