Attenuation of oxidant-induced lung injury by 21-aminosteroids (lazaroids): correlation with the mRNA 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 hyperoxic lung injury and the associated expression of mRNA for several adhesion molecules in rats. Inhalation of > 95% oxygen for up to 72 hr in Sprague-Dawley rats produced a marked increase in lung weight and an accumulation of fluid in the thorax when compared with air-breathing controls. Hyperoxia also induced a marked neutrophil-rich influx of inflammatory cells into the bronchial lumen as measured by bronchoalveolar lavage. Neutrophil numbers in bronchoalveolar lavage fluid peaked after 60 hr of exposure to s 95% oxygen; this was associated with a marked upregulation of mRNA for the adhesion molecules P-selectin and E-selectin 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 exposed to high concentrations of oxygen. Pretreatment with the 21-aminosteroids reduced hyperoxic lung damage and improved survival times in animals exposed to > 95% oxygen. However, treatment with methylprednisolone significantly decreased survival times. Treatment with U-74389 did not significantly (p > 0.05) inhibit the BAL neutrophilia and did not significantly (p > 0.05) reduce hyperoxia-induced increases in mRNA expression for P-selectin and E-selectin. The inhibition of hyperoxic lung damage coupled with improved survival seen in treated animals suggests that 21-aminosteroids may provide valuable treatments for pulmonary disorders in which oxidant damage has been implicated.
Griffin
R L
RL
Upjohn Laboratories, Kalamazoo, Michigan 49001.
Krzesicki
R F
RF
Fidler
S F
SF
Rosenbloom
C L
CL
Auchampach
J A
JA
Manning
A M
AM
Haas
J V
JV
Cammarata
S K
SK
Chin
J E
JE
Richards
I M
IM
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics; D019040:E-Selectin; D016166:Free Radical Scavengers / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008168:Lung / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology; D016877:Oxidants; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins / Q000235:genetics; D011281:Pregnatrienes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019010:Vascular Cell Adhesion Molecule-1
D000975:Antioxidants; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D016166:Free Radical Scavengers; D016877:Oxidants; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D011281:Pregnatrienes; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; C074965:U 74389F; D018799:Intercellular Adhesion Molecule-1; D008775:Methylprednisolone; C053355:tirilazad