Oxidant and protease injury of the lung.
Oxidants are generated in vivo by multiple mechanisms, including stimulation of leukocytes, hyperoxia, metabolism of arachidonic acid, and the activation of various oxidases. When the biochemical defences to the oxidants are inadequate, injury of tissues results. This injury was observed in rabbits and rhesus monkeys when pulmonary inflammation was induced with phorbol esters or formylated peptide given intrabronchially. We have recently investigated metabolic changes in various cells exposed to oxidants that are generated from stimulated leukocytes, including H2O2, O2, and HOCl. The target cells used were P388D1 murine macrophage-like tumour cells, human peripheral lymphocytes, GM 1380 human fibroblasts and rabbit alveolar macrophages. The oxidants used were H2O2 and PMA stimulated PMNs or neutroplasts. Lysis could only be prevented when catalase was added within the first 30-40 min of H2O2 exposure indicating that early metabolic changes determined the fate of the cell. Within seconds after the addition of H2O2 to P388D1 cells activation of the hexose monophosphate shunt (HMPS) was observed indicative of increased glutathione cycle activity. At the same time DNA strand breaks (determined by an alkaline unwinding technique) were detected. They resulted in the activation of the DNA repair enzyme poly-ADP-ribose polymerase (pADP-RP) within minutes after the addition of H2O2. At the same time ATP and NAD (the substrate of pADP-RP) concentrations dropped and nicotinamide accumulated extracellularly. 10-15 min after oxidant exposure free intracellular Ca++ concentrations determined by Quin 2 fluorescence started to increase due to release from intracellular stores.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Immunology, Scripps Clinic and Research Foundation, La Jolla, CA 92037.
I U
IU
Schraufstatter
P A
PA
Hyslop
J
J
Jackson
S D
SD
Revak
C C
CC
Cochrane
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008253:Macaca mulatta; D010196:Pancreatic Elastase / Q000378:metabolism; D011817:Rabbits; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
D004247:DNA; D006861:Hydrogen Peroxide; D010196:Pancreatic Elastase; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate