Pathogenesis Of Idiopathic Pulmonary Fibrosis Research Articles

Gremlin-1 for the Differential Diagnosis of Idiopathic Pulmonary Fibrosis Versus Other Interstitial Lung Diseases: A Clinical and Pathophysiological Analysis

PurposeThe differential diagnosis of interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF) versus other non-IPF ILDs, is important for selecting the appropriate treatment. This retrospective study aimed to explore the utility of gremlin-1 for the differential diagnosis.MethodsSerum gremlin-1 concentrations were measured using an ELISA in 50 patients with IPF, 42 patients with non-IPF ILD, and 30 healthy controls. The baseline clinical data, including pulmonary functions, prognosis, and three serum biomarkers (Krebs von den Lungen-6 [KL6], surfactant protein-D [SP-D], and lactate dehydrogenase [LDH]), were obtained through a medical record review for analyzing their associations with serum gremlin-1 concentrations. To evaluate the origin of gremlin-1, we performed immunostaining on lung sections.ResultsSerum gremlin-1 concentrations were significantly higher in patients with IPF (mean concentration, 14.4 ng/mL), followed by those with non-IPF ILD (8.8 ng/mL) and healthy controls (1.6 ng/mL). The area under the curve for IPF versus non-IPF ILDs was 0.759 (95% confidence interval, 0.661–0.857), which was superior to that of KL6/SP-D/LDH. The sensitivity and specificity for gremlin-1 (cutoff, 10.4 ng/mL) was 72 and 69%, respectively. By contrast, serum gremlin-1 concentrations were not associated with the pulmonary functions nor the prognosis in all patients with ILDs. In immunostaining, the gremlin-1 was broadly upregulated in IPF lungs, particularly at myofibroblasts, bronchiolar/alveolar epithelium, and CD163-positive M2-like macrophages.ConclusionsGremlin-1 may be a useful biomarker to improve the diagnostic accuracy for IPF compared to non-IPF ILDs, suggesting a role of this molecule in the pathogenesis of IPF.

Trajectory modeling of endothelial-to-mesenchymal transition reveals galectin-3 as a mediator in pulmonary fibrosis

The endothelial-to-mesenchymal transition (EndMT) is an important source of fibrotic cells in idiopathic pulmonary fibrosis (IPF). However, how endothelial cells (ECs) are activated and how EndMT impact IPF remain largely elusive. Here, we use unsupervised pseudotemporal analysis to recognize the heterogeneity of ECs and reconstruct EndMT trajectory of bleomycin (BLM)-treated Tie2creER/+;Rosa26tdTomato/+ IPF mice. Genes like C3ar1 and Lgals3 (protein name galectin-3) are highly correlated with the transitional pseudotime, whose expression is gradually upregulated during the fate switch of ECs from quiescence to activation in fibrosis. Inhibition of galectin-3 via siRNA or protein antagonists in mice could alleviate the pathogenesis of IPF and the transition of ECs. With the stimulation of human pulmonary microvascular endothelial cells (HPMECs) by recombinant proteins and/or siRNAs for galectin-3 in vitro, β-catenin/GSK3β signaling and its upstream regulator AKT are perturbed, which indicates they mediate the EndMT progress. These results suggest that EndMT is essential to IPF process and provide potential therapeutic targets for vascular remodeling.

Multi-Modal Characterization of Monocytes in Idiopathic Pulmonary Fibrosis Reveals a Primed Type I Interferon Immune Phenotype.

Idiopathic pulmonary fibrosis (IPF) is the most severe form of chronic lung fibrosis. Circulating monocytes have been implicated in immune pathology in IPF but their phenotype is unknown. In this work, we determined the immune phenotype of monocytes in IPF using multi-colour flow cytometry, RNA sequencing and corresponding serum factors, and mapped the main findings to amount of lung fibrosis and single cell transcriptomic landscape of myeloid cells in IPF lungs. We show that monocytes from IPF patients displayed increased expression of CD64 (FcγR1) which correlated with amount of lung fibrosis, and an amplified type I IFN response ex vivo. These were accompanied by markedly raised CSF-1 levels, IL-6, and CCL-2 in serum of IPF patients. Interrogation of single cell transcriptomic data from human IPF lungs revealed increased proportion of CD64hi monocytes and “transitional macrophages” with higher expression of CCL-2 and type I IFN genes. Our study shows that monocytes in IPF patients are phenotypically distinct from age-matched controls, with a primed type I IFN pathway that may contribute to driving chronic inflammation and fibrosis. These findings strengthen the potential role of monocytes in the pathogenesis of IPF.

