ToxSci Advance Access originally published online on August 5, 2009
Toxicological Sciences 2009 112(1):4-16; doi:10.1093/toxsci/kfp179
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Nitrative and Oxidative Stress in Toxicology and Disease
* AstraZeneca R&D Safety Assessment, Alderley Park, UK SK9 1DG
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey NJ08854
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington 77030
Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas IA52242
¶ College of Pharmacy, University of Iowa, Iowa City, Iowa
|| NCTR, USFDA, Jefferson, Arkansas 72079
1 To whom correspondence should be addressed at AstraZeneca R&D Safety Assessment, Alderley Park, UK. E-mail: ruth.roberts{at}astrazeneca.com.
Received June 15, 2009; accepted July 24, 2009
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Abstract |
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Persistent inflammation and the generation of reactive oxygen and nitrogen species play pivotal roles in tissue injury during disease pathogenesis and as a reaction to toxicant exposures. The associated oxidative and nitrative stress promote diverse pathologic reactions including neurodegenerative disorders, atherosclerosis, chronic inflammation, cancer, and premature labor and stillbirth. These effects occur via sustained inflammation, cellular proliferation and cytotoxicity and via induction of a proangiogenic environment. For example, exposure to the ubiquitous air pollutant ozone leads to generation of reactive oxygen and nitrogen species in lung macrophages that play a key role in subsequent tissue damage. Similarly, studies indicate that genes involved in regulating oxidative stress are altered by anesthetic treatment resulting in brain injury, most notable during development. In addition to a role in tissue injury in the brain, inflammation, and oxidative stress are implicated in Parkinson's disease, a neurodegenerative disease characterized by the loss of dopamine neurons. Recent data suggest a mechanistic link between oxidative stress and elevated levels of 3,4-dihydroxyphenylacetaldehyde, a neurotoxin endogenous to dopamine neurons. These findings have significant implications for development of therapeutics and identification of novel biomarkers for Parkinson's disease pathogenesis. Oxidative and nitrative stress is also thought to play a role in creating the proinflammatory microenvironment associated with the aggressive phenotype of inflammatory breast cancer. An understanding of fundamental concepts of oxidative and nitrative stress can underpin a rational plan of treatment for diseases and toxicities associated with excessive production of reactive oxygen and nitrogen species.
Key Words: cytokine signaling; carcinogenesis; developmental toxicity; prenatal; inflammation.