RT Journal Article
SR Electronic
T1 Cigarette smoke activates ER overload response in Z-AT mice
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P3904
VO 42
IS Suppl 57
A1 Sam Alam
A1 Zhenjun Li
A1 Ravi Mahadeva
YR 2013
UL http://erj.ersjournals.com/content/42/Suppl_57/P3904.abstract
AB Severe deficiency of the major anti-elastase α1-antitrypsin (AT) due to the Z (Glu342Lys) variant (Z-AT) is the commonest genetic reason for the development of COPD. Cigarette smoke (CS) accelerates decline in lung function in PiZZ homozygotes. We investigated whether CS exposed Z-AT is associated with activation of endoplasmic reticulum (ER) overload response (EOR; PERK, ATF4) compared to CS exposed normal AT (M-AT). Female transgenic mice (n=8) for M-AT or Z-AT were exposed to 4 1R3F cigarettes daily for 5 days. BALF and perfused lungs homogenized were assessed for lung injury/inflammation and EOR. CS Z-AT mice was compared with CS M-AT unless stated. Z-AT had significantly more lung injury than M-AT; wet:dry ratio of lungs (P=0.001), BALF total protein (P<0.001). ELISA and immunoblot showed Z-AT had significantly activated NF-κB than M-AT (P<0.001). Z-AT BALF had significantly increased secretion of TNF-α (428±23pg/ml vs. 248±31, P<0.001) and IL-6 (373±20pg/ml vs. 250±23, P=0.001) than M-AT. RT-PCR of lung tissues showed Z-AT had significantly upregulated mRNA for TNF-α (P<0.001) and IL-6 (P<0.001) than M-AT. RT-PCR also showed non-CS Z-AT when compared to non-CS M-AT had significant upregulation of PERK (1.4-fold increase, P=0.026) and ATF4 (1.5-fold increase, P=0.006). CS Z-AT when compared to CS M-AT had upregulated PERK (1.26-fold increase, P=0.010) and ATF4 (1.7-fold increase, P=0.002). In Z-AT mice CS activates EOR and inflammatory mediators. This predisposes Z-AT individuals to exaggerated lung inflammation. We postulate that ER accumulation of oxidized polymer Z-AT activates EOR; PERK-dependant NF-κB resulting in exaggerated inflammatory phenotype in Z-AT.