scholarly journals Airway epithelial specific deletion of Jun-N-terminal kinase 1 attenuates pulmonary fibrosis in two independent mouse models

PLoS ONE ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. e0226904 ◽  
Author(s):  
Jos L. van der Velden ◽  
John F. Alcorn ◽  
David G. Chapman ◽  
Lennart K. A. Lundblad ◽  
Charles G. Irvin ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Mouse Models ◽  
Airway Epithelial ◽  
Specific Deletion

scholarly journals Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ian T. Stancil ◽  
Jacob E. Michalski ◽  
Duncan Davis-Hall ◽  
Hong Wei Chu ◽  
Jin-Ah Park ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Airway Epithelium ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Chronic Lung Diseases ◽  
Distal Airway ◽  
Signaling Axis

AbstractThe airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

scholarly journals Potential role of senescent macrophages in radiation-induced pulmonary fibrosis

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Lulu Su ◽  
Yinping Dong ◽  
Yueying Wang ◽  
Yuquan Wang ◽  
Bowen Guan ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Pulmonary Fibrosis ◽  
Late Toxicity ◽  
Airway Epithelial ◽  
Tnf Α ◽  
Elevated Expression ◽  
Radiation Induced ◽  
Therapeutic Radiation ◽  
Tgf Β1

AbstractRadiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation in clinic with poor prognosis and limited therapeutic options. Previous results have shown that senescent cells, such as fibroblast and type II airway epithelial cell, are strongly implicated in pathology of RIPF. However, the role of senescent macrophages in the development RIPF is still unknown. In this study, we report that ionizing radiation (IR) increase cellular senescence with higher expression of senescence-associated β-galactosidase (SA-β-Gal) and senescence-specific genes (p16, p21, Bcl-2, and Bcl-xl) in irradiated bone marrow-derived monocytes/macrophages (BMMs). Besides, there’s a significant increase in the expression of pro-fibrogenic factors (TGF-β1 and Arg-1), senescence-associated secretory phenotype (SASP) proinflammatory factors (Il-1α, Il-6, and Tnf-α), SASP chemokines (Ccl2, Cxcl10, and Ccl17), and SASP matrix metalloproteinases (Mmp2, Mmp9 and Mmp12) in BMMs exposed to 10 Gy IR. In addition, the percentages of SA-β-Gal+ senescent macrophages are significantly increased in the macrophages of murine irradiated lung tissue. Moreover, robustly elevated expression of p16, SASP chemokines (Ccl2, Cxcl10, and Ccl17) and SASP matrix metalloproteinases (Mmp2, Mmp9, and Mmp12) is observed in the macrophages of irradiated lung, which might stimulate a fibrotic phenotype in pulmonary fibroblasts. In summary, irradiation can induce macrophage senescence, and increase the secretion of SASP in senescent macrophages. Our findings provide important evidence that senescent macrophages might be the target for prevention and treatment of RIPF.

scholarly journals Nanoapproaches to Modifying Epigenetics of Epithelial Mesenchymal Transition for Treatment of Pulmonary Fibrosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Melissa Skibba ◽  
Adam Drelich ◽  
Michael Poellmann ◽  
Seungpyo Hong ◽  
Allan R. Brasier
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Polymeric Nanoparticles ◽  
Pulmonary Delivery ◽  
High Morbidity ◽  
Airway Epithelial ◽  
Mesenchymal Transition ◽  
Rate Of Decline ◽  
Preclinical Work

Idiopathic Pulmonary Fibrosis (IPF) is a chronically progressive interstitial lung that affects over 3 M people worldwide and rising in incidence. With a median survival of 2–3 years, IPF is consequently associated with high morbidity, mortality, and healthcare burden. Although two antifibrotic therapies, pirfenidone and nintedanib, are approved for human use, these agents reduce the rate of decline of pulmonary function but are not curative and do not reverse established fibrosis. In this review, we discuss the prevailing epithelial injury hypothesis, wherein pathogenic airway epithelial cell-state changes known as Epithelial Mesenchymal Transition (EMT) promotes the expansion of myofibroblast populations. Myofibroblasts are principal components of extracellular matrix production that result in airspace loss and mortality. We review the epigenetic transition driving EMT, a process produced by changes in histone acetylation regulating mesenchymal gene expression programs. This mechanistic work has focused on the central role of bromodomain-containing protein 4 in mediating EMT and myofibroblast transition and initial preclinical work has provided evidence of efficacy. As nanomedicine presents a promising approach to enhancing the efficacy of such anti-IPF agents, we then focus on the state of nanomedicine formulations for inhalable delivery in the treatment of pulmonary diseases, including liposomes, polymeric nanoparticles (NPs), inorganic NPs, and exosomes. These nanoscale agents potentially provide unique properties to existing pulmonary therapeutics, including controlled release, reduced systemic toxicity, and combination delivery. NP-based approaches for pulmonary delivery thus offer substantial promise to modify epigenetic regulators of EMT and advance treatments for IPF.

