scholarly journals Cellular Mechanisms of Tissue Fibrosis. 7. New insights into the cellular mechanisms of pulmonary fibrosis

2014 ◽  
Vol 306 (11) ◽  
pp. C987-C996 ◽  
Author(s):  
Christina E. Barkauskas ◽  
Paul W. Noble
Keyword(s):  
Gas Exchange ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Current Knowledge ◽  
Alveolar Epithelium ◽  
Scar Formation ◽  
Current Understanding ◽  
Cellular Mechanisms ◽  
Tissue Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by severe and progressive scar formation in the gas-exchange regions of the lung. Despite years of research, therapeutic treatments remain elusive and there is a pressing need for deeper mechanistic insights into the pathogenesis of the disease. In this article, we review our current knowledge of the triggers and/or perpetuators of pulmonary fibrosis with special emphasis on the alveolar epithelium and the underlying mesenchyme. In doing so, we raise a number of questions highlighting critical voids and limitations in our current understanding and study of this disease.

scholarly journals Insights Into Development and Progression of Idiopathic Pulmonary Fibrosis From Single Cell RNA Studies

2020 ◽  
Vol 7 ◽  
Author(s):  
Julia Nemeth ◽  
Annika Schundner ◽  
Manfred Frick
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Single Cell ◽  
Large Scale ◽  
Current Knowledge ◽  
Current Model ◽  
Alveolar Epithelium ◽  
Mesenchymal Cell ◽  
Alveolar Type ◽  
Sequencing Studies

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options. The current model suggests that chronic or repetitive “micro-injuries” of the alveolar epithelium lead to activation and proliferation of fibroblasts and excessive extracellular matrix (ECM) deposition. Disruption of alveolar type II (ATII) epithelial cell homeostasis and the characteristics of mesenchymal cell populations in IPF have received particular attention in recent years. Emerging data from single cell RNA sequencing (scRNAseq) analysis shed novel light on alterations in ATII cell progenitor dysfunction and the diversity of mesenchymal cells within the fibrotic lung. Within this minireview, we summarize the data from most recent human scRNAseq studies. We aim to collate the current knowledge on cellular plasticity and heterogeneity in the development and progression of IPF, effects of drug treatment on transcriptional changes. Finally, we provide a brief outlook on future challenges and promises for large scale sequencing studies in the development of novel therapeutics for IPF.

Cross-species integration of single-cell RNA-seq resolved alveolar-epithelial transitional states in idiopathic pulmonary fibrosis

2021 ◽  
Author(s):  
Kevin Y. Huang ◽  
Enrico Petretto
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Single Cell ◽  
Transitional Cell ◽  
Notch Pathway ◽  
Alveolar Epithelium ◽  
State Transitions ◽  
Specific Cell ◽  
Differentiation Process ◽  
Cell State

Single-cell transcriptomics analyses of the fibrotic lung uncovered two cell states critical to lung injury recovery in the alveolar epithelium- a reparative transitional cell state in the mouse and a disease-specific cell state (KRT5-/KRT17+) in human idiopathic pulmonary fibrosis (IPF). The murine transitional cell state lies between the differentiation from type 2 (AT2) to type 1 pneumocyte (AT1), and the human KRT5-/KRT17+ cell state may arise from the dysregulation of this differentiation process. We review major findings of single-cell transcriptomics analyses of the fibrotic lung and re-analyzed data from 7 single-cell RNA sequencing studies of human and murine models of IPF, focusing on the alveolar epithelium. Our comparative and cross-species single-cell transcriptomics analyses allowed us to further delineate the differentiation trajectories from AT2 to AT1 and AT2 to the KRT5-/KRT17+ cell state. We observed AT1 cells in human IPF retain the transcriptional signature of the murine transitional cell state. Using pseudotime analysis, we recapitulated the differentiation trajectories from AT2 to AT1 and from AT2 to KRT5-/KRT17+ cell state in multiple human IPF studies. We further delineated transcriptional programs underlying cell state transitions and determined the molecular phenotypes at terminal differentiation. We hypothesize that in addition to the reactivation of developmental programs (SOX4, SOX9), senescence (TP63, SOX4) and the Notch pathway (HES1) are predicted to steer intermediate progenitors to the KRT5-/KRT17+ cell state. Our analyses suggest that activation of SMAD3 later in the differentiation process may explain the fibrotic molecular phenotype typical of KRT5-/KRT17+ cells.

scholarly journals Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes?