Cigarette smoke-inactivated SIRT1 promotes autophagy-dependent senescence of alveolar epithelial type 2 cells to induce pulmonary fibrosis

AimsThe senescence of alveolar epithelial type 2 (AT2) cells is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cigarette smoke (CS) is a strong risk factor for IPF and it is also a pro-senescent factor. Here we aimed to investigate whether and how CS induces AT2 cells senescence via a SIRT1/autophagy dependent pathway. Our results showed that CS extract (CSE) reduced autophagy and mitophagy and increased mitochondrial reactive oxygen species (mitoROS) in MLE-12 cells, an AT2 cell line. The autophagy inducer rapamycin (RAPA) and the mitochondria-targeted antioxidant mitoquinone (mitoQ) inhibited CSE-related senescence and decreased mitoROS. Next, we found that CSE promoted DNA damage, downregulated the nicotinamide adenine dinucleotide (NAD+)/nicotinamide adenine dinucleotide (NADH) ratio and suppressed SIRT1 activity. Activating SIRT1 with its activator SRT1720 attenuated senescence through an autophagy-dependent pathway. The NAD+ precursor nicotinamide mononucleotide and the poly ADP-ribose polymerase (PARP1) inhibitor olaparib also exerted anti-senescent effects by activating SIRT1. Moreover, the results showed that mitoQ and RAPA, in turn, elevated SIRT1 activity by inhibiting DNA damage. Consistent with these results, SRT1720 and mitoQ mitigated CS-induced AT2 cells senescence and lung fibrosis in vivo. Moreover, autophagy in AT2 cells was rescued by SRT1720. Taken together, our results suggested that CS-induced senescence of AT2 cells was due to decreased autophagy mediated by SIRT1 inactivation, which was attributed to competitive consumption of NAD+ caused by DNA damage-induced PARP1 activation. The reduction in autophagy, in turn, decreased SIRT1 activity by promoting mitochondrial oxidative stress-related DNA damage, thereby establishing a positive feedback loop between SIRT1 and autophagy in CS-induced AT2 cells senescence. Consequently, CS-inactivated SIRT1 promoted autophagy-dependent senescence of AT2 cells to induce pulmonary fibrosis.

Hermansky-Pudlak syndrome-2 alters mitochondrial homeostasis in the alveolar epithelium of the lung

BackgroundMitochondrial dysfunction has emerged as an important player in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a common cause of idiopathic interstitial lung disease in adults. Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that causes a similar type of pulmonary fibrosis in younger adults, although the role of mitochondrial dysfunction in this condition is not understood.MethodsWe performed a detailed characterization of mitochondrial structure and function in lung tissues and alveolar epithelial cells deficient in the adaptor protein complex 3 beta 1 (Ap3b1) subunit, the gene responsible for causing subtype 2 of HPS (HPS-2).ResultsWe observed widespread changes in mitochondrial homeostasis in HPS-2 cells, including the acquisition of abnormally shaped mitochondria, with reduced number of cristae, and markedly reduced activity of the electron transport chain and the tricarboxylic acid cycle. We also found that mitochondrial redox imbalance and activity of the mitochondrial unfolded protein response were dysregulated in HPS-2 cells and this associated with various other changes that appeared to be compensatory to mitochondrial dysfunction. This included an increase in glycolytic activity, an upregulation in the expression of mitochondrial biogenesis factors and enhanced activation of the energy-conserving enzyme AMP-activated protein kinase.ConclusionIn summary, our findings indicate that mitochondrial function is dramatically altered in HPS-2 lung tissues, suggesting dysfunction of this organelle might be a driver of HPS lung disease.

Role of various imbalances centered on alveolar epithelial cell/fibroblast apoptosis imbalance in the pathogenesis of idiopathic pulmonary fibrosis.

There have been recent extensive studies and rapid advancement on the pathogenesis underlying idiopathic pulmonary fibrosis (IPF), and intricate pathogenesis of IPF has been suggested. The purpose of this study was to clarify the logical relationship between these mechanisms. An extensive search was undertaken of the PubMed using the following keywords: “etiology,” “pathogenesis,” “alveolar epithelial cell (AEC),” “fibroblast,” “lymphocyte,” “macrophage,” “epigenomics,” “histone,” acetylation,” “methylation,” “endoplasmic reticulum stress,” “mitochondrial dysfunction,” “telomerase,” “proteases,” “plasminogen,” “epithelial-mesenchymal transition,” “oxidative stress,” “inflammation,” “apoptosis,” and “idiopathic pulmonary fibrosis.” This search covered relevant research articles published up to April 30, 2020. Original articles, reviews, and other articles were searched and reviewed for content; 240 highly relevant studies were obtained after screening. IPF is likely the result of complex interactions between environmental, genetic, and epigenetic factors: environmental exposures affect epigenetic marks; epigenetic processes translate environmental exposures into the regulation of chromatin; epigenetic processes shape gene expression profiles; in turn, an individual's genetic background determines epigenetic marks; finally, these genetic and epigenetic factors act in concert to dysregulate gene expression in IPF lung tissue. The pathogenesis of IPF involves various imbalances including endoplasmic reticulum, telomere length homeostasis, mitochondrial dysfunction, oxidant/antioxidant imbalance, Th1/Th2 imbalance, M1–M2 polarization of macrophages, protease/antiprotease imbalance, and plasminogen activation/inhibition imbalance. These affect each other, promote each other, and ultimately promote AEC/fibroblast apoptosis imbalance directly or indirectly. Excessive AEC apoptosis and impaired apoptosis of fibroblasts contribute to fibrosis. IPF is likely the result of complex interactions between environmental, genetic, and epigenetic factors. The pathogenesis of IPF involves various imbalances centered on AEC/fibroblast apoptosis imbalance.

