scholarly journals Lost after translation: insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease

2015 ◽  
Vol 309 (6) ◽  
pp. L507-L525 ◽  
Author(s):  
Surafel Mulugeta ◽  
Shin-Ichi Nureki ◽  
Michael F. Beers
Keyword(s):  
Quality Control ◽  
Pulmonary Fibrosis ◽  
Er Stress ◽  
Lung Disease ◽  
Pulmonary Surfactant ◽  
Model Systems ◽  
Cell Dysfunction ◽  
Fibrotic Lung Disease ◽  
Epithelial Dysfunction

Dating back nearly 35 years ago to the Witschi hypothesis, epithelial cell dysfunction and abnormal wound healing have reemerged as central concepts in the pathophysiology of idiopathic pulmonary fibrosis (IPF) in adults and in interstitial lung disease in children. Alveolar type 2 (AT2) cells represent a metabolically active compartment in the distal air spaces responsible for pulmonary surfactant biosynthesis and function as a progenitor population required for maintenance of alveolar integrity. Rare mutations in surfactant system components have provided new clues to understanding broader questions regarding the role of AT2 cell dysfunction in the pathophysiology of fibrotic lung diseases. Drawing on data generated from a variety of model systems expressing disease-related surfactant component mutations [surfactant proteins A and C (SP-A and SP-C); the lipid transporter ABCA3], this review will examine the concept of epithelial dysfunction in fibrotic lung disease, provide an update on AT2 cell and surfactant biology, summarize cellular responses to mutant surfactant components [including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and intrinsic apoptosis], and examine quality control pathways (unfolded protein response, the ubiquitin-proteasome system, macroautophagy) that can be utilized to restore AT2 homeostasis. This integrated response and its derangement will be placed in the context of cell stress and quality control signatures found in patients with familial or sporadic IPF as well as non-surfactant-related AT2 cell dysfunction syndromes associated with a fibrotic lung phenotype. Finally, the need for targeted therapeutic strategies for pulmonary fibrosis that address epithelial ER stress, its downstream signaling, and cell quality control are discussed.

scholarly journals FK506-binding protein 13 expression is upregulated in interstitial lung disease and correlated with clinical severity: a potentially protective role

2019 ◽  
Author(s):  
V Tat ◽  
EA Ayaub ◽  
A Ayoub ◽  
M Vierhout ◽  
S Naiel ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Pulmonary Fibrosis ◽  
Er Stress ◽  
Lung Disease ◽  
Binding Protein ◽  
Clinical Severity ◽  
Fk506 Binding Protein ◽  
Matrix Deposition ◽  
Gene And Protein Expression

ABSTRACTPulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition. Endoplasmic reticulum (ER) stress initiates the unfolded protein response (UPR), a cellular stress response pathway that has been implicated in both inflammatory and fibrotic processes. Here, we sought to investigate the role of the 13 kDa FK506-binding protein (FKBP13), an ER stress-inducible molecular chaperone, in various forms of pulmonary fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy samples from 24 patients with idiopathic pulmonary fibrosis (IPF) and 17 control subjects. FKBP13 expression was found to be elevated in the fibrotic regions of IPF lung tissues, and within this cohort, was correlated with declining forced vital capacity and dyspnea severity. FKBP13 expression was also increased in lung biopsies of patients with hypersensitivity pneumonitis, rheumatoid arthritis, and sarcoidosis-associated interstitial lung disease. We next evaluated the role of this protein using FKBP13-/- mice in a bleomycin model of pulmonary fibrosis. Animals were assessed for lung function and histopathology at different stages of lung injury including the inflammatory (Day 7), fibrotic (Day 21) and resolution (Day 50) phase. FKBP13-/- mice showed increased infiltration of inflammatory cells and cytokines at Day 7, increased lung elastance and fibrosis at Day 21, and impaired resolution of fibrosis at Day 50. These changes were associated with an increased number of cells that stained positive for TUNEL and cleaved caspase 3 in the FKBP13-/- lungs, indicating a heightened cellular sensitivity to bleomycin. Our findings suggest that FKBP13 is a potential biomarker for severity or progression of interstitial lung diseases, and that it has a biologically relevant role in protecting mice against bleomycin-induced injury, inflammation and fibrosis.

scholarly journals Complications in Idiopathic Pulmonary Fibrosis: Focus on Their Clinical and Radiological Features

Diagnostics ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 450
Author(s):  
Federica Galioto ◽  
Stefano Palmucci ◽  
Giovanna M. Astuti ◽  
Ada Vancheri ◽  
Giulio Distefano ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Integrated Approach ◽  
Correct Treatment ◽  
Radiological Features ◽  
Palliative Care Services ◽  
Pictorial Essay ◽  
Personalized Approach ◽  
Fibrotic Lung Disease

