Quantitative Proteomics Identifies Cannabinoid Receptor 2 as Candidate Marker of Idiopathic Pulmonary Fibrosis and Dysregulation of Endogenous Cannabinoids Pathway

Abstract Background: Idiopathic pulmonary fibrosis (IPF) a chronic, progressive, and lung fibrosis disease of unknown etiology with less effective treatment. It is important to discover new biomarker and therapeutic target for the diagnosis and cure of IPF. Method: Differential metabolic profiles may be useful for the diagnosis of IPF and provide additional insight into the molecular mechanisms underlying IPF. Plasma samples from IPF, COPD and normal controls were investigated using liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS) and these datasets were analyzed using multiple pattern performance methods. Multivariate statistical methods, pathway enrichment analysis and univariate receiver operating characteristic (ROC) curve analysis were performed. Results: OPLS-DA results showed that it exhibited significant separation between any two groups. ROC curve analyses revealed that 8 metabolites with high AUC above 0.7 between three groups in the plasma samples. Pathway analysis revealed that 3 metabolites are involved in endogenous cannabinoids/cannabinoid receptor 2 (CB2) signaling. Moreover, we found that the specific elevation of CB2 could be a signature of PF(Pulmonary Fibrosis) lung tissues in rat model. Conclusions: LC-MS-based plasma metabolomics provides a important tool to identify the potential biomarkers for IPF. Taken together, we performed quantitative chemoproteomic profiling and identified endogenous cannabinoids/CB2 as the key target of ICA in bleomycin-induced pulmonary fibrosis. Trial Registration: The study was approved by the the Ethics Committee of Huashan Hospital, Fudan University (KY2021-453)

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The Role of TGF-β Signaling in Lung Cancer Associated with Idiopathic Pulmonary Fibrosis

International Journal of Molecular Sciences ◽

10.3390/ijms19113611 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3611 ◽

Cited By ~ 8

Author(s):

Akira Saito ◽

Masafumi Horie ◽

Patrick Micke ◽

Takahide Nagase

Keyword(s):

Lung Cancer ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Current Knowledge ◽

Field Cancerization ◽

Unknown Etiology ◽

Dismal Prognosis ◽

Increased Risk

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown etiology and dismal prognosis. IPF patients are known to have an increased risk of lung cancer and careful decision-making is required for the treatment of lung cancer associated with IPF. Transforming growth factor (TGF)-β signaling plays a central role in tissue fibrosis and tumorigenesis. TGF-β-mediated pathological changes that occur in IPF lung tissue may promote the process of field cancerization and provide the microenvironment favorable to cancer initiation and progression. This review summarizes the current knowledge related to IPF pathogenesis and explores the molecular mechanisms that underlie the occurrence of lung cancer in the background of IPF, with an emphasis on the multifaceted effects of TGF-β signaling.

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When things go wrong: Exploring possible mechanisms driving the progressive fibrosis phenotype in interstitial lung diseases

European Respiratory Journal ◽

10.1183/13993003.04507-2020 ◽

2021 ◽

pp. 2004507

Author(s):

Moisés Selman ◽

Annie Pardo

Keyword(s):

Pulmonary Fibrosis ◽

Lung Diseases ◽

Molecular Mechanisms ◽

Lung Parenchyma ◽

Interstitial Lung Diseases ◽

Unknown Etiology ◽

Clinical Behavior ◽

The Past ◽

Appropriate Treatment ◽

Different Types

Interstitial lung diseases (ILD) comprise a large and heterogeneous group of disorders of known and unknown etiology characterised by diffuse damage of the lung parenchyma. In the past years, it has become evident that patients with different types of ILD are at risk of developing progressive pulmonary fibrosis known as pulmonary fibrosing ILD (PF-ILD). This is a phenotype behaving similar to idiopathic pulmonary fibrosis, the archetypical example of progressive fibrosis. PF-ILD is not a distinct clinical entity but describes a group of ILD with a similar clinical behavior. This phenotype may occur in diseases displaying distinct etiologies and different biopathology during their initiation and development. Importantly, these entities may have the potential for improvement or stabilisation prior to entering in the progressive fibrosing phase. The crucial questions are (1) why a subset of patients develops a progressive and irreversible fibrotic phenotype even with appropriate treatment, and (2) what the pathogenic mechanisms driving progression possibly are. We here provide a framework highlighting putative mechanisms underlying progression, including genetic susceptibility, aging, epigenetics, the structural fibrotic distortion, the aberrant composition and stiffness of the extracellular matrix, and the emergence of distinct profibrotic cell subsets. Understanding the cellular and molecular mechanisms behind PF-ILD will provide the basis for identifying risk factors and appropriate therapeutical strategies.

