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PULMONARY GENE EXPRESSION PROFILES OF SPONTANEOUSLY HYPERTENSIVE RATS EXPOSED TO ENVIRONMENTAL TOBACCO SMOKE (ETS)
Citation:
NADADUR, S. S., K. E. PINKERTON, AND U. P. KODAVANTI. PULMONARY GENE EXPRESSION PROFILES OF SPONTANEOUSLY HYPERTENSIVE RATS EXPOSED TO ENVIRONMENTAL TOBACCO SMOKE (ETS) . Presented at 44th Aspen Lung Conference, Aspen, CO, June 05 - 09, 2001.
Description:
Global gene expression profile analysis can be utilized to derive molecular footprints to understand biochemical
pathways implicated in the origin and progression of disease. Functional genomics efforts with tissue-specific focused
genearray appears to be the most reasonable approach to derive relevant and meaningful information. In our efforts to
understand the molecular basis for the toxicity and exacerbations in susceptible populations to environmental exposures,
we are developing a gene expression data base for rat cardiopulmonary disease model exposed to air pollutants. The
Spontaneously Hypertensive (SH) rat with underlying cardiovascular and pulmonary disease risk is being utilized towards these efforts. The SH rats with polygenic traits towards hypertension, exhibits similar heritable risk factors that are found
in patients with chronic obstructive pulmonary disease. We have shown that SH rats are more susceptible to lung
injury/inflammation, and oxidative stress from exposure to combustion source particles, and from experimental induction
of emphysema compared to healthy normotensive Wistar rats. SH rats also elicited an inflammatory response to ETS
exposure which is less remarkable in other conventional rat strains used in laboratory studies. To understand the
molecular basis for the inflammatory response, we screened for a pulmonary gene expression profile in SH rats exposed to ETS. Male SH rats (II wks old) were exposed either to filtered air (FA) or ETS at a concentration of80-89 mg/mJ, 6h/day for 2 consecutive days, and on the third day total RNA was isolated from right lung lobes. Pulmonary gene expression was assayed by hybridizing 32P-labeled cDNA generated from total RNA to Atlas Rat cDNA expression array
filter containing 588 genes (Clontech, Palo Alto, CA). Gene expression profile data indicated strong hybridization signals for 40 genes including N-myc, p53, TGF-p, p21, bax-a and cytokine MIP-2. Pairwise comparison indicated ETS
exposure-associated differential expression in 16 genes: increased expression of CYPIA I, calcium pump, RhoGAP, p122, and decreased expression of bile salt activated lipase precursor, a fatty acid binding protein and fatty acid amide hydrolase. ETS-induced a 2- 3 fold increase in MIP-2 expression suggest lung injury and inflammation. Overexpression of MMP-7 suggests a possible release of proteases from ETS-induced infiltration of neutrophils into the airways, consistent with our earlier observations (Smith K. et.al., The Toxicologist, vol: 60, 200 I). Increased expression of
p27(Kip I), caspase- I, Stat3 observed in the present study further supports apoptosis of infiltrating neutrophils in the
lungs following exposure to ETS. Efforts are underway to explore whether long-term ETS exposure ofSH rats will lead
to a chronic disease state. Comprehensive expression data base indicating ETS-induced changes in susceptible animal
models will provide identification and the role of risk factors in understanding health effects of ETS and other environmental pollutant-induced cardiopulmonary disease. (This abstract does not reflect US EPA policy).