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Endoplasmic reticulum stress and pulmonary fibrosis

Ehab A Ayaub, Philipp S Kolb, Zahraa Mohammed-Ali, Victor Tat, James Murphy, Pierre-Simon Bellaye, Chiko Shimbori, Felix J Boivin, Rocky Lai, Edward G Lynn, Šárka Lhoták, Darren Bridgewater, Martin Rj Kolb, Mark D Inman, Jeffrey G Dickhout, Richard C Austin, Kjetil Ask
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been associated with fibrotic lung disease, although exactly how they modulate this process remains unclear. Here we investigated the role of GRP78, the main UPR regulator, in an experimental model of lung injury and fibrosis. Grp78(+/-) , Chop(-/-) and wild type C57BL6/J mice were exposed to bleomycin by oropharyngeal intubation and lungs were examined at days 7 and 21. We demonstrate here that Grp78(+/-) mice were strongly protected from bleomycin-induced fibrosis, as shown by immunohistochemical analysis, collagen content and lung function measurements...
August 2016: Journal of Pathology
Yingying Yao, Yi Wang, Zhijun Zhang, Long He, Jianghui Zhu, Meng Zhang, Xiaoyu He, Zhenshun Cheng, Qilin Ao, Yong Cao, Ping Yang, Yunchao Su, Jianping Zhao, Shu Zhang, Qilin Yu, Qin Ning, Xudong Xiang, Weining Xiong, Cong-Yi Wang, Yongjian Xu
C/EBP homologous protein (Chop) has been shown to have altered expression in patients with idiopathic pulmonary fibrosis (IPF), but its exact role in IPF pathoaetiology has not been fully addressed. Studies conducted in patients with IPF and Chop(-/-) mice have dissected the role of Chop and endoplasmic reticulum (ER) stress in pulmonary fibrosis pathogenesis. The effect of Chop deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis were affected by the altered Chop expression and ER stress...
May 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Christopher J Winters, Olha Koval, Shubha Murthy, Chantal Allamargot, Sara C Sebag, John D Paschke, Omar A Jaffer, A Brent Carter, Isabella M Grumbach
The calcium and calmodulin-dependent kinase II (CaMKII) translates increases in intracellular Ca(2+) into downstream signaling events. Its function in pulmonary pathologies remains largely unknown. CaMKII is a well-known mediator of apoptosis and regulator of endoplasmic reticulum (ER) Ca(2+). ER stress and apoptosis of type II pneumocytes lead to aberrant tissue repair and progressive collagen deposition in pulmonary fibrosis. Thus we hypothesized that CaMKII inhibition alleviates fibrosis in response to bleomycin by attenuating apoptosis and ER stress of type II pneumocytes...
January 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
Martina Korfei, Sylwia Skwarna, Ingrid Henneke, BreAnne MacKenzie, Oleksiy Klymenko, Shigeki Saito, Clemens Ruppert, Daniel von der Beck, Poornima Mahavadi, Walter Klepetko, Saverio Bellusci, Bruno Crestani, Soni Savai Pullamsetti, Ludger Fink, Werner Seeger, Oliver Holger Krämer, Andreas Guenther
BACKGROUND: Activation and differentiation of fibroblasts into contractile protein-expressing myofibroblasts and their acquired apoptosis-resistant phenotype are critical factors towards the development of idiopathic pulmonary fibrosis (IPF), a fatal disease characterised by distorted pulmonary structure and excessive extracellular matrix (ECM) deposition. The molecular mechanisms underlying these processes in IPF remain incompletely understood. We investigated the possible implication of aberrant overexpression and activity of histone deacetylases (HDACs) in IPF...
