Role of unfolded proteins in lung disease DOI Creative Commons

Kirsty L. Bradley,

Clare Stokes, Stefan J. Marciniak

et al.

Thorax, Journal Year: 2020, Volume and Issue: 76(1), P. 92 - 99

Published: Oct. 19, 2020

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

Language: Английский

Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis DOI
B.J. Moss, Stefan W. Ryter, Iván O. Rosas

et al.

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2021, Volume and Issue: 17(1), P. 515 - 546

Published: Nov. 23, 2021

The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay cell types and signaling pathways. Recurrent alveolar epithelial (AEC) injury may occur in the context predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, gerontologic), leading to metabolic dysfunction, senescence, aberrant activation, dysregulated repair. interacts with mesenchymal, immune, endothelial cells via multiple mechanisms trigger fibroblast myofibroblast activation. Recent single-cell RNA sequencing studies IPF lungs support model. These have uncovered novel type AEC characteristics an basal cell, which disrupt normal repair propagate profibrotic phenotype. Here, we review bioinformatics tools as strategies discover pathways disease, cell-specific mechanisms, cell-cell interactions that niche.

Language: Английский

Citations

438
Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis DOI
Changfu Yao,

Xiangrong Guan,

Gianni Carraro

et al.

American Journal of Respiratory and Critical Care Medicine, Journal Year: 2020, Volume and Issue: 203(6), P. 707 - 717

Published: Sept. 29, 2020

Rationale: Idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining function. Accelerated aging, loss of epithelial progenitor cell function and/or numbers, cellular senescence are implicated in the pathogenies IPF. Objectives: We sought to investigate role alveolar type 2 (AT2) initiation progression therapeutic potential targeting senescence-related pathways senescent cells. Methods: Epithelial cells 9 control donor proximal distal tissues 11 IPF fibrotic were profiled by single-cell RNA sequencing assesses contribution fraction for A novel mouse model conditional AT2 was generated study fibrosis. Measurements Main Results: show that isolated from tissue exhibit characteristic transcriptomic features senescence. used Sin3a adult initiate a program p53-dependent senescence, depletion, spontaneous, progressive establish rather than promotes either genetic or pharmacologic interventions p53 activation block fibrogenesis. Conclusions: Senescence sufficient drive Early attenuation elimination promising approaches prevent

Language: Английский

Citations

346
The aging lung: Physiology, disease, and immunity DOI Creative Commons
Jaime L. Schneider, Jared H. Rowe, Carolina García de Alba

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(8), P. 1990 - 2019

Published: April 1, 2021

Language: Английский

Citations

312
Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis DOI Open Access
Tanyalak Parimon, Changfu Yao, Barry R. Stripp

et al.

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(7), P. 2269 - 2269

Published: March 25, 2020

: Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment their normal functional capacity development of pro-fibrotic phenotype has been demonstrated contribute idiopathic pulmonary fibrosis (IPF). A number factors AT2 death dysfunction. As mucosal surface, exposed environmental stresses can lasting effects fibrogenesis. Genetical risks also identified cause fibrosis. Furthermore, aging is final factor adds pathogenic changes cells. Here, we will discuss homeostatic role studies recently defined heterogeneity this review mechanisms dysfunction context

Language: Английский

Citations

289
Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis DOI Creative Commons

Qianru Mei,

Zhe Liu,

He Zuo

et al.

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 12

Published: Jan. 19, 2022

Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal fibrotic lung disease that occurs primarily in middle-aged and elderly adults. It major cause of morbidity mortality. With an increase life expectancy, the economic burden IPF expected to continuously rise near future. Although exact pathophysiological mechanisms underlying remain not known. Significant progress has been made our understanding pathogenesis this devastating last decade. The current paradigm assumes results from sustained or repetitive epithelial injury subsequent activation fibroblasts myofibroblast differentiation. Persistent phenotype contributes excessive deposition extracellular matrix (ECM) aberrant repair, leading tissue scar formation, distortion alveolar structure, irreversible loss function. Treatments patients with by pirfenidone nintedanib have shown significant reduction function decline slowing progression IPF. However, these drugs do cure disease. In review, we discuss recent advances on highlight development novel therapeutic strategies against

Language: Английский

Citations

219
The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling DOI Creative Commons
Kashi Raj Bhattarai, Thoufiqul Alam Riaz, Hyung‐Ryong Kim

et al.