Persistent, Progressive Pulmonary Fibrosis and Epithelial Remodeling in Mice.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease with underlying mechanisms that have been primarily investigated in mice after intratracheal instillation of a single dose of bleomycin. However, the model has significant limitations, including transient fibrosis that spontaneously resolves and its failure to fully recapitulate the epithelial remodeling in the lungs of patients with IPF. Thus, there remains an unmet need for a preclinical model with features that more closely resemble the human disease. Repetitive intratracheal instillation of bleomycin has previously been shown to recapitulate some of these features, but the instillation procedure is complex, and the long-term consequences on epithelial remodeling and fibrosis persistence and progression remain poorly understood. Here, we developed a simplified repetitive bleomycin instillation strategy consisting of three bi-weekly instillations that leads to persistent and progressive pulmonary fibrosis. Lung histology demonstrates increased collagen deposition, fibroblast accumulation, loss of type I and type II alveolar epithelial cells within fibrotic areas, bronchiolization of the lung parenchyma with CCSP+ cells, remodeling of the distal lung into cysts reminiscent of simple honeycombing, and accumulation of hyperplastic transitional KRT8+ epithelial cells. Micro-computed tomographic imaging demonstrated significant traction bronchiectasis and subpleural fibrosis. Thus, the simplified repetitive bleomycin instillation strategy leads to progressive fibrosis and recapitulates the histological and radiographic characteristics of IPF. Compared with the single bleomycin instillation model, we suggest that the simplified repetitive instillation model may be better suited to address mechanistic questions about IPF pathogenesis and preclinical studies of antifibrotic drug candidates.

Gene fusion of IL7 involved in the regulation of idiopathic pulmonary fibrosis.

Background:Idiopathic pulmonary fibrosis (IPF) is a rare form of immune-mediated interstitial lung disease characterized by progressive pulmonary fibrosis and scarring. The pathogenesis of IPF is still unclear. Gene fusion events exist universally during transcription and show alternated patterns in a variety of lung diseases. Therefore, the comprehension of the function of gene fusion in IPF might shed light on IPF pathogenesis research and facilitate treatment development.Methods:In this study, we included 91 transcriptome datasets from the National Center for Biotechnology Information (NCBI), including 52 IPF patients and 39 healthy controls. We detected fusion events in these datasets and probed gene fusion-associated differential gene expression and functional pathways. To obtain robust results, we corrected the batch bias across different projects.Results:We identified 1550 gene fusion events in all transcriptomes and studied the possible impacts of IL7 = AC083837.1 gene fusion. The two genes locate adjacently in chromosome 8 and share the same promoters. Their fusion is associated with differential expression of 282 genes enriched in six Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and 35 functional gene sets. Gene ontology (GO) enrichment analysis shows that IL7 = AC083837.1 gene fusion is associated with the enrichment of 187 gene sets. The co-expression network of interleukin-7 (IL7) indicates that decreased IL7 expression is associated with many pathways that regulate IPF progress.Conclusion:Based on the results, we conclude that IL7 = AC083837.1 gene fusion might exacerbate fibrosis in IPF via enhancing activities of natural killer cell-mediated cytotoxicity, skin cell apoptosis, and vessel angiogenesis, the interaction of which contributes to the development of fibrosis and the deterioration of respiratory function of IPF patients. Our work unveils the possible roles of gene fusion in regulating IPF and demonstrates that gene fusion investigation is a valid approach in probing immunologic mechanisms and searching potential therapeutic targets for treating IPF. The reviews of this paper are available via the supplemental material section.

Co-delivery of siPTPN13 and siNOX4 via (myo)fibroblast-targeting polymeric micelles for idiopathic pulmonary fibrosis therapy.

