CIGARETTE SMOKE-INDUCED DAMAGE IN GUINEA PIGS--MODULATION BY VITAMINS C&E

  • El-Bayoumy, Karam (PI)
  • FIALA, EMERICH SILVIO (PI)
  • Prokopczyk, Bogdan (PI)
  • FIALA, EMERICH SILVIO (PI)
  • El-Bayoumy, Karam (PI)
  • Prokopczyk, Bogdan (PI)
  • MELIKIAN, ASSIEH ALEXY (PI)

Project: Research project

Project Details

Description

Besides numerous toxic, carcinogenic, co-carcinogenic and tumor-
promoting chemicals, cigarette smoke is a source of nitric oxide, and
of quinones which generate superoxide by redox cycling. Superoxide is
a potential source of hydrogen peroxide, a precursor of the highly
destructive hydroxyl radical. Superoxide also combines spontaneously
with nitric oxide to form peroxynitrite. The latter decomposes to a
species with a reactivity similar to that of the hydroxy radical as
well as to a species which is chemically similar to the nitronium ion,
capable of nitrating aromatic amino acids in proteins. Numerous studies
have shown that the reactive oxidizing and nitrating species that can
be derived from cigarette smoke produce damage to lipids, proteins and
DNA in vitro, and it is suspected that similar damage can occur in
vivo. Further damage to the pulmonary system can take place when
macrophages and neutrophils, attracted to the site of primary cellular
damage caused by cigarette smoke, release proteolytic enzymes, HOCl,
as well as additional amounts of nitric oxide and superoxide. Cells of
the pulmonary system possess various defenses against oxidative damage,
including the powerful antioxidants, ascorbic acid and alpha-
tocopherol. It is well established that ascorbic acid is partially
depleted in cigarette smokers, presumably through participation in
antioxidant reactions. Surprisingly, neither the potential of cigarette
smoke to cause specific oxidative damage, nor the possible protective
effects of antioxidant vitamins have thus far been adequately studied
in vivo. The goals of this program are to characterize oxidative and
other damage produced in the pulmonary system of guinea pigs by
exposure to cigarette smoke, and to determine the effects of dietary
vitamins C and E on the process. The guinea pig was chosen as the
experimental model because, of all rodent species, it most resembles
man in requiring a dietary source of vitamin C. Our specific aims
are:, 1) To determine oxidative damage to DNA, RNA, proteins and lipids
of the guinea pig lung and trachea produced by chronic exposure to
cigarette smoke; 2) To systematically vary the dietary levels of
vitamins C and E of cigarette smoke-exposed guinea pigs in order to
determine possible protective (or enhancing) effects on pulmonary
oxidative damage; 3) To attempt to separately estimate part of the
initial damage caused by peroxynitrite derived from cigarette smoke by
spiking the cigarettes used in these studies with 15N-labeled nitrate,
and by quantitating 15N/14N ratios in 3-nitrotyrosine residues of
respiratory tract proteins. The results obtained from our studies will
be the first to comprehensively characterize oxidative damage due to
cigarette smoke in an appropriate animal model, and will yield
important information on the mechanisms involved. The studies will also
furnish additional strong rationale for dietary antioxidant vitamin
recommendations to those smokers who are unable to quit.
StatusFinished
Effective start/end date1/1/012/28/09

Funding

  • National Cancer Institute: $1,395,941.00
  • National Cancer Institute
  • National Cancer Institute: $1,395,357.00
  • National Cancer Institute: $1,433,809.00
  • National Cancer Institute
  • National Cancer Institute: $1,210,148.00
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute: $1,419,959.00

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