2021 ◽  
Vol 12 ◽  
Author(s):  
Chiel van Geffen ◽  
Astrid Deißler ◽  
Markus Quante ◽  
Harald Renz ◽  
Dominik Hartl ◽  
...  
Keyword(s):  
Immune System ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Immune Responses ◽  
Immune Cells ◽  
Current Knowledge ◽  
Suppressor Cells ◽  
Interstitial Lung Diseases ◽  
Stromal Stem Cells

The immune system is receiving increasing attention for interstitial lung diseases, as knowledge on its role in fibrosis development and response to therapies is expanding. Uncontrolled immune responses and unbalanced injury-inflammation-repair processes drive the initiation and progression of idiopathic pulmonary fibrosis. The regulatory immune system plays important roles in controlling pathogenic immune responses, regulating inflammation and modulating the transition of inflammation to fibrosis. This review aims to summarize and critically discuss the current knowledge on the potential role of regulatory immune cells, including mesenchymal stromal/stem cells, regulatory T cells, regulatory B cells, macrophages, dendritic cells and myeloid-derived suppressor cells in idiopathic pulmonary fibrosis. Furthermore, we review the emerging role of regulatory immune cells in anti-fibrotic therapy and lung transplantation. A comprehensive understanding of immune regulation could pave the way towards new therapeutic or preventive approaches in idiopathic pulmonary fibrosis.

scholarly journals Epithelial–Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Medicina ◽  
2019 ◽  
Vol 55 (4) ◽  
pp. 83 ◽  
Author(s):  
Francesco Salton ◽  
Maria Volpe ◽  
Marco Confalonieri
Keyword(s):  
Epithelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Treatment Options ◽  
Alveolar Epithelium ◽  
Alveolar Epithelial Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Serious Disease

Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung, which leads to extensive parenchymal scarring and death from respiratory failure. The most accepted hypothesis for IPF pathogenesis relies on the inability of the alveolar epithelium to regenerate after injury. Alveolar epithelial cells become apoptotic and rare, fibroblasts/myofibroblasts accumulate and extracellular matrix (ECM) is deposited in response to the aberrant activation of several pathways that are physiologically implicated in alveologenesis and repair but also favor the creation of excessive fibrosis via different mechanisms, including epithelial–mesenchymal transition (EMT). EMT is a pathophysiological process in which epithelial cells lose part of their characteristics and markers, while gaining mesenchymal ones. A role for EMT in the pathogenesis of IPF has been widely hypothesized and indirectly demonstrated; however, precise definition of its mechanisms and relevance has been hindered by the lack of a reliable animal model and needs further studies. The overall available evidence conceptualizes EMT as an alternative cell and tissue normal regeneration, which could open the way to novel diagnostic and prognostic biomarkers, as well as to more effective treatment options.

scholarly journals Quantification of pulmonary perfusion in idiopathic pulmonary fibrosis with first pass dynamic contrast-enhanced perfusion MRI

Thorax ◽  
2020 ◽  
pp. thoraxjnl-2019-214375
Author(s):  
Nicholas D Weatherley ◽  
James A Eaden ◽  
Paul J C Hughes ◽  
Matthew Austin ◽  
Laurie Smith ◽  
...  
Keyword(s):  
Gas Exchange ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Pulmonary Function Tests ◽  
Pulmonary Vascular Disease ◽  
Bolus Transit ◽  
Dce Mri ◽  
Dynamic Contrast Enhanced ◽  
Contrast Enhanced ◽  
First Pass

IntroductionIdiopathic pulmonary fibrosis (IPF) is a fatal disease of lung scarring. Many patients later develop raised pulmonary vascular pressures, sometimes disproportionate to the interstitial disease. Previous therapeutic approaches that have targeted pulmonary vascular changes have not demonstrated clinical efficacy, and quantitative assessment of regional pulmonary vascular involvement using perfusion imaging may provide a biomarker for further therapeutic insights.MethodsWe studied 23 participants with IPF, using dynamic contrast-enhanced MRI (DCE-MRI) and pulmonary function tests, including forced vital capacity (FVC), transfer factor (TLCO) and coefficient (KCO) of the lungs for carbon monoxide. DCE-MRI parametric maps were generated including the full width at half maximum (FWHM) of the bolus transit time through the lungs. Key metrics used were mean (FWHMmean) and heterogeneity (FWHMIQR). Nineteen participants returned at 6 months for repeat assessment.ResultsSpearman correlation coefficients were identified between TLCO and FWHMIQR (r=−0.46; p=0.026), KCO and FWHMmean (r=−0.42; p=0.047) and KCO and FWHMIQR (r=−0.51; p=0.013) at baseline. No statistically significant correlations were seen between FVC and DCE-MRI metrics. Follow-up at 6 months demonstrated statistically significant decline in FVC (p=0.040) and KCO (p=0.014), with an increase in FWHMmean (p=0.040), but no significant changes in TLCO (p=0.090) nor FWHMIQR (p=0.821).ConclusionsDCE-MRI first pass perfusion demonstrates correlations with existing physiological gas exchange metrics, suggesting that capillary perfusion deficit (as well as impaired interstitial diffusion) may contribute to gas exchange limitation in IPF. FWHMmean showed a significant increase over a 6-month period and has potential as a quantitative biomarker of pulmonary vascular disease progression in IPF.

