Acrolein induces endoplasmic reticulum stress and causes airspace enlargement.
BACKGROUND
Given the relative abundance and toxic potential of acrolein in inhaled cigarette smoke, it is surprising how little is known about the pulmonary and systemic effects of acrolein. Here we test the hypothesis whether systemic administration of acrolein could cause endoplasmic reticulum (ER) stress, and lung cell apoptosis, leading to the enlargement of the alveolar air spaces in rats.


METHODS
Acute and chronic effects of intraperitoneally administered acrolein were tested. Mean alveolar airspace area was measured by using light microscopy and imaging system software. TUNEL staining and immunohistochemistry (IHC) for active caspase 3 and Western blot analysis for active caspase 3, and caspase 12 were performed to detect apoptosis. The ER-stress related gene expression in the lungs was determined by Quantitative real-time PCR analysis. Acrolein-protein adducts in the lung tissue were detected by IHC.


RESULTS
Acute administration of acrolein caused a significant elevation of activated caspase 3, upregulation of VEGF expression and induced ER stress proteins in the lung tissue. The chronic administration of acrolein in rats led to emphysematous lung tissue remodeling. TUNEL staining and IHC for cleaved caspase 3 showed a large number of apoptotic septal cells in the acrolein-treated rat lungs. Chronic acrolein administration cause the endoplasmic reticulum stress response manifested by significant upregulation of ATF4, CHOP and GADd34 expression. In smokers with COPD there was a considerable accumulation of acrolein-protein adducts in the inflammatory, airway and vascular cells.


CONCLUSIONS
Systemic administration of acrolein causes endoplasmic reticulum stress response, lung cell apoptosis, and chronic administration leads to the enlargement of the alveolar air spaces and emphysema in rats. The substantial accumulation of acrolein-protein adducts in the lungs of COPD patients suggest a role of acrolein in the pathogenesis of emphysema.
Pulmonary and Critical Care Medicine Division, The Victoria Johnson Laboratory for Obstructive Lung Disease Research, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Yoshiaki
Y
Kitaguchi
Laimute
L
Taraseviciene-Stewart
Masayuki
M
Hanaoka
Ramesh
R
Natarajan
Donatas
D
Kraskauskas
Norbert F
NF
Voelkel
D000171:Acrolein / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D011485:Protein Binding; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D000171:Acrolein; D053148:Caspase 3