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with uncertain origins and pathogenesis; it represents the most common interstitial lung disease (ILD), associated with a pathological pattern of usual interstitial pneumonitis (UIP). This disease has a poor prognosis, having the most lethal prognosis among ILDs. In fact, the progressive fibrosis related to IPF could lead to the development of complications, such as acute exacerbation, lung cancer, infections, pneumothorax and pulmonary hypertension. Pneumologists, radiologists and pathologists play a key role in the identification of IPF disease, and in the characterization of its complications—which unfortunately increase disease mortality and reduce overall survival. The early identification of these complications is very important, and requires an integrated approach among specialists, in order to plane the correct treatment. In some cases, the degree of severity of patients having IPF complications may require a personalized approach, based on palliative care services. Therefore, in this paper, we have focused on clinical and radiological features of the complications that occurred in our IPF patients, providing a comprehensive and accurate pictorial essay for clinicians, radiologists and surgeons involved in their management.

scholarly journals The loss of IL-31 signaling attenuates bleomycin-induced pulmonary fibrosis

2020 ◽  
Author(s):  
Dan JK Yombo ◽  
Nishanth Gupta ◽  
Anil G. Jegga ◽  
Satish K Madala
Keyword(s):  
T Cells ◽  
Lung Function ◽  
Pulmonary Fibrosis ◽  
Gene Networks ◽  
Pulmonary Inflammation ◽  
Collagen Deposition ◽  
Lung Function Decline ◽  
Elevated Expression ◽  
Fibrotic Lung Disease

AbstractIdiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Multiple Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 TH2 T cells, but its signaling receptor called IL-31RA has been shown predominately expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31 signaling in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. However, the loss of IL-31RA signaling did not affect inflammation in the lungs. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including ECM- and epithelial cell-associated gene networks. Furthermore, the lungs of IPF showed an elevated expression of IL-31 when compared to control subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. In summary, therapeutic targeting of the IL-31-IL-31RA axis could be beneficial in pulmonary fibrosis and has translational benefits specifically by preventing collagen deposition and improving lung function.

scholarly journals Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease

2020 ◽  
Author(s):  
Konstantinos-Dionysios Alysandratos ◽  
Scott J. Russo ◽  
Anton Petcherski ◽  
Evan P. Taddeo ◽  
Rebeca Acín-Pérez ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Disease Onset ◽  
Metabolic Reprogramming ◽  
Patient Specific ◽  
Autophagic Flux ◽  
Alveolar Epithelial ◽  
Epithelial Dysfunction

SummaryThe incompletely understood pathogenesis of pulmonary fibrosis (PF) and lack of reliable preclinical disease models have limited development of effective therapies. An emerging literature now implicates alveolar epithelial type 2 cell (AEC2) dysfunction as an initiating pathogenic event in the onset of a variety of PF syndromes, including adult idiopathic pulmonary fibrosis (IPF) and childhood interstitial lung disease (chILD). However, inability to access primary AEC2s from patients, particularly at early disease stages, has impeded identification of disease-initiating mechanisms. Here we present an in vitro reductionist model system that permits investigation of epithelial-intrinsic events that lead to AEC2 dysfunction over time using patient-derived cells that carry a disease-associated variant, SFTPCI73T, known to be expressed solely in AEC2s. After generating patient-specific induced pluripotent stem cells (iPSCs) and engineering their gene-edited (corrected) counterparts, we employ directed differentiation to produce pure populations of syngeneic corrected and mutant AEC2s, which we expand >1015 fold in vitro, providing a renewable source of cells for modeling disease onset. We find that mutant iPSC-derived AEC2s (iAEC2s) accumulate large amounts of misprocessed pro-SFTPC protein which mistrafficks to the plasma membrane, similar to changes observed in vivo in the donor patient’s AEC2s. These changes result in marked reduction in AEC2 progenitor capacity and several downstream perturbations in AEC2 proteostatic and bioenergetic programs, including a late block in autophagic flux, accumulation of dysfunctional mitochondria with consequent time-dependent metabolic reprograming from oxidative phosphorylation to glycolysis, and activation of an NF-κB dependent inflammatory response. Treatment of SFTPCI73T expressing iAEC2s with hydroxychloroquine, a medication commonly prescribed to these patients, results in aggravation of autophagy perturbations and metabolic reprogramming. Thus, iAEC2s provide a patientspecific preclinical platform for modeling the intrinsic epithelial dysfunction associated with the inception of interstitial lung disease.

scholarly journals The Its Not JUST Idiopathic pulmonary fibrosis Study (INJUSTIS): description of the protocol for a multicentre prospective observational cohort study identifying biomarkers of progressive fibrotic lung disease

