We propose to study the sequence of alterations in metabolism and function that occurs in cells during the O-2 toxicity. The hypothesis to be tested is that reversible metabolic changes in the cellular antioxidant defenses allow oxygen-induced irreversible loss of cellular functions. This will be tested in cell types with reported differences in resistance to O-2 toxicity: rat and guinea pig alveolar macrophages and rat granular pneumocytes (type II cells). The cells will be exposed in vitro for O-48 and assays made for: NADPH, glutathione, mixed disulfides, ascorbate, lipid peroxidation products, superoxide dismutase and catalase activities, ATP, ADP, Ca2+ mobilization and distribution, membrane potentials, the respiratory burst of the macrophages, and isoproterenol stimulated dipalmitoyl lecithin secretion by type II cells. Manipulation of antioxidant defenses through selenium deficiency, inhibition of superoxide dismutase and catalase, glutathione depletion, and augmentation of antioxidant enzymes and/or mimetics with liposomes will be used to alter the rates of change in metabolism and function. Both the respiratory burst and Beta-adrenergic stimulated dipalmitoyl lecithin secretion are under regulatory control involving several of the parameters that we will be measuring. Comparison of the rates of alterations in cellular activities in both single cell types and between these cell types should reveal: (a) the sequence of events in O-2 toxicity; (b) which alterations are crucial in development of toxicity or resistance to hyperoxia; and (c) the interrelationships of functions in regulatory processes. The methodology includes spectrophotometric, fluorometric and chemiluminescence assays, HPLC, distribution of radiolabeled ions, radiolabeled precursor incorporation, and use of liposomes. Our long-term objective is an understanding of the molecular mechanisms in normal regulatory and toxicologic processes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL037556-02
Application #
3353320
Study Section
Toxicology Study Section (TOX)
Project Start
1986-04-01
Project End
1991-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Forman, Henry Jay (2016) Redox signaling: An evolution from free radicals to aging. Free Radic Biol Med 97:398-407
Soñanez-Organis, José G; Peregrino-Uriarte, Alma B; Sotelo-Mundo, Rogerio R et al. (2011) Hexokinase from the white shrimp Litopenaeus vannamei: cDNA sequence, structural protein model and regulation via HIF-1 in response to hypoxia. Comp Biochem Physiol B Biochem Mol Biol 158:242-9
Forman, Henry Jay (2010) Reactive oxygen species and alpha,beta-unsaturated aldehydes as second messengers in signal transduction. Ann N Y Acad Sci 1203:35-44
Forman, Henry Jay; Maiorino, Matilde; Ursini, Fulvio (2010) Signaling functions of reactive oxygen species. Biochemistry 49:835-42
Cruz, Cristiane M; Rinna, Alessandra; Forman, Henry Jay et al. (2007) ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J Biol Chem 282:2871-9
Forman, Henry Jay (2007) Use and abuse of exogenous H2O2 in studies of signal transduction. Free Radic Biol Med 42:926-32
Liu, Honglei; Zhang, Hongqiao; Forman, Henry Jay (2007) Silica induces macrophage cytokines through phosphatidylcholine-specific phospholipase C with hydrogen peroxide. Am J Respir Cell Mol Biol 36:594-9
Liu, Honglei; Zhang, Hongqiao; Iles, Karen E et al. (2006) The ADP-stimulated NADPH oxidase activates the ASK-1/MKK4/JNK pathway in alveolar macrophages. Free Radic Res 40:865-74
Rinna, Alessandra; Torres, Martine; Forman, Henry Jay (2006) Stimulation of the alveolar macrophage respiratory burst by ADP causes selective glutathionylation of protein tyrosine phosphatase 1B. Free Radic Biol Med 41:86-91
Rahman, Irfan; Biswas, Saibal K; Jimenez, Luis A et al. (2005) Glutathione, stress responses, and redox signaling in lung inflammation. Antioxid Redox Signal 7:42-59

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