ATTENUATION OF OXIDANT-INDUCED LUNG INJURY BY 21-AMINOSTEROIDS (LAZAROIDS) - CORRELATION WITH THE MESSENGER-RNA EXPRESSION FOR E-SELECTIN, P-SELECTIN, ICAM-1, AND VCAM-1

We compared the effects of treatment with methylprednisolone or the 21 -aminosteroids, U-74389 and U-74006F (Tirilizad mesylate), on hyperoxi c lung injury and the associated expression of mRNA for several adhesi on molecules in rats. Inhalation of >95% oxygen for up to 72 hr in Spr ague-Dawley rats produced a marked increase in lung weight and an accu mulation of fluid in the thorax when compared with air-breathing contr ols. Hyperoxia also induced a marked neutrophil-rich influx of inflamm ation cells into the bronchial lumen as measured by bronchoalveolar ra vage. Neutrophil numbers in bronchoalveolar lavage fluid peaked after 60 hr of exposure to >95% oxygen; this was associated with a marked up regulation of mRMA for the adhesion molecules P-selectin and E-selecti n but not VCAM-1. mRNA for ICAM-1 was constitutively expressed at high levels in both air-breathing controls and in the lungs of rats expose d to high concentrations of oxygen. Pretreatment with the 21-aminoster oids reduced hyperoxic lung damage and improved survival times in anim als exposed to >95% oxygen. However, treatment with methylprednisolone significantly decreased survival times. Treatment with U-74389 did no t significantly (p > 0.05) inhibit the BAL neutrophilia and did not si gnificantly (p > 0.05) reduce hyperoxia-induced increases in mRNA expr ession for P-selectin and E-selectin. The inhibition of hyperoxic lung damage coupled with improved survival seen in treated animals suggest s that 21-aminosteroids may provide valuable treatments for pulmonary disorders in which oxidant damage has been implicated.