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Instructions,
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Inhibition
of Tobacco Smoke-induced Lung Inflammation by a Catalytic Antioxidant. Introduction: Cigarette
smoking is the major risk factor for both chronic obstructive pulmonary disease
(COPD) and lung cancer. Though the
mechanisms of these diseases are not known, a number of factors leading to
tobacco smoke-induced inflammation and airway damage may be similar in COPD and
lung cancer. The pathology of
chronic bronchitis includes airway mucus gland hyperplasia, mucous
hypersecretion, and an influx of inflammatory cells including neutrophils,
macrophages, and lymphocytes. In
addition, airways may undergo other changes leading to epithelial cell dysplasia.
The purpose of this study was to investigate whether
manganese(III)meso-tetrakis(N,N’-diethyl-1,3-imidazolium-2-yl) porphyrin (AEOL
10150) would provide protection against tobacco smoke-induced inflammation and
damage to the airways of rats. Study
Design: Spontaneously
hypertensive (SH) rats were exposed to cigarette smoke for 6 hours/day at a
total suspended particulate concentration of 70-80 mg/m3 for 2 days
or 8 weeks (3 days/week). Selected
animals were intratracheally instilled weekly with AEOL 10150 prior to exposure
to tobacco smoke. The dose of AEOL
10150 was 5 mg/kg or 2 mg/kg b.wt. for animals exposed to tobacco smoke for 2
days or 8 weeks, respectively. Eighteen
hours after the last exposure to tobacco smoke, animals were killed and the
right lung lobe was lavaged while the left lobe was inflation-fixed for
histology. Macrophages, neutrophils,
and lymphocytes were counted on cytospin preparations.
Lung cross-sections containing the left mainstream intrapulmonary
bronchus (airway generation 2 to 4) were embedded, sectioned, and stained with
hematoxylin and eosin. Epithelial composition of each airway was classified as
simple cuboidal, pseudostratified columnar, or stratified squamous.
For stratified squamous epithelium, the fraction of total airway surface
covered by these cells was determined. Results: Exposure
to tobacco smoke for 2 days or 8 weeks significantly increased the total numbers
of macrophages, neutrophils, and lymphocytes in BAL.
AEOL 10150 significantly decreased BAL macrophages after 8 weeks of
tobacco smoke exposure. Instillation
of AEOL 10150 also reduced neutrophil number following 2 days of exposure and
lymphocyte number following both 2 days and 8 weeks of exposure. Histological
examination of lungs from rats exposed to tobacco smoke for 8 weeks demonstrated
stratified squamous metaplasia of the mainstem intrapulmonary bronchial
epithelium. AEOL 10150
significantly decreased the ratio of stratified squamous epithelium to total
epithelium from 0.12 ± 0.06 to 0.02 ± 0.02 (p<.05). Discussion: The
investigators have shown that tobacco smoke causes chronic inflammation in the
lungs of SH rats at a concentration of 60-80 mg/m3 with up to 8 weeks
of exposure. Biochemical markers in
BAL and pathological changes in the pulmonary airways were documented. Pulmonary inflammation and epithelial damage were reduced by
administration of the catalytic antioxidant AEOL 10150.
MIP-2 and ICAM-1 proinflammatory mediators were increased with 2 days of
smoke exposure, but attenuated with intratracheal instillation of AEOL 10150
prior to exposure to tobacco smoke. The
authors speculate more frequent instillation of the antioxidant into the lungs
may result in further inhibition of tobacco smoke-induced inflammation and
squamous cell metaplasia. Further,
they suggest that optimization of the dose may also provide additional reduction
in the effects of tobacco smoke. The
ability of an antioxidant to decrease tobacco smoke-induced inflammation in the
lungs strongly suggests a role of oxygen radicals in the induction of
inflammatory mediators, possibly through activation of the oxidant-sensitive
transcription factor, nuclear factor (NF)-κB.
The authors suggest that pharmacological activity of AEOL10150 may be a
result of inactivation of superoxide, preventing formation of peroxynitrite. This catalytic antioxidant may also directly scavenge
peroxynitrite, limiting the oxidative damage caused by this molecule. The authors conclude that metalloporphyrins could serve as therapeutic agents in diseases that involve overproduction of reactive oxygen species that include inflammation and epithelial metaplasia. By:
Kevin Smith, PhD, Center for Health and the Environment, University of
California, Davis.
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