The perplexing role of RAGE in pulmonary fibrosis: causality or casualty?

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease in which most patients die within 3 years of diagnosis. With an unknown etiology, IPF results in progressive fibrosis of the lung parenchyma, diminishing normal lung function, which results in respiratory failure, and eventually, death. While few therapies are available to reduce disease progression, patients continue to advance toward respiratory failure, leaving lung transplantation the only viable option for survival. As incidence and mortality rates steadily increase, the need for novel therapeutics is imperative. The receptor for advanced glycation endproducts (RAGE) is most highly expressed in the lungs and plays a significant role in a number of chronic lung diseases. RAGE has long been linked to IPF; however, confounding data from both human and experimental studies have left an incomplete and perplexing story. This review examines the present understanding of the role of RAGE in human and experimental models of IPF, drawing parallels to recent advances in RAGE biology. Moreover, this review discusses the role of RAGE in lung injury response, type 2 immunity, and cellular senescence, and how such mechanisms may relate to RAGE as both a biomarker of disease progression and potential therapeutic target in IPF. The reviews of this paper are available via the supplemental material section.

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Bacterial and Viral Coinfection in Idiopathic Pulmonary Fibrosis Patients: the Prevalence and Possible Role in Disease Progression

10.21203/rs.3.rs-790046/v1 ◽

2021 ◽

Author(s):

Mohsen Moghoofei ◽

Shayan Mostafaei ◽

Nasim Kondori ◽

Michelle E. Armstrong ◽

Farhad Babaei

Keyword(s):

Pulmonary Fibrosis ◽

Bacterial Infection ◽

Viral Infection ◽

Disease Progression ◽

Principal Component ◽

Unknown Etiology ◽

Risk Of Mortality ◽

Increased Risk ◽

Viral Coinfection

Abstract BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial pneumonia of unknown etiology with a mean survival rate of less than 3 years. Gap StatementNo previous studies have been performed on the role of co-infection (viral and bacterial infection) in the pathogensis and progression of IPF.AimIn this study, we investigated the role of viral/bacterial infection and coinfection and their possible association with pathogensis and progression of IPF.MethodsWe investigated the prevalence and impact of bacterial and viral coinfection in IPF patients (n = 67) in the context of pulmonary function (FVC, FEV1 and DLCO), disease status and mortality risk. Using principal component analysis (PCA), we also investigated the relationship between and distribution of bacterial and viral co-infection in the IPF cohort.ResultsOf the 67 samples, 17.9% samples were positive for viral infection, 10.4% samples were positive for bacterial infection and 59.7% samples were positive coinfection. We demonstrated that IPF patients who were co-infected had a significantly increased risk of mortality compared (p = 0.031) with IPF patients who were non-infected [Hazard ratio: 8.12; 95% C.I.: 1.3–26.9]. Furthermore, coinfection has also been implicated in disease progression during acute exacerbations in IPF (AE-IPF).ConclusionIn this study, we report for the first time that IPF patients who were coinfected with bacteria and viral infection have significantly decreased FVC and DLCO (% predicted), increased incidence of AE-IPF, increased incidence of death and risk of mortality compared with non-infected IPF patients.

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Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

Nature Communications ◽

10.1038/s41467-021-24853-8 ◽

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.

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Fibroblasts positive for meflin have anti-fibrotic property in pulmonary fibrosis

European Respiratory Journal ◽

10.1183/13993003.03397-2020 ◽

2021 ◽

pp. 2003397

Author(s):

Yoshio Nakahara ◽

Naozumi Hashimoto ◽

Koji Sakamoto ◽

Atsushi Enomoto ◽

Taylor S. Adams ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Single Cell ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Normal Lung ◽

Potential Marker ◽

Rna Hybridisation ◽

Secretory Phenotype

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine of the pathogenesis of IPF, identification of functional fibroblasts is warranted. This study was aimed to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis. We characterised meflin-positive cells in a single cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic property to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution. These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.