November 2015: Thorax
Surafel Mulugeta, Shin-Ichi Nureki, Michael F Beers
Dating back nearly 35 years ago to the Witschi hypothesis, epithelial cell dysfunction and abnormal wound healing have reemerged as central concepts in the pathophysiology of idiopathic pulmonary fibrosis (IPF) in adults and in interstitial lung disease in children. Alveolar type 2 (AT2) cells represent a metabolically active compartment in the distal air spaces responsible for pulmonary surfactant biosynthesis and function as a progenitor population required for maintenance of alveolar integrity. Rare mutations in surfactant system components have provided new clues to understanding broader questions regarding the role of AT2 cell dysfunction in the pathophysiology of fibrotic lung diseases...
September 15, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
Emily F A van 't Wout, Annemarie van Schadewijk, Ria van Boxtel, Lucy E Dalton, Hanna J Clarke, Jan Tommassen, Stefan J Marciniak, Pieter S Hiemstra
Pseudomonas aeruginosa infection can be disastrous in chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. Its toxic effects are largely mediated by secreted virulence factors including pyocyanin, elastase and alkaline protease (AprA). Efficient functioning of the endoplasmic reticulum (ER) is crucial for cell survival and appropriate immune responses, while an excess of unfolded proteins within the ER leads to "ER stress" and activation of the "unfolded protein response" (UPR)...
June 2015: PLoS Pathogens
Xiao-Ting Mo, Wen-Cheng Zhou, Wen-Hui Cui, De-Lin Li, Liu-Cheng Li, Liang Xu, Ping Zhao, Jian Gao
Epithelial-mesenchymal transition (EMT) is a complex biological program during which cells loss epithelial phenotype and acquire mesenchymal features. EMT is thought to be involved in the pathogenesis of various fibrotic diseases including pulmonary fibrosis (PF). Recent studies suggest that endoplasmic reticulum (ER) stress is associated with EMT in the progression of PF. However, the exact mechanism is unclear. Here, we developed a PF model with bleomycin (BLM) administration in rats and conducted several simulation experiments in alveolar epithelial cell (AECs) RLE-6TN to unravel the role of inositol-requiring protein 1 (IRE1) - X-box-binding protein 1 (XBP1) signal pathway in ER stress-induced EMT in PF...
August 2015: International Journal of Biochemistry & Cell Biology
Claudia A Staab-Weijnitz, Isis E Fernandez, Larissa Knüppel, Julia Maul, Katharina Heinzelmann, Brenda M Juan-Guardela, Elisabeth Hennen, Gerhard Preissler, Hauke Winter, Claus Neurohr, Rudolf Hatz, Michael Lindner, Jürgen Behr, Naftali Kaminski, Oliver Eickelberg
RATIONALE: Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta). OBJECTIVES: To assess the expression and function of FKBP10 in IPF. METHODS: We assessed FKBP10 expression in bleomycin-induced lung fibrosis (using quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U...
August 15, 2015: American Journal of Respiratory and Critical Care Medicine
Yuta Tanaka, Yoichi Ishitsuka, Marina Hayasaka, Yusei Yamada, Keishi Miyata, Motoyoshi Endo, Yuki Kondo, Hiroshi Moriuchi, Mitsuru Irikura, Ken-ichiro Tanaka, Tohru Mizushima, Yuichi Oike, Tetsumi Irie
The purpose of this study was to evaluate the role of CCAAT/enhancer-binding protein homologous protein (CHOP), an important transcription factor that regulates the inflammatory reaction during the endoplasmic reticulum (ER) stress response, in the development of pulmonary fibrosis induced by bleomycin (BLM) in mice. An intratracheal injection of BLM transiently increased the expression of CHOP mRNA and protein in an early phase (days 1 and 3) in mice lungs. BLM-induced pulmonary fibrosis was significantly attenuated in Chop gene deficient (Chop KO) mice, compared with wild-type (WT) mice...
September 2015: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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No abstract text is available yet for this article.