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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

BMJ Open Respiratory Research ◽

10.1136/bmjresp-2019-000439 ◽

2019 ◽

Vol 6 (1) ◽

pp. e000439 ◽

Cited By ~ 2

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.

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Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00142.2016 ◽

2016 ◽

Vol 311 (2) ◽

pp. L238-L254 ◽

Cited By ~ 28

Author(s):

Ning-Yuan Chen ◽

Scott D. Collum ◽

Fayong Luo ◽

Tingting Weng ◽

Thuy-Trahn Le ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Diseases ◽

Vascular Lesions ◽

Unknown Etiology ◽

Group Iii ◽

Chronic Lung Diseases ◽

Protein Receptor ◽

Stat3 Phosphorylation

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. The development of pulmonary hypertension (PH) is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced BMPR2 expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3, demonstrating reduced BMPR2 signaling and elevated TGF-β activity in IPF. In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 expression compared with control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2. We also demonstrate that isolated bone marrow-derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with immunohistochemistry showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of BMPR2 mediated by a collection of miRs induced by IL6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF.

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Effects of cannabinoid receptor 2 synthetic agonist, AM1241, on bleomycin induced pulmonary fibrosis

Biotechnic & Histochemistry ◽

10.1080/10520295.2020.1758343 ◽

2020 ◽

Vol 96 (1) ◽

pp. 48-59

Author(s):

Ali Parlar ◽

Seyfullah Oktay Arslan ◽

Onder Yumrutas ◽

Ebru Elibol ◽

Alper Yalcin ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Cannabinoid Receptor ◽

Cannabinoid Receptor 2

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Latest progress on the molecular mechanisms of idiopathic pulmonary fibrosis

Molecular Biology Reports ◽

10.1007/s11033-020-06000-6 ◽

2020 ◽

Vol 47 (12) ◽

pp. 9811-9820

Author(s):

Yue Fang ◽

Jingya Tian ◽

Yumei Fan ◽

Pengxiu Cao

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Molecular Mechanisms

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Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-β signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1415111112 ◽

2015 ◽

Vol 112 (16) ◽

pp. E2048-E2057 ◽

Cited By ~ 53

Author(s):

Gani Oruqaj ◽

Srikanth Karnati ◽

Vijith Vijayan ◽

Lakshmi Kanth Kotarkonda ◽

Eistine Boateng ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Lung Fibroblasts ◽

Fibrotic Response ◽

Down Regulation ◽

Necrosis Factor Alpha ◽

Isolated Lung

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces liver fibrosis. However, altered peroxisome functions in IPF pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and IPF patients, we found that IPF lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism (e.g., PEX13p and acyl-CoA oxidase 1). Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta (TGF-β) receptor II knockout mice indicating a role for TGF-β signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of IPF fibroblasts with the profibrotic factors TGF-β1 or tumor necrosis factor alpha (TNF-α) was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced fibrosis were further studied. Direct down-regulation of PEX13 by RNAi induced the activation of Smad-dependent TGF-β signaling accompanied by increased ROS production and resulted in the release of cytokines (e.g., IL-6, TGF-β) and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-α activators, led to peroxisome proliferation and reduced the TGF-β–induced myofibroblast differentiation and collagen protein in IPF cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of IPF and fibrosis progression, possibly by exacerbating pulmonary inflammation and intensifying the fibrotic response in the patients.

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Smoking and Idiopathic Pulmonary Fibrosis

Pulmonary Medicine ◽

10.1155/2012/808260 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 27

Author(s):

Chad K. Oh ◽

Lynne A. Murray ◽

Nestor A. Molfino

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cigarette Smoking ◽

Unknown Etiology ◽

Potential Candidate ◽

Genetic Studies ◽

Gene Environment ◽

Former Smokers ◽

Considerable Morbidity ◽

Smoking Interaction

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology with considerable morbidity and mortality. Cigarette smoking is one of the most recognized risk factors for development of IPF. Furthermore, recent work suggests that smoking may have a detrimental effect on survival of patients with IPF. The mechanism by which smoking may contribute to the pathogenesis of IPF is largely unknown. However, accumulating evidence suggests that increased oxidative stress might promote disease progression in IPF patients who are current and former smokers. In this review, potential mechanisms by which cigarette smoking affects IPF, the effects of cigarette smoking on accelerated loss of lung function in patients with IPF, key genetic studies evaluating the potential candidate genes and gene-environment (smoking) interaction, diagnosis, and treatment with emphasis on recently closed and ongoing clinical trials are presented.

