Endoplasmic reticulum (ER) stress, a condition caused by accumulation of unfolded or misfolded proteins in the ER lumen, is Rationale: heightened in the COPD lung as a result of impaired protein degradation. Normally, a highly sophisticated, compensatory response termed the unfolded protein response (UPR) relieves ER stress by up-regulating expression of a multi-gene program which codes for molecules that regulate protein folding, transport, degradation and translation. The present study examined UPR gene expression in cultured human type I and II pneumocytes in which ER stress was induced by thapsigargin, a SERCA pump inhibitor which depletes ER calcium. We also examined UPR gene expression in the lungs of subjects with advanced COPD (GOLD 4, n=24), moderate COPD (GOLD 2, n=12), and subjects at risk but without COPD (GOLD 0, n=11).Pneumocytes were treated with 1μM thapsigargin for 24 hr. Lung tissues were obtained from the Temple University Tissue Bank Methods: and the NIH Lung Tissue Research Consortium. Total RNA from cells and tissues was isolated with TRI reagent (Sigma-Aldrich) and purified by RNeasy column (Qiagen). Within each GOLD group, individual RNA samples were assayed for integrity (Bioanalyzer 2100, Agilent) and pooled in equal amounts. UPR gene expression was assessed using a commercially available RT kit and 84 gene PCR array (RT² Profiler PCR Array system, SABiosciences).Thapsigargin treatment increased (> 2-fold up-regulation) expression of 15 UPR genes in cultured type I cells and 22 genes in Results: type II pneumocytes, including the canonical UPR effectors i.e., the chaperones, GRP78, calreticulin and calnexin; the foldase phosphodiesterase isomerase (PDI); and the apoptosis-inducing transcription factor, CHOP. In contrast to thapsigargin-treated pneumocytes, GRP78, calnexin, calreticulin, and PDI mRNA levels were similar in lung tissue obtained from all 3 GOLD groups. However, CHOP mRNA was increased 1.8 fold in the GOLD 2 group compared to GOLD 0 and GOLD 4. This increase was validated (p<0.02 by ANOVA) by RT-PCR of all individual samples.These data indicate that a canonical UPR can be induced in vitro in human pneumocytes. In contrast, a UPR does not seem to Conclusion: occur in the lungs of subjects with advanced COPD. Failure to express a classic UPR chaperone response may contribute to heightened ER stress, CHOP up-regulation and pneumocyte apoptosis in COPD.