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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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Detection and monitoring of localized matrix metalloproteinase upregulation in a murine model of asthma

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00371.2013 ◽

2014 ◽

Vol 306 (8) ◽

pp. L764-L774 ◽

Cited By ~ 14

Author(s):

Csilla N. Felsen ◽

Elamprakash N. Savariar ◽

Michael Whitney ◽

Roger Y. Tsien

Keyword(s):

Disease Progression ◽

Protease Activity ◽

Lung Parenchyma ◽

Cell Penetrating Peptides ◽

Normal Lung ◽

Therapeutic Drug ◽

Extracellular Proteases ◽

Gelatinase Activity ◽

Chronic Lung Diseases

Extracellular proteases including matrix metalloproteinases (MMPs) are speculated to play a significant role in chronic lung diseases, such as asthma. Although increased protease expression has been correlated with lung pathogenesis, the relationship between localized enzyme activity and disease progression remains poorly understood. We report the application of MMP-2/9 activatable cell-penetrating peptides (ACPPs) and their ratiometric analogs (RACPPs) for in vivo measurement of protease activity and distribution in the lungs of mice that were challenged with the allergen ovalbumin. MMP-2/9 activity was increased greater than twofold in whole, dissected lungs from acutely challenged mice compared with control mice ( P = 1.8 × 10−4). This upregulation of MMP-2/9 activity was localized around inflamed airways with 1.6-fold higher protease-dependent ACPP uptake surrounding diseased airways compared with adjacent, pathologically normal lung parenchyma ( P = 0.03). MMP-2/9 activity detected by ACPP cleavage colocalized with gelatinase activity measured with in situ dye-quenched gelatin. For comparison, neutrophil elastase activity and thrombin activity, detected with elastase- and thrombin-cleavable RACPPs, respectively, were not significantly elevated in acutely allergen-challenged mouse lungs. The results demonstrate that ACPPs, like the MMP-2/9-activated and related ACPPs, allow for real-time detection of protease activity in a murine asthma model, which should improve our understanding of protease activation in asthma disease progression and help elucidate new therapy targets or act as a mechanism for therapeutic drug delivery.

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Role of atmospheric pollution on the natural history of idiopathic pulmonary fibrosis

Thorax ◽

10.1136/thoraxjnl-2017-209967 ◽

2017 ◽

Vol 73 (2) ◽

pp. 145-150 ◽

Cited By ~ 56

Author(s):

Lucile Sesé ◽

Hilario Nunes ◽

Vincent Cottin ◽

Shreosi Sanyal ◽

Morgane Didier ◽

...

Keyword(s):

Air Pollution ◽

Natural History ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Disease Progression ◽

Air Pollutant ◽

Rapid Decline ◽

History Of ◽

The Impact

IntroductionIdiopathic pulmonary fibrosis (IPF) has an unpredictable course corresponding to various profiles: stability, physiological disease progression and rapid decline. A minority of patients experience acute exacerbations (AEs). A recent study suggested that ozone and nitrogen dioxide might contribute to the occurrence of AE. We hypothesised that outdoor air pollution might influence the natural history of IPF.MethodsPatients were selected from the French cohort COhorte FIbrose (COFI), a national multicentre longitudinal prospective cohort of IPF (n=192). Air pollutant levels were assigned to each patient from the air quality monitoring station closest to the patient’s geocoded residence. Cox proportional hazards model was used to evaluate the impact of air pollution on AE, disease progression and death.ResultsOnset of AEs was significantly associated with an increased mean level of ozone in the six preceding weeks, with an HR of 1.47 (95% CI 1.13 to 1.92) per 10 µg/m3 (p=0.005). Cumulative levels of exposure to particulate matter PM10 and PM2.5 were above WHO recommendations in 34% and 100% of patients, respectively. Mortality was significantly associated with increased levels of exposure to PM10 (HR=2.01, 95% CI 1.07 to 3.77) per 10 µg/m3 (p=0.03), and PM2.5 (HR=7.93, 95% CI 2.93 to 21.33) per 10 µg/m3 (p<0.001).ConclusionThis study suggests that air pollution has a negative impact on IPF outcomes, corroborating the role of ozone on AEs and establishing, for the first time, the potential role of long-term exposure to PM10 and PM2.5 on overall mortality.