2015: PloS One
So Ri Kim, Yong Chul Lee
The endoplasmic reticulum (ER) is a specialized organelle that plays a central role in biosynthesis, correct protein folding, and posttranslational modifications of secretory and membrane proteins. Loss of homeostasis in ER functions triggers the ER stress response, resulting in activation of unfolded protein response (UPR), a hallmark of many inflammatory diseases. These pathways have been reported as critical players in the pathogenesis of various pulmonary disorders, including pulmonary fibrosis, lung injury, and chronic airway disorders...
March 2015: Allergy, Asthma & Immunology Research
Wanda K O'Neal, Paul Gallins, Rhonda G Pace, Hong Dang, Whitney E Wolf, Lisa C Jones, XueLiang Guo, Yi-Hui Zhou, Vered Madar, Jinyan Huang, Liming Liang, Miriam F Moffatt, Garry R Cutting, Mitchell L Drumm, Johanna M Rommens, Lisa J Strug, Wei Sun, Jaclyn R Stonebraker, Fred A Wright, Michael R Knowles
Variation in cystic fibrosis (CF) phenotypes, including lung disease severity, age of onset of persistent Pseudomonas aeruginosa (P. aeruginosa) lung infection, and presence of meconium ileus (MI), has been partially explained by genome-wide association studies (GWASs). It is not expected that GWASs alone are sufficiently powered to uncover all heritable traits associated with CF phenotypic diversity. Therefore, we utilized gene expression association from lymphoblastoid cells lines from 754 p.Phe508del CF-affected homozygous individuals to identify genes and pathways...
February 5, 2015: American Journal of Human Genetics
Marta Bueno, Yen-Chun Lai, Yair Romero, Judith Brands, Claudette M St Croix, Christelle Kamga, Catherine Corey, Jose D Herazo-Maya, John Sembrat, Janet S Lee, Steve R Duncan, Mauricio Rojas, Sruti Shiva, Charleen T Chu, Ana L Mora
Although aging is a known risk factor for idiopathic pulmonary fibrosis (IPF), the pathogenic mechanisms that underlie the effects of advancing age remain largely unexplained. Some age-related neurodegenerative diseases have an etiology that is related to mitochondrial dysfunction. Here, we found that alveolar type II cells (AECIIs) in the lungs of IPF patients exhibit marked accumulation of dysmorphic and dysfunctional mitochondria. These mitochondrial abnormalities in AECIIs of IPF lungs were associated with upregulation of ER stress markers and were recapitulated in normal mice with advancing age in response to stimulation of ER stress...
February 2015: Journal of Clinical Investigation
Hui Zhao, Hou-Ying Qin, Lin-Feng Cao, Yuan-Hua Chen, Zhu-Xia Tan, Cheng Zhang, De-Xiang Xu
A recent report showed that unfolded protein response (UPR) signaling was activated during bleomycin (BLM)-induced pulmonary fibrosis. Phenylbutyric acid (PBA) is an endoplasmic reticulum (ER) chemical chaperone that inhibits the UPR signaling. The present study investigated the effects of PBA on BLM-induced epithelial-mesenchymal transition (EMT) and pulmonary fibrosis. For induction of pulmonary fibrosis, all mice except controls were intratracheally injected with a single dose of BLM (3.0mg/kg). In PBA+BLM group, mice were intraperitoneally injected with PBA (150mg/kg) daily...
January 5, 2015: Toxicology Letters
Manabu Ono, Shinya Ohkouchi, Masahiko Kanehira, Naoki Tode, Makoto Kobayashi, Masahito Ebina, Toshihiro Nukiwa, Toshiya Irokawa, Hiromasa Ogawa, Takaaki Akaike, Yoshinori Okada, Hajime Kurosawa, Toshiaki Kikuchi, Masakazu Ichinose
Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In these hypotheses, continuous TGF-β1 secretion by alveolar epithelial cells (AECs) in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells (MSCs) home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in IPF. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 (Stanniocalcin-1) secretion in a bleomycin-induced IPF model...