Muc5b-Overexpression Promotes Increased ER Stress in Mouse Models of Pulmonary Fibrosis

2019 ◽  
Author(s):  
J.E. Michalski ◽  
A.M. Estrella ◽  
C.E. Hennessy ◽  
I.T. Stancil ◽  
E. Dobrinskikh ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Er Stress ◽  
Mouse Models

scholarly journals Mesenchymal-Specific Deletion of C/EBPβ Suppresses Pulmonary Fibrosis

2012 ◽  
Vol 180 (6) ◽  
pp. 2257-2267 ◽  
Author(s):  
Biao Hu ◽  
Zhe Wu ◽  
Taku Nakashima ◽  
Sem H. Phan
Keyword(s):  
Pulmonary Fibrosis ◽  
Specific Deletion

scholarly journals Chemokine receptor 2-targeted molecular imaging in pulmonary fibrosis

2020 ◽  
Author(s):  
Steven L. Brody ◽  
Sean P. Gunsten ◽  
Hannah P. Luehmann ◽  
Debbie H. Sultan ◽  
Michelle Hoelscher ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Mouse Models ◽  
Chemokine Receptor ◽  
Pet Imaging ◽  
Lung Fibrosis ◽  
Ex Vivo ◽  
Inflammatory Monocytes ◽  
Fibrotic Process ◽  
Fibrotic Lung Disease

AbstractIdiopathic pulmonary fibrosis (IPF) is a progressive, inflammatory lung disease that is monitored clinically by measures of lung function, without effective molecular markers of disease activity or therapeutic efficacy. Lung immune cells active in the pro-fibrotic process include inflammatory monocyte and interstitial macrophages that express the C-C motif chemokine receptor 2 (CCR2). CCR2+ monocyte lung influx is essential for disease phenotypes in models of fibrosis and identified in lungs from subjects with IPF. Here, we show that our peptide-based radiotracer 64Cu-DOTA-ECL1i identifies CCR2+ inflammatory monocytes and interstitial macrophages in multiple preclinical mouse models of lung fibrosis, using positron emission tomography (PET) imaging. Mice with bleomycin-induced fibrosis treated with blocking antibodies to interleukin-1β, a mediator of fibrosis associated with CCR2+ cell inflammation, or with pirfenidone, an approved anti-fibrotic agent, demonstrated decreased CCR2-dependent interstitial macrophage accumulation and reduced 64Cu-DOTA-ECL1i PET uptake, compared to controls. Lung tissues from patients with fibrotic lung disease demonstrated abundant CCR2+ cells surrounding regions of fibrosis, and an ex vivo tissue-binding assay showed correlation between radiotracer localization and CCR2+ cells. In a phase 0/1 clinical study of 64Cu-DOTA-ECL1i PET, healthy volunteers showed little lung uptake, while subjects with pulmonary fibrosis exhibited increased uptake, notably in zones of subpleural fibrosis, reflecting the distribution of CCR2+ cells in the profibrotic niche. These findings support a pathologic role of inflammatory lung monocytes/macrophages in fibrotic lung disease and the translational use of 64Cu-DOTA-ECL1i PET to track CCR2-specific inflammation for image-guided therapy.One Sentence SummaryPET imaging of CCR2+ cells in lung fibrosis identifies a therapeutic response in mouse models and displays a perifibrotic signal in subjects with IPF.

scholarly journals Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis

2011 ◽  
Vol 121 (1) ◽  
pp. 277-287 ◽  
Author(s):  
Min Li ◽  
Manda Sai Krishnaveni ◽  
Changgong Li ◽  
Beiyun Zhou ◽  
Yiming Xing ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Receptor Type ◽  
Type Ii ◽  
Β Receptor ◽  
Specific Deletion

scholarly journals Grainyhead-like 2 (GRHL2) distribution reveals novel pathophysiological differences between human idiopathic pulmonary fibrosis and mouse models of pulmonary fibrosis

2014 ◽  
Vol 306 (5) ◽  
pp. L405-L419 ◽  
Author(s):  
Saaket Varma ◽  
Poornima Mahavadi ◽  
Satish Sasikumar ◽  
Leah Cushing ◽  
Tessa Hyland ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Mouse Models ◽  
Human Lung ◽  
Alveolar Epithelial Cell ◽  
Lung Epithelium ◽  
Chronic Injury ◽  
Alveolar Epithelial

Chronic injury of alveolar lung epithelium leads to epithelial disintegrity in idiopathic pulmonary fibrosis (IPF). We had reported earlier that Grhl2, a transcriptional factor, maintains alveolar epithelial cell integrity by directly regulating components of adherens and tight junctions and thus hypothesized an important role of GRHL2 in pathogenesis of IPF. Comparison of GRHL2 distribution at different stages of human lung development showed its abundance in developing lung epithelium and in adult lung epithelium. However, GRHL2 is detected in normal human lung mesenchyme only at early fetal stage (week 9). Similar mesenchymal reexpression of GRHL2 was also observed in IPF. Immunofluorescence analysis in serial sections from three IPF patients revealed at least two subsets of alveolar epithelial cells (AEC), based on differential GRHL2 expression and the converse fluorescence intensities for epithelial vs. mesenchymal markers. Grhl2 was not detected in mesenchyme in intraperitoneal bleomycin-induced injury as well as in spontaneously occurring fibrosis in double-mutant HPS1 and HPS2 mice, whereas in contrast in a radiation-induced fibrosis model, with forced Forkhead box M1 (Foxm1) expression, an overlap of Grhl2 with a mesenchymal marker was observed in fibrotic regions. Grhl2's role in alveolar epithelial cell plasticity was confirmed by altered Grhl2 gene expression analysis in IPF and further validated by in vitro manipulation of its expression in alveolar epithelial cell lines. Our findings reveal important pathophysiological differences between human IPF and specific mouse models of fibrosis and support a crucial role of GRHL2 in epithelial activation in lung fibrosis and perhaps also in epithelial plasticity.

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