Role of unfolded proteins in lung disease

Our plain-English summary of Role of unfolded proteins in lung disease, by K.L. Bradley, C.A. Stokes, S.J. Marciniak, et al (Thorax, 2021).

The study

• Authors: K.L. Bradley, C.A. Stokes, S.J. Marciniak, L.C. Parker, A.M. Condliffe
• Journal: Thorax
• Published: 2021;76(1):92-99
• Type of article: Review
• Cited by: 53 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The lungs are exposed to a range of environmental toxins (including cigarette smoke, air pollution, asbestos) and pathogens (bacterial, viral and fungal), and most respiratory diseases are associated with local or systemic hypoxia. All of these adverse factors can trigger endoplasmic reticulum (ER) stress. The ER is a key intracellular site for synthesis of secretory and membrane proteins, regulating their folding, assembly into complexes, transport and degradation. Accumulation of misfolded proteins within the lumen results in ER stress, which activates the unfolded protein response (UPR). Effectors of the UPR temporarily reduce protein synthesis, while enhancing degradation of misfolded proteins and increasing the folding capacity of the ER. If successful, homeostasis is restored and protein synthesis resumes, but if ER stress persists, cell death pathways are activated. ER stress and the resulting UPR occur in a range of pulmonary insults and the outcome plays an important role in many respiratory diseases. The UPR is triggered in the airway of patients with several respiratory diseases and in corresponding experimental models. ER stress has been implicated in the initiation and progression of pulmonary fibrosis, and evidence is accumulating suggesting that ER stress occurs in obstructive lung diseases (particularly in asthma), in pulmonary infections (some viral infections and in the setting of the cystic fibrosis airway) and in lung cancer. While a number of small molecule inhibitors have been used to interrogate the role of the UPR in disease models, many of these tools have complex and off-target effects, hence additional evidence (eg, from genetic manipulation) may be required to support conclusions based on the impact of such pharmacological agents. Aberrant activation of the UPR may be linked to disease pathogenesis and progression, but at present, our understanding of the context-specific and disease-specific mechanisms linking these processes is incomplete. Despite this, the ability of the UPR to defend against ER stress and influence a range of respiratory diseases is becoming increasingly evident, and the UPR is therefore attracting attention as a prospective target for therapeutic intervention strategies.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This "state of the art review" reports no new data of its own. It describes research on endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), a cell's reaction to misfolded proteins, in lung disease. Reviewed triggers included cigarette smoke, particulate matter, asbestos, infections and low oxygen. Reviewed diseases included pulmonary fibrosis, asthma, COPD, cystic fibrosis and lung cancer. On asbestos, the reviewed studies reported three things. First, asbestos-treated A549 lung cancer-derived cells and rat airway cells showed increased IRE1 and XBP1s mRNA and, to a lesser extent, protein. The authors said IRE1 and PERK protein is hard to detect directly, and that the minor changes reported should be interpreted with caution. Second, higher CHOP in human mesothelioma tissue independently predicted poor survival; the mechanism is uncertain. Third, UPR signs were found in macrophages exposed to asbestos in vitro, and in alveolar macrophages of asbestos-exposed mice and of humans with asbestosis. The authors concluded that many respiratory insults are associated with ER stress, but causality cannot be assumed. They noted that reports of UPR activation in fibrotic conditions other than idiopathic pulmonary fibrosis (IPF), including the asbestos findings, are limited in number. They also noted that many small-molecule tools have complex, off-target effects.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review ("state of the art review") of published laboratory, animal and human studies; no new data
• Who was studied: Published studies in patient-derived lung tissue, cell cultures and animal models; the article gives no search method or count of studies reviewed
• Exposure: Triggers of ER stress relevant to lung disease, including cigarette smoke, particulate matter, asbestos (fiber type not specified), bacterial, fungal and viral pathogens, and hypoxia
• Main results:
  • Reviewed study: treating A549 lung adenocarcinoma-derived cells and rat primary airway epithelial cells with asbestos increased IRE1 and XBP1s mRNAs, and to a lesser extent proteins. The authors noted that direct detection of IRE1 and PERK protein is challenging and that the minor changes reported should be interpreted with caution.
  • Reviewed study: increased expression of CHOP in human mesothelioma tissue was an independent predictor of poor survival; the authors said the mechanism of this association is uncertain.
  • Reviewed study: UPR was detected in macrophages exposed to asbestos in vitro, and in the alveolar macrophages of mice exposed to asbestos and of humans with asbestosis.
  • Reviewed studies in cystic fibrosis: UPR induction in CF airway epithelia was described as likely secondary to infection rather than to CFTR misfolding.
• The authors' conclusion: The authors concluded that many respiratory insults are associated with ER stress, but causality cannot be assumed. In their view, there is reasonable evidence for a causal role only in a restricted range of lung diseases, such as familial and perhaps sporadic IPF, infection in CF and treatment-resistance in certain lung cancers.
• Limitations the authors state:
  • Most studies have focused on IPF. Reports of UPR activation in other pulmonary fibrotic conditions, including the asbestos studies, are limited in number.
  • Many of the small-molecule tools used to study the UPR have complex and off-target effects.
  • Genetic models may give more definitive mechanistic insights than poorly characterised small-molecule inhibitors.
  • Direct detection of IRE1 and PERK protein is challenging.

Topics

Medical terms in this study, explained in our Lexicon: Hypoxia, Pulmonary Fibrosis, Obstructive Lung Disease, Fibrosis, Lung Cancer.

Related studies

• Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma — D. Xu, S.Q. Liang, et al. (2018)
• A protein kinase Cdelta-dependent protein kinase D pathway modulates ERK1/2 and JNK1/2 phosphorylation and Bim-associated apoptosis by asbestos — S.A. Buder-Hoffmann, A. Shukla, et al. (2009)
• Asbestos-induced alveolar epithelial cell apoptosis. The role of endoplasmic reticulum stress response — D.W. Kamp, G. Liu, et al. (2013)
• Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1) — U. Petrausch, P.C. Schuberth, et al. (2012)
• HEG1 is a novel mucin-like membrane protein that serves as a diagnostic and therapeutic target for malignant mesothelioma — S. Tsuji, K. Washimi, et al. (2017)
• Asbestos-induced peribronchiolar cell proliferation and cytokine production are attenuated in lungs of protein kinase C-delta knockout mice — A. Shukla, K.M. Lounsbury, et al. (2007)

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