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Management of patients with end stage pulmonary fibrosis: Challenges, tempations and possibilities

Medicinski pregled ◽

10.2298/mpns13s1106r ◽

2013 ◽

Vol 66 (suppl. 1) ◽

pp. 106-112

Author(s):

Lidija Ristic ◽

Milan Rancic ◽

Milan Radovic ◽

Slavica Golubovic ◽

Snezana Djordjevic ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Lung Transplantation ◽

Treatment Modalities ◽

Stable Phase ◽

Rapid Progression ◽

Stage Of Disease ◽

Risk Of Death ◽

Chronic Lung Diseases ◽

Incidence And Mortality ◽

End Stage

Introduction. Pulmonary fibrosis is a heterogeneous group of chronic lung diseases of unclear pathogenesis, with progressive, irreversible development of various forms of fibrotic processes in the lung, whose incidence and mortality rate increases worldwide. Prognostic Evaluation. Some clinical forms have a long, stable phase, some are slowly progressive, and some have a very rapid progression from diagnosis to death. Their clinical course is characterized by acute exacerbations with high mortality. The staging of this disease includes diagnostics of the stable condition, progression and the end stage of disease. This paper presents the diagnostic criteria necessary for the diagnosis of pulmonary fibrosis and its monitoring. The latest research suggests that the decrease in forced vital capacity values by more than 10% during the 24 weeks doubles the risk of death over the next 12 months, and the reduction in the 6-minute walk test by 50 meters increases it four times. Therefore, monitoring of these prognostic parameters is now regarded as the most reliable predictor of death in patients with pulmonary fibrosis. Therapy. This paper also presents the newest recommendations for treatment modalities based on strong evidence. Conclusion. Treatment of pulmonary fibrosis in our conditions includes conventional therapy with corticosteroids as monotherapy or in combination with cyclophosphamide or azathioprine, whereas the management of end-stage patients consists of long-term controlled oxygen therapy, noninvasive and mechanical ventilation. Lung transplantation is considered to be the only therapeutic measure resulting in a significant extension of life. Unfortunately, our health legislation allows lung transplantation only in case of cystic fibrosis and this cannot be done in Serbia but in health centres abroad. Therefore, management in end-stage of disease is reduced to mere palliative care, even at intensive care units.

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Role of integrin-mediated TGFβ activation in the pathogenesis of pulmonary fibrosis

Biochemical Society Transactions ◽

10.1042/bst0370849 ◽

2009 ◽

Vol 37 (4) ◽

pp. 849-854 ◽

Cited By ~ 65

Author(s):

Amanda Goodwin ◽

Gisli Jenkins

Keyword(s):

Pulmonary Fibrosis ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Transforming Growth Factor Β ◽

