Sublethal oxidant injury inhibits signal transduction in rat type II pneumocytes.
The production of reduced forms of O2 in oxidant injury can lead to lipid peroxidation, which would pose a threat to cell membrane integrity and therefore to signal transduction pathways located in the membrane. We studied the effects of oxidant injury with t-butyl hydroperoxide (tBOOH) on signal transduction in rat type II pneumocytes in culture. Exposure of 1 x 10(6) type II pneumocytes to tBOOH concentrations less than or equal to 100 microM did not cause significant release of lactate dehydrogenase and was therefore termed sublethal. Exposure to sublethal concentrations of tBOOH caused a dose-dependent inhibition of surfactant secretion stimulated both by terbutaline (10(-4)M) and by extracellular ATP (10(-5)M). Adenosine 3',5'-cyclic monophosphate production in response both to terbutaline and to extracellular ATP was also inhibited by exposure to 100 microM tBOOH. In addition, exposure to 100 microM tBOOH inhibited inositol phosphate formation in response to extracellular ATP. We conclude that sublethal oxidant injury inhibits not only receptor-mediated agonist stimulation of surfactant secretion but also receptor-mediated agonist stimulation of second messenger formation in type II pneumocytes in culture. Such inhibition may be important in the pathogenesis of both the adult and neonatal forms of respiratory distress syndrome, in which alveolar surfactant deficiency may be exacerbated by oxidant injury.
Warburton
D
D
Developmental Lung Biology Research Center, Children's Hospital of Los Angeles, California.
Buckley
S
S
Cosico
L
L
Forman
H J
HJ
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010545:Peroxides / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013726:Terbutaline / Q000494:pharmacology; D020122:tert-Butylhydroperoxide
D007295:Inositol Phosphates; D010545:Peroxides; D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; D000255:Adenosine Triphosphate; D020122:tert-Butylhydroperoxide; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D013726:Terbutaline