Rationale: (Myo)fibroblasts are the ultimate effector cells responsible for the production of collagen within alveolar structures, a core phenomenon in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Although (myo)fibroblast-targeted therapy holds great promise for suppressing the progression of IPF, its development is hindered by the limited drug delivery efficacy to (myo)fibroblasts and the vicious circle of (myo)fibroblast activation and evasion of apoptosis.Methods: Here, a dual small interfering RNA (siRNA)-loaded delivery system of polymeric micelles is developed to suppress the development of pulmonary fibrosis via a two-arm mechanism. The micelles are endowed with (myo)fibroblast-targeting ability by modifying the Fab' fragment of the anti-platelet-derived growth factor receptor-α (PDGFRα) antibody onto their surface. Two different sequences of siRNA targeting protein tyrosine phosphatase-N13 (PTPN13, a promoter of the resistance of (myo)fibroblasts to Fas-induced apoptosis) and NADPH oxidase-4 (NOX4, a key regulator for (myo)fibroblast differentiation and activation) are loaded into micelles to inhibit the formation of fibroblastic foci.Results: We demonstrate that Fab'-conjugated dual siRNA-micelles exhibit higher affinity to (myo)fibroblasts in fibrotic lung tissue. This Fab'-conjugated dual siRNA-micelle can achieve remarkable antifibrotic effects on the formation of fibroblastic foci by, on the one hand, suppressing (myo)fibroblast activation via siRNA-induced knockdown of NOX4 and, on the other hand, sensitizing (myo)fibroblasts to Fas-induced apoptosis by siRNA-mediated PTPN13 silencing. In addition, this (myo)fibroblast-targeting siRNA-loaded micelle did not induce significant damage to major organs, and no histopathological abnormities were observed in murine models.Conclusion: The (myo)fibroblast-targeting dual siRNA-loaded micelles offer a potential strategy with promising prospects in molecular-targeted fibrosis therapy.

Treatment with Number 2 Feibi Recipe, a Compound Traditional Chinese Medicine Reduces Bleomycin-induced Pulmonary Fibrosis in Mice

Objective: Oxidative stress with reactive oxygen species (ROS) generated from exogenous oxidants and pollutants exposure is involved in the pathogenesis of Idiopathic pulmonary fibrosis (IPF). Number 2 Feibi Recipe (Number 2 FBR) is a traditional Chinese herbal formula which can attenuate the lung injury induced by PM2.5. The present study is to explore the effect and mechanism of Number 2 FBR on bleomycin (BLM)-induced pulmonary fibrosis in C57BL/6Cnc mice. Method: Bleomycin-induced C57BL/6Cnc mice were treated with Number 2 FBR and Sulforphane for two weeks. HE and Masson trichrome staining were performed to evaluate pathological changes in lung tissues. The extent of lung fibrosis was evaluated with fibrosis scores, collagen volume fraction, and hydroxyproline concentration. Levels of SOD and 8-iso-PGF2α in lung tissues were measured by using commercial assay kits. The levels of Nrf2, SOD, GSH-Px, and TGF-β1 relative protein and mRNA in lung tissues were measured by real time PCR and Western blot respectively. Results: The results showed that Number 2 FBR ameliorated bleomycin-induced pathological changes, collagen deposition and significantly decreased fibrosis scores, collagen volume fraction, and hydroxyproline concentration in the mice lungs. Additionally, Number 2 FBR inhibited the expression of 8-iso-prostaglandin F2α (8-iso-PGF2α) and transforming growth factor beta1 (TGF-β1), and increased the expression of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), superoxide dismutase (SOD) and Glutathione peroxidase (GSH-Px) in lung tissues. Conclusion: Number 2 FBR has an effect of anti-fibrosis by regulating the lung oxidants and antioxidants balance.

Suppressing Sart1 to modulate macrophage polarization by siRNA-loaded liposomes: a promising therapeutic strategy for pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and diffuse form of interstitial lung disease of unknown etiology with a fatal outcome. Although various strategies for IPF have been developed over the last few decades, no significant positive impact on the prognosis of IPF has been observed. According to the current paradigm, macrophages have been recognized to play a significant role in IPF pathogenesis. Here, we report a potential nanomedicine-based gene therapy for IPF based on regulate macrophage polarization.Method: C57BL/6 mice were obtained and used to establish a bleomycin (BLM)-induced pulmonary fibrosis animal model, and Sart1 siRNA-loaded liposomes were designed for in vivo experiment. The experimental animals were administered BLM intratracheally on day 0 and treated with Sart1 siRNA on days 14 and 17. In the in vitro experiment, we further examined the function of Sart1 in macrophages.Results: Our data indicated that the liposomes could passively target the fibrotic area in the lung and efficiently accumulate in macrophages. The suppression of Sart1 by siRNA-loaded liposomes significantly protected mice against BLM-induced lung injury and fibrosis, which was attributed to attenuated M2 macrophage infiltration in the lung.Conclusion: Our study provides a valuable reference for modulating macrophage polarization and a promising strategy for the treatment of pulmonary fibrosis in clinical settings.

Network analysis of transcriptomics data for the prediction and