Experimental & Molecular Medicine, Journal Year: 2021, Volume and Issue: 53(2), P. 151 - 167

Published: Feb. 1, 2021

Abstract The endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper folding, modification, and the transportation synthesized proteins. Any perturbations in ER function, such as increased demand for folding or accumulation unfolded misfolded proteins lumen, lead to a stress response called (UPR). primary aim UPR restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. core mechanisms response, failure respond stress, final fate cell are not yet clear. Here, we discuss cross talk between mitochondria its significance, conditions that can trigger failure. We also describe how redox environment affects vice versa, aftermath integrating discussion on imbalance-induced progressing death dynamic pathophysiological changes.

Language: Английский

Citations

196
Contributions of alveolar epithelial cell quality control to pulmonary fibrosis DOI Open Access
Jeremy Katzen, Michael F. Beers

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(10), P. 5088 - 5099

Published: Sept. 1, 2020

Epithelial cell dysfunction has emerged as a central component of the pathophysiology diffuse parenchymal diseases including idiopathic pulmonary fibrosis (IPF). Alveolar type 2 (AT2) cells represent metabolically active lung population important for surfactant biosynthesis and alveolar homeostasis. AT2 other distal epithelia, like all eukaryotic cells, contain an elegant quality control network to respond intrinsic metabolic biosynthetic challenges imparted by mutant protein conformers, dysfunctional subcellular organelles, dysregulated telomeres. Failed components (the ubiquitin-proteasome system, unfolded response, macroautophagy, mitophagy, telomere maintenance) result in diverse cellular endophenotypes molecular signatures ER stress, defective autophagy, mitochondrial dysfunction, apoptosis, inflammatory recruitment, profibrotic signaling, altered progenitor function that ultimately converge drive downstream fibrotic remodeling IPF lung. As this complex becomes increasingly better understood, opportunities will emerge identify targets therapeutic strategies IPF.

Language: Английский

Citations

190
Regulation of epithelial transitional states in murine and human pulmonary fibrosis DOI Creative Commons
Fa Wang,

Christopher Ting,

Kent Riemondy

et al.

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(22)

Published: Sept. 28, 2023

Idiopathic Pulmonary Fibrosis (IPF) is a progressive scarring disease arising from impaired regeneration of the alveolar epithelium after injury. During regeneration, type 2 epithelial cells (AEC2s) assume transitional state that upregulates multiple keratins, and ultimately differentiate into AEC1s. In IPF, AECs accumulate with ineffectual AEC1 differentiation. However, whether how cause fibrosis, keratins regulate cell accumulation why fibrosis resolve in mouse models but IPF are unclear. Here, we show human keratin (KRT) 8 genetic variants associated IPF. Krt8-/- mice protected state. Keratin (K) regulates expression macrophage chemokines recruitment. Profibrotic macrophages myofibroblasts promote AECs, establishing K8-dependent positive feedback loop driving fibrogenesis. Finally, rare murine highly senescent, basaloid, do not AEC1s, recapitulating aberrant basaloid We conclude induce maintained by manner; mice, most resolve, whereas evolve an which persists fibrosis.

Language: Английский

Citations

60
Current and Future Treatment Landscape for Idiopathic Pulmonary Fibrosis DOI Creative Commons
Francesco Bonella, Paolo Spagnolo,

C.J. Ryerson

et al.

Drugs, Journal Year: 2023, Volume and Issue: 83(17), P. 1581 - 1593

Published: Oct. 26, 2023

Idiopathic pulmonary fibrosis (IPF) remains a disease with poor survival. The pathogenesis is complex and encompasses multiple molecular pathways. first-generation antifibrotics pirfenidone nintedanib, approved more than 10 years ago, have been shown to reduce the rate of progression, increase length life for patients IPF, work other fibrotic lung diseases. In last two decades, most clinical trials on IPF failed meet primary endpoint an urgent unmet need identify agents or treatment strategies that can stop progression. pharmacotherapeutic landscape moving forward number new drugs currently in development, mostly phase I II trials, while only few III are running. Since our understanding still limited, we should keep focusing efforts deeper understand mechanisms underlying this their reflection phenotypes. This review discusses key pathogenetic concepts development antifibrotic agents, presents newest data therapies, summarizes compounds development. Finally, future directions discussed.

Language: Английский

Citations

57
Polystyrene nanoplastics-induced lung apoptosis and ferroptosis via ROS-dependent endoplasmic reticulum stress DOI
Qiumei Wu, Chao Liu, Dan Liu

et al.

The Science of The Total Environment, Journal Year: 2023, Volume and Issue: 912, P. 169260 - 169260

Published: Dec. 10, 2023

Language: Английский

Citations

45