Pulmonary epithelial cells are exposed to a diverse array of oxidants. Cytotoxicity occurs when the oxidant burden exceeds defenses but how injury induction occurs remains largely undefined. The aqueous fluid compartment (epithelial lining fluid; ELF) that covers airspace cells is initially contacted by inhaled oxidants. Endogenously derived oxidants (e.g. NO, ONOO- H2O2) are also secreted into or formed within it due to cellular activities and clinical therapeutics. An adaptive response, not exclusively linked to cellular alterations, occurs in a temporal and oxidant exposure-dependent manner. The oxidants NO2 and O3 undergo """"""""reactive absorption"""""""" which couples uptake to their chemical reaction with similar ELF constituents. Despite this, recent data suggests NO2 & 03 display dissimilar ELF physiochemical interactions, making differential toxicity pathways probable. We hypothesize that: the mechanisms and extent of acute toxicity and development of adaptation are dependent on the specific chemical species that are formed within and diffuse through the ELF to contact the underlying epithelium. Thus, while heterogeneities in ELF chemistry likely govern the extent of injury from extracellular oxidants, the ELF contributions to the governance and mechanisms of acute injury and adaptation remain insufficiently defined. Due to their unique absorption but differential reaction/diffusion properties, we will employ NO2 & 03 as model ELF oxidants of disparate toxicity pathways. Our hypothesis will be tested by interrelated experimental aims utilizing novel investigational approaches that span from pure biochemical constructs to whole animal models. Accomplishment of the proposed aims will 1) delineate the temporal and spatial distribution of oxidative vs. nitrosative stress and their impact on acute cell injury from NO2 and 03, 2) characterize the ELF physicochemical conditions that alter dose/response relationships via modulating the formation and delivery of oxidative/nitrosative species to targets, and 3) define adaptation mechanisms relative to oxidative vs. nitrosative stress from extracellular oxidants and ascertain whether one form of stress imparts tolerance to the other. These proposed experiments will reveal new insights regarding the pathways of oxidant lung injury, especially related to the mechanisms that govern the magnitude of biological responses, and the potential to ameliorate lung injury

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054696-06
Application #
6644146
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Harabin, Andrea L
Project Start
1996-07-01
Project End
2007-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
6
Fiscal Year
2003
Total Cost
$286,715
Indirect Cost
Name
University of Alabama Birmingham
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Theis, Whitney S; Andringa, Kelly K; Millender-Swain, Telisha et al. (2014) Ozone inhalation modifies the rat liver proteome. Redox Biol 2:52-60
Adgent, Margaret A; Squadrito, Giuseppe L; Ballinger, Carol A et al. (2012) Desferrioxamine inhibits protein tyrosine nitration: mechanisms and implications. Free Radic Biol Med 53:951-61
Liu, Rui-Ming; Vayalil, Praveen Kumar; Ballinger, Carol et al. (2012) Transforming growth factor ýý suppresses glutamate-cysteine ligase gene expression and induces oxidative stress in a lung fibrosis model. Free Radic Biol Med 53:554-63
Katre, Ashwini; Ballinger, Carol; Akhter, Hasina et al. (2011) Increased transforming growth factor beta 1 expression mediates ozone-induced airway fibrosis in mice. Inhal Toxicol 23:486-94
Liu, Rui-Ming; Choi, Jinah; Wu, Jian-He et al. (2010) Oxidative modification of nuclear mitogen-activated protein kinase phosphatase 1 is involved in transforming growth factor beta1-induced expression of plasminogen activator inhibitor 1 in fibroblasts. J Biol Chem 285:16239-47
Squadrito, Giuseppe L; Postlethwait, Edward M; Matalon, Sadis (2010) Elucidating mechanisms of chlorine toxicity: reaction kinetics, thermodynamics, and physiological implications. Am J Physiol Lung Cell Mol Physiol 299:L289-300
Chuang, Gin C; Yang, Zhen; Westbrook, David G et al. (2009) Pulmonary ozone exposure induces vascular dysfunction, mitochondrial damage, and atherogenesis. Am J Physiol Lung Cell Mol Physiol 297:L209-16
Squadrito, Giuseppe L; Postlethwait, Edward M (2009) On the hydrophobicity of nitrogen dioxide: could there be a ""lens"" effect for NO(2) reaction kinetics? Nitric Oxide 21:104-9
Vayalil, Praveen K; Iles, Karen E; Choi, Jinah et al. (2007) Glutathione suppresses TGF-beta-induced PAI-1 expression by inhibiting p38 and JNK MAPK and the binding of AP-1, SP-1, and Smad to the PAI-1 promoter. Am J Physiol Lung Cell Mol Physiol 293:L1281-92
Vayalil, Praveen K; Olman, Mitchell; Murphy-Ullrich, Joanne E et al. (2005) Glutathione restores collagen degradation in TGF-beta-treated fibroblasts by blocking plasminogen activator inhibitor-1 expression and activating plasminogen. Am J Physiol Lung Cell Mol Physiol 289:L937-45

Showing the most recent 10 out of 17 publications