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Occupational and Environmental Risk Factors for Idiopathic Pulmonary Fibrosis: A Multicenter Case-Control Study

American Journal of Epidemiology ◽

10.1093/aje/152.4.307 ◽

2000 ◽

Vol 152 (4) ◽

pp. 307-315 ◽

Cited By ~ 198

Author(s):

Kathy B. Baumgartner ◽

Jonathan M. Samet ◽

David B. Coultas ◽

Christine A. Stidley ◽

William C. Hunt ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Case Control Study ◽

Occupational Exposures ◽

Case Control ◽

Geographic Region ◽

Unknown Etiology ◽

Occupational Factors ◽

Increased Risk ◽

Control Study

Abstract Occupational exposures were investigated in a multicenter case-control study of clinically and histologically diagnosed idiopathic pulmonary fibrosis (IPF), a chronic diffuse interstitial lung disease of unknown etiology. Results are based on 248 cases, aged 20–75 years, diagnosed at 16 referral centers between January 1989 and July 1993. There were 491 controls ascertained by random digit dialing and matched to cases on sex, age, and geographic region. Data were collected using a standard telephone questionnaire. Occupational factors were based on a detailed history of jobs lasting 6 months or more and job activity, hobby, and specific substance checklists. Several occupational factors, adjusted for age and smoking in conditional multivariate logistic regression analyses, were significantly associated with IPF: farming (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.5); livestock (OR = 2.7, 95% CI: 1.3, 5.5); hairdressing (OR = 4.4, 95% CI: 1.2, 16.3); metal dust (OR = 2.0, 95% CI: 1.0, 4.0); raising birds (OR = 4.7, 95% CI: 1.6, 14.1); stone cutting/polishing (OR = 3.9, 95% CI: 1.2, 12.7); and vegetable dust/animal dust (OR = 4.7, 95% CI: 2.1, 10.4). Interaction was detected between smoking and exposure to livestock (p = 0.06) and farming (p = 0.08). Results confirm previous studies showing increased risk associated with dusty environments. Am J Epidemiol 2000;152:307–15.

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Effects of low-dose pirfenidone on survival and lung function decline in patients with idiopathic pulmonary fibrosis (IPF): Results from a real-world study

PLoS ONE ◽

10.1371/journal.pone.0261684 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0261684

Author(s):

Eung Gu Lee ◽

Tae-Hee Lee ◽

Yujin Hong ◽

Jiwon Ryoo ◽

Jung Won Heo ◽

...

Keyword(s):

Clinical Trials ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Pulmonary Function ◽

Real World ◽

Low Dose ◽

Randomized Clinical Trials ◽

Laboratory Data ◽

Unknown Etiology ◽

The Real

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia of unknown etiology. In several randomized clinical trials, and in the clinical practice, pirfenidone is used to effectively and safely treat IPF. However, sometimes it is difficult to use the dose of pirfenidone used in clinical trials. This study evaluated the effects of low-dose pirfenidone on IPF disease progression and patient survival in the real-world. Methods This retrospective, observational study enrolled IPF patients seen at the time of diagnosis at a single center from 2008 to 2018. Longitudinal clinical and laboratory data were prospectively collected. We compared the clinical characteristics, survival, and pulmonary function decline between patients treated and untreated with various dose of pirfenidone. Results Of 295 IPF patients, 100 (33.9%) received pirfenidone and 195 (66.1%) received no antifibrotic agent. Of the 100 patients who received pirfenidone, 24 (24%), 50 (50%), and 26 (26%), respectively, were given 600, 1200, and 1800 mg pirfenidone daily. The mean survival time was 57.03 ± 3.90 months in the no-antifibrotic drug group and 73.26 ± 7.87 months in the pirfenidone-treated group (p = 0.027). In the unadjusted analysis, the survival of the patients given pirfenidone was significantly better (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.48–0.99, p = 0.04). After adjusting for age, gender, body mass index, and the GAP score [based on gender (G), age (A), and two physiological lung parameters (P)], survival remained better in the patients given pirfenidone (HR = 0.56, 95% CI: 0.37–0.85, p = 0.006). In terms of pulmonary function, the decreases in forced vital capacity (%), forced expiratory volume in 1 s (%) and the diffusing capacity of lung for carbon monoxide (%) were significantly smaller (p = 0.000, p = 0.001, and p = 0.007, respectively) in patients given pirfenidone. Conclusions Low-dose pirfenidone provided beneficial effects on survival and pulmonary function decline in the real-world practice.

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