Normal Lung ◽

Membrane Repair ◽

Mesenchymal Transition ◽

Chronic Progressive Disease ◽

Activation Pathways

IPF (idiopathic pulmonary fibrosis) is a chronic progressive disease of unknown aetiology without effective treatment. IPF is characterized by excessive collagen deposition within the lung. Recent evidence suggests that the lung epithelium plays a key role in driving the fibrotic response. The current paradigm suggests that, after epithelial injury, there is impaired epithelial proliferation and enhanced epithelial apoptosis. This in turn promotes lung fibrosis through impaired basement membrane repair and increased epithelial–mesenchymal transition. Furthermore, fibroblasts are recruited to the wounded area and adopt a myofibroblast phenotype, with the up-regulation of matrix-synthesizing genes and down-regulation of matrix-degradation genes. There is compelling evidence that the cytokine TGFβ (transforming growth factor β) plays a central role in this process. In normal lung, TGFβ is maintained in an inactive state that is tightly regulated temporally and spatially. One of the major TGFβ-activation pathways involves integrins, and the role of the αvβ6 integrin has been particularly well described in the pathogenesis of IPF. Owing to the pleiotropic nature of TGFβ, strategies that inhibit activation of TGFβ in a cell- or disease-specific manner are attractive for the treatment of chronic fibrotic lung conditions. Therefore the molecular pathways that lead to integrin-mediated TGFβ activation must be precisely defined to identify and fully exploit novel therapeutic targets that might ultimately improve the prognosis for patients with IPF.

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MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis

ERJ Open Research ◽

10.1183/23120541.00074-2016 ◽

2017 ◽

Vol 3 (1) ◽

pp. 00074-2016 ◽

Cited By ~ 33

Author(s):

Yasmina Bauer ◽

Eric S. White ◽

Simon de Bernard ◽

Peter Cornelisse ◽

Isabelle Leconte ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Disease ◽

Disease Progression ◽

Therapeutic Interventions ◽

Normal Lung ◽

Type I ◽

Objective Evidence ◽

Baseline Levels

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis, which is characterised by destruction of normal lung architecture and excessive deposition of lung extracellular matrix. The heterogeneity of disease progression in patients with IPF poses significant obstacles to patient care and prevents efficient development of novel therapeutic interventions. Blood biomarkers, reflecting pathobiological processes in the lung, could provide objective evidence of the underlying disease.Longitudinally collected serum samples from the Bosentan Use in Interstitial Lung Disease (BUILD)-3 trial were used to measure four biomarkers (metalloproteinase-7 (MMP-7), Fas death receptor ligand, osteopontin and procollagen type I C-peptide), to assess their potential prognostic capabilities and to follow changes during disease progression in patients with IPF.In baseline BUILD-3 samples, only MMP-7 showed clearly elevated protein levels compared with samples from healthy controls, and further investigations demonstrated that MMP-7 levels also increased over time. Baseline levels of MMP-7 were able to predict patients who had higher risk of worsening and, notably, baseline levels of MMP-7 could predict changes in FVC as early as month 4.MMP-7 shows potential to be a reliable predictor of lung function decline and disease progression.

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Deleterious Role of Th9 Cells in Pulmonary Fibrosis

Cells ◽

10.3390/cells10113209 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3209

Author(s):

Kui Miao Deng ◽

Xiang Sheng Yang ◽

Qun Luo ◽

Yi Xin She ◽

Qing Yang Yu ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Underlying Mechanism ◽

Th2 Cells ◽

Unknown Etiology ◽

The Novel ◽

Collagen Secretion ◽

Th9 Cells ◽

The One ◽

Therapeutic Settings

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Immune disorders play an important role in IPF pathogenesis. Here, we show that Th9 cells differentiate and activate in the lung tissue of patients with IPF and bleomycin (BLM)-induced lung fibrosis mice. Moreover, we found that Th9 cells promote pulmonary fibrosis in two ways. On the one hand, Th9 cells promote fibroblast differentiation, activation, and collagen secretion by secreting IL-9. On the other hand, they promote differentiation of Th0 cells into Th2 cells by secreting IL-4. Th9 cells and Th2 cells can promote each other, accelerating the Th1/Th2 imbalance and eventually forming a positive feedback of pulmonary fibrosis. In addition, we found that neutralizing IL-9 in both preventive and therapeutic settings ameliorates bleomycin-induced pulmonary fibrosis. Furthermore, we identified several critical signaling pathways involved in the effect of neutralizing IL-9 on pulmonary fibrosis by proteomics study. From an immunological perspective, we elucidated the novel role and underlying mechanism of Th9 cells in pulmonary fibrosis. Our study suggested that Th9-based immunotherapy may be employed as a treatment strategy for IPF.

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