scholarly journals P2 Purinergic Signaling in the Distal Lung in Health and Disease

2020 ◽  
Vol 21 (14) ◽  
pp. 4973 ◽  
Author(s):  
Eva Wirsching ◽  
Michael Fauler ◽  
Giorgio Fois ◽  
Manfred Frick
Keyword(s):  
Gas Exchange ◽  
Pulmonary Fibrosis ◽  
Current Knowledge ◽  
Purinergic Signaling ◽  
Pulmonary Inflammation ◽  
P2 Receptors ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Health And Disease ◽  
Distal Lung

The distal lung provides an intricate structure for gas exchange in mammalian lungs. Efficient gas exchange depends on the functional integrity of lung alveoli. The cells in the alveolar tissue serve various functions to maintain alveolar structure, integrity and homeostasis. Alveolar epithelial cells secrete pulmonary surfactant, regulate the alveolar surface liquid (ASL) volume and, together with resident and infiltrating immune cells, provide a powerful host-defense system against a multitude of particles, microbes and toxicants. It is well established that all of these cells express purinergic P2 receptors and that purinergic signaling plays important roles in maintaining alveolar homeostasis. Therefore, it is not surprising that purinergic signaling also contributes to development and progression of severe pathological conditions like pulmonary inflammation, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pulmonary fibrosis. Within this review we focus on the role of P2 purinergic signaling in the distal lung in health and disease. We recapitulate the expression of P2 receptors within the cells in the alveoli, the possible sources of ATP (adenosine triphosphate) within alveoli and the contribution of purinergic signaling to regulation of surfactant secretion, ASL volume and composition, as well as immune homeostasis. Finally, we summarize current knowledge of the role for P2 signaling in infectious pneumonia, ALI/ARDS and idiopathic pulmonary fibrosis (IPF).

scholarly journals Upregulation and Nuclear Location of MMP28 in Alveolar Epithelium of Idiopathic Pulmonary Fibrosis

2018 ◽  
Vol 59 (1) ◽  
pp. 77-86 ◽  
Author(s):  
Mariel Maldonado ◽  
Alfonso Salgado-Aguayo ◽  
Iliana Herrera ◽  
Sandra Cabrera ◽  
Blanca Ortíz-Quintero ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Alveolar Epithelium ◽  
Nuclear Location

scholarly journals Idiopathic pulmonary fibrosis: Current knowledge, future perspectives and its importance in radiation oncology

2021 ◽  
Vol 155 ◽  
pp. 269-277
Author(s):  
Görkem Türkkan ◽  
Yves Willems ◽  
Lizza E.L. Hendriks ◽  
Rémy Mostard ◽  
Lennart Conemans ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Radiation Oncology ◽  
Current Knowledge ◽  
Future Perspectives

scholarly journals Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets

2019 ◽  
Vol 20 (3) ◽  
pp. 593 ◽  
Author(s):  
Beatriz Ballester ◽  
Javier Milara ◽  
Julio Cortijo
Keyword(s):  
Lung Cancer ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Current Knowledge ◽  
Molecular Targets ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
History Of

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 2–4 years after diagnosis. A significant number of IPF patients have risk factors, such as a history of smoking or concomitant emphysema, both of which can predispose the patient to lung cancer (LC) (mostly non-small cell lung cancer (NSCLC)). In fact, IPF itself increases the risk of LC development by 7% to 20%. In this regard, there are multiple common genetic, molecular, and cellular processes that connect lung fibrosis with LC, such as myofibroblast/mesenchymal transition, myofibroblast activation and uncontrolled proliferation, endoplasmic reticulum stress, alterations of growth factors expression, oxidative stress, and large genetic and epigenetic variations that can predispose the patient to develop IPF and LC. The current approved IPF therapies, pirfenidone and nintedanib, are also active in LC. In fact, nintedanib is approved as a second line treatment in NSCLC, and pirfenidone has shown anti-neoplastic effects in preclinical studies. In this review, we focus on the current knowledge on the mechanisms implicated in the development of LC in patients with IPF as well as in current IPF and LC-IPF candidate therapies based on novel molecular advances.

Sign in / Sign up

Export Citation Format

Share Document