RATIONALE: The molecular pathomechanisms underlying idiopathic pulmonary fibrosis (IPF) are elusive, but chronic epithelial injury has recently been suggested as key event. OBJECTIVES: We investigated the possible implication of endoplasmic reticulum (ER) stress-mediated apoptosis in sporadic IPF. METHODS: We analyzed peripheral explanted lung tissues from patients with sporadic IPF (n = 24), chronic obstructive pulmonary disease (COPD) (n = 9), and organ donors (n = 12) for expression of major ER stress mediators and apoptosis markers by means of immunoblotting, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and the TUNEL method. MEASUREMENTS AND MAIN RESULTS: Compared with COPD and donor lungs, protein levels of ER stress mediators, such as processed p50 activating transcription factor (ATF)-6 and ATF-4 and the apoptosis-inductor CHOP (C/EBP-homologous protein), as well as transcript levels of spliced X-box binding protein (XBP)-1, were significantly elevated in lung homogenates and type II alveolar epithelial cells (AECIIs) of IPF lungs. Proapoptotic, oligomeric forms of Bax, which play a key role in ER stress-mediated apoptosis downstream of CHOP induction, as well as caspase-3 cleavage, could be detected in IPF lungs. By means of immunohistochemistry, exclusive induction of active ATF-6, ATF-4, and CHOP in AECIIs was encountered in IPF but not in COPD or donor lungs. Immunoreactivity was most prominent in the epithelium near dense zones of fibrosis and fibroblast foci, where these ER stress markers colocalized with markers of apoptosis (TUNEL, cleaved caspase-3). CONCLUSIONS: Severe ER stress response in the AECIIs of patients with sporadic IPF may underlie the apoptosis of this cell type and development of fibrosis in this disease.
RATIONALE: The molecular pathomechanisms underlying idiopathic pulmonary fibrosis (IPF) are elusive, but chronic epithelial injury has recently been suggested as key event. OBJECTIVES: We investigated the possible implication of endoplasmic reticulum (ER) stress-mediated apoptosis in sporadic IPF. METHODS: We analyzed peripheral explanted lung tissues from patients with sporadic IPF (n = 24), chronic obstructive pulmonary disease (COPD) (n = 9), and organ donors (n = 12) for expression of major ER stress mediators and apoptosis markers by means of immunoblotting, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and the TUNEL method. MEASUREMENTS AND MAIN RESULTS: Compared with COPD and donor lungs, protein levels of ER stress mediators, such as processed p50 activating transcription factor (ATF)-6 and ATF-4 and the apoptosis-inductor CHOP (C/EBP-homologous protein), as well as transcript levels of spliced X-box binding protein (XBP)-1, were significantly elevated in lung homogenates and type II alveolar epithelial cells (AECIIs) of IPF lungs. Proapoptotic, oligomeric forms of Bax, which play a key role in ER stress-mediated apoptosis downstream of CHOP induction, as well as caspase-3 cleavage, could be detected in IPF lungs. By means of immunohistochemistry, exclusive induction of active ATF-6, ATF-4, and CHOP in AECIIs was encountered in IPF but not in COPD or donor lungs. Immunoreactivity was most prominent in the epithelium near dense zones of fibrosis and fibroblast foci, where these ER stress markers colocalized with markers of apoptosis (TUNEL, cleaved caspase-3). CONCLUSIONS: Severe ER stress response in the AECIIs of patients with sporadic IPF may underlie the apoptosis of this cell type and development of fibrosis in this disease.
Authors: Maurits Demedts; Juergen Behr; Roland Buhl; Ulrich Costabel; Richard Dekhuijzen; Henk M Jansen; William MacNee; Michiel Thomeer; Benoit Wallaert; François Laurent; Andrew G Nicholson; Eric K Verbeken; Johny Verschakelen; Christopher D R Flower; Frédérique Capron; Stefano Petruzzelli; Paul De Vuyst; Jules M M van den Bosch; Eulogio Rodriguez-Becerra; Giuseppina Corvasce; Ida Lankhorst; Marco Sardina; Mauro Montanari Journal: N Engl J Med Date: 2005-11-24 Impact factor: 91.245
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Authors: H Zinszner; M Kuroda; X Wang; N Batchvarova; R T Lightfoot; H Remotti; J L Stevens; D Ron Journal: Genes Dev Date: 1998-04-01 Impact factor: 11.361
Authors: Mary Y Armanios; Julian J-L Chen; Joy D Cogan; Jonathan K Alder; Roxann G Ingersoll; Cheryl Markin; William E Lawson; Mingyi Xie; Irma Vulto; John A Phillips; Peter M Lansdorp; Carol W Greider; James E Loyd Journal: N Engl J Med Date: 2007-03-29 Impact factor: 91.245
Authors: Jeffrey C Horowitz; Iyabode O Ajayi; Priya Kulasekaran; David S Rogers; Joshua B White; Sarah K Townsend; Eric S White; Richard S Nho; Peter D R Higgins; Steven K Huang; Thomas H Sisson Journal: Int J Biochem Cell Biol Date: 2011-10-25 Impact factor: 5.085
Authors: Iyabode O Ajayi; Thomas H Sisson; Peter D R Higgins; Adam J Booth; Rommel L Sagana; Steven K Huang; Eric S White; Jessie E King; Bethany B Moore; Jeffrey C Horowitz Journal: Am J Respir Cell Mol Biol Date: 2013-07 Impact factor: 6.914