March 2015: Molecular Therapy: the Journal of the American Society of Gene Therapy
Fukami Nakajima, Satoko Aratani, Hidetoshi Fujita, Naoko Yagishita, Shizuko Ichinose, Koshi Makita, Yasuhiro Setoguchi, Toshihiro Nakajima
The deletion mutation of exon 4 in surfactant protein C (SP-C), a lung surfactant protein, has been identified in parent-child cases of familial interstitial pneumonia. It has been shown that this mutation induces endoplasmic reticulum (ER) stress. Synoviolin is an E3 ubiquitin ligase that is localized to the ER and is an important factor in the degradation of ER-related proteins. It has been demonstrated that synoviolin is involved in liver fibrosis. In the present study, we investigated the involvement of synoviolin in the pathogenesis of interstitial pneumonia caused by the exon 4 deletion in the SP-C gene...
January 2015: International Journal of Molecular Medicine
Alan J Ryan, Jennifer L Larson-Casey, Chao He, Shuhba Murthy, A Brent Carter
Although the mechanisms for fibrosis development remain largely unknown, recent evidence indicates that endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) may act as an important fibrotic stimulus in diseased lungs. ER stress is observed in lungs of patients with idiopathic pulmonary fibrosis. In this study we evaluated if ER stress and the UPR was present in macrophages exposed to chrysotile asbestos and if ER stress in macrophages was associated with asbestos-induced pulmonary fibrosis...
November 28, 2014: Journal of Biological Chemistry
Elisabetta Renzoni, Veeraraghavan Srihari, Piersante Sestini
Idiopathic pulmonary fibrosis (IPF) is likely to result from the interaction between environmental exposures, including cigarette smoke, and genetic predisposition. This review focuses on clues provided by recent genetic association studies and other selected data and hypotheses. In IPF, association with surfactant mutations has highlighted the importance of type II epithelial cells, while shortened telomeres in some patients suggest that accelerated aging may play a role in the pathogenesis of lung fibrosis, possibly by affecting the renewal/differentiation potential of epithelial cells...
2014: F1000Prime Reports
Poornima Mahavadi, Ingrid Henneke, Clemens Ruppert, Lars Knudsen, Shalini Venkatesan, Gerhard Liebisch, Rachel C Chambers, Matthias Ochs, Gerd Schmitz, Carlo Vancheri, Werner Seeger, Martina Korfei, Andreas Guenther
Amiodarone (AD) is a highly efficient antiarrhythmic drug with potentially serious side effects. Severe pulmonary toxicity is reported in patients receiving AD even at low doses and may cause interstitial pneumonia as well as lung fibrosis. Apoptosis of alveolar epithelial type II cells (AECII) has been suggested to play an important role in this disease. In the current study, we aimed to establish a murine model of AD-induced lung fibrosis and analyze surfactant homeostasis, lysosomal, and endoplasmic reticulum (ER) stress in this model...
November 2014: Toxicological Sciences: An Official Journal of the Society of Toxicology
Jaume Aguero, Kiyotake Ishikawa, Lahouaria Hadri, Carlos Santos-Gallego, Kenneth Fish, Nadjib Hammoudi, Antoine Chaanine, Samantha Torquato, Charbel Naim, Borja Ibanez, Daniel Pereda, Ana García-Alvarez, Valentin Fuster, Partho P Sengupta, Jane A Leopold, Roger J Hajjar
In pulmonary hypertension (PH), right ventricular (RV) dysfunction and failure is the main determinant of a poor prognosis. We aimed to characterize RV structural and functional differences during adaptive RV remodeling and progression to RV failure in a large animal model of chronic PH. Postcapillary PH was created surgically in swine (n = 21). After an 8- to 14-wk follow-up, two groups were identified based on the development of overt heart failure (HF): PH-NF (nonfailing, n = 12) and PH-HF (n = 8). In both groups, invasive hemodynamics, pressure-volume relationships, and echocardiography confirmed a significant increase in pulmonary pressures and vascular resistance consistent with PH...
October 15, 2014: American Journal of Physiology. Heart and Circulatory Physiology
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