2019 ◽  
Vol 6 (1) ◽  
pp. e000439 ◽  
Author(s):  
Fasihul Khan ◽  
Iain Stewart ◽  
Lucy Howard ◽  
Tricia M McKeever ◽  
Steve Jones ◽  
...  
Keyword(s):  
Cohort Study ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Molecular Mechanisms ◽  
Observational Cohort Study ◽  
Prospective Observational Cohort Study ◽  
Ethical Approval ◽  
Observational Cohort ◽  
Fibrotic Lung Disease

IntroductionThe Its Not JUST Idiopathic pulmonary fibrosis Study (INJUSTIS) is a multicentre, prospective, observational cohort study. The aims of this study are to identify genetic, serum and other biomarkers that may identify specific molecular mechanisms, reflecting disease endotypes that are shared among patients with progressive pulmonary fibrosis regardless of aetiology. Furthermore, it is anticipated that these biomarkers will help predict fibrotic activity that may identify patterns of disease behaviour with greater accuracy than current clinical phenotyping.Methods and analysis200 participants with the multidisciplinary team confirmed fibrotic lung disease (50 each of rheumatoid-interstitial lung disease (ILD), asbestosis, chronic hypersensitivity pneumonitis and unclassifiable ILD) and 50 idiopathic pulmonary fibrosis participants, recruited as positive controls, will be followed up for 2 years. Participants will have blood samples, lung function tests, quality of life questionnaires and a subgroup will be offered bronchoscopy. Participants will also be given the option of undertaking blinded home handheld spirometry for the first 3 months of the study. The primary end point will be identification of a biomarker that predicts disease progression, defined as 10% relative change in forced vital capacity (FVC) or death at 12 months.Ethics and disseminationThe trial has received ethical approval from the National Research Ethics Committee Nottingham (18/EM/0139). All participants must provide written informed consent. The trial will be overseen by the INJUSTIS steering group that will include a patient representative, and an independent chairperson. The results from this study will be submitted for publication in peer-reviewed journals and disseminated at regional and national conferences.Trial registration numberNCT03670576.

TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease

2007 ◽  
Vol 293 (3) ◽  
pp. L525-L534 ◽  
Author(s):  
Brigham C. Willis ◽  
Zea Borok
Keyword(s):  
Epithelial Cells ◽  
Lung Disease ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Alveolar Epithelial Cells ◽  
Mesenchymal Transition ◽  
Fibrotic Lung Disease

Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to fibrosis following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor (TGF)-β induces EMT in alveolar epithelial cells (AEC) in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II (AT2) cells in lung tissue from patients with idiopathic pulmonary fibrosis (IPF), suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to fibrosis in adult tissues following injury, focusing especially on the critical role of TGF-β and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of fibrotic lung disease. Treatment for fibrosis of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.

scholarly journals Hermansky–Pudlak syndrome pulmonary fibrosis: a rare inherited interstitial lung disease

2021 ◽  
Vol 30 (159) ◽  
pp. 200193
Author(s):  
Tadafumi Yokoyama ◽  
Bernadette R. Gochuico
Keyword(s):  
Interstitial Lung Disease ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Genetic Diseases ◽  
Autosomal Recessive Disorder ◽  
Oculocutaneous Albinism ◽  
Excessive Bleeding ◽  
Lung Physiology ◽  
Hermansky Pudlak Syndrome ◽  
Fibrotic Lung Disease

Pulmonary fibrosis is a progressive interstitial lung disease of unknown aetiology with a poor prognosis. Studying genetic diseases associated with pulmonary fibrosis provides insights into the pathogenesis of the disease. Hermansky–Pudlak syndrome (HPS), a rare autosomal recessive disorder characterised by abnormal biogenesis of lysosome-related organelles, manifests with oculocutaneous albinism and excessive bleeding of variable severity. Pulmonary fibrosis is highly prevalent in three out of 10 genetic types of HPS (HPS-1, HPS-2 and HPS-4). Thus, genotyping of individuals with HPS is clinically relevant. HPS-1 tends to affect Puerto Rican individuals due to a genetic founder effect. HPS pulmonary fibrosis shares some clinical features with idiopathic pulmonary fibrosis (IPF), including dyspnoea, cough, restrictive lung physiology and computed tomography (CT) findings of fibrosis. In contrast to IPF, HPS pulmonary fibrosis generally affects children (HPS-2) or middle-aged adults (HPS-1 or HPS-4) and may be associated with ground-glass opacification in CT scans. Histopathology of HPS pulmonary fibrosis, and not IPF, shows vacuolated hyperplastic type II cells with enlarged lamellar bodies and alveolar macrophages with lipofuscin-like deposits. Antifibrotic drugs approved as treatment for IPF are not approved for HPS pulmonary fibrosis. However, lung transplantation has been performed in patients with severe HPS pulmonary fibrosis. HPS pulmonary fibrosis serves as a model for studying fibrotic lung disease and fibrosis in general.

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.

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