Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis
Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, ref...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/7/1642 |
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| author | Pawan Sharma Javad Alizadeh Maya Juarez Afshin Samali Andrew J. Halayko Nicholas J. Kenyon Saeid Ghavami Amir A. Zeki |
| author_facet | Pawan Sharma Javad Alizadeh Maya Juarez Afshin Samali Andrew J. Halayko Nicholas J. Kenyon Saeid Ghavami Amir A. Zeki |
| author_sort | Pawan Sharma |
| collection | DOAJ |
| description | Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3β) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject’s lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3β puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3β puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar–capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3β puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3β puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF. |
| first_indexed | 2024-03-10T09:56:04Z |
| format | Article |
| id | doaj.art-b79c494bc31f4572b77059e31128d56c |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T09:56:04Z |
| publishDate | 2021-06-01 |
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| series | Cells |
| spelling | doaj.art-b79c494bc31f4572b77059e31128d56c2023-11-22T02:22:52ZengMDPI AGCells2073-44092021-06-01107164210.3390/cells10071642Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary FibrosisPawan Sharma0Javad Alizadeh1Maya Juarez2Afshin Samali3Andrew J. Halayko4Nicholas J. Kenyon5Saeid Ghavami6Amir A. Zeki7Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, CanadaDavis Lung Center, School of Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, Davis, CA 95616, USAApoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, IrelandDepartment of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, CanadaDavis Lung Center, School of Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, Davis, CA 95616, USADepartment of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, CanadaDavis Lung Center, School of Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, Davis, CA 95616, USAAutophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3β) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject’s lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3β puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3β puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar–capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3β puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3β puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF.https://www.mdpi.com/2073-4409/10/7/1642unfolded protein responseendoplasmic reticulum stressautophagyapoptosisidiopathic pulmonary fibrosislung fibrosis |
| spellingShingle | Pawan Sharma Javad Alizadeh Maya Juarez Afshin Samali Andrew J. Halayko Nicholas J. Kenyon Saeid Ghavami Amir A. Zeki Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis Cells unfolded protein response endoplasmic reticulum stress autophagy apoptosis idiopathic pulmonary fibrosis lung fibrosis |
| title | Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis |
| title_full | Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis |
| title_fullStr | Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis |
| title_full_unstemmed | Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis |
| title_short | Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis |
| title_sort | autophagy apoptosis the unfolded protein response and lung function in idiopathic pulmonary fibrosis |
| topic | unfolded protein response endoplasmic reticulum stress autophagy apoptosis idiopathic pulmonary fibrosis lung fibrosis |
| url | https://www.mdpi.com/2073-4409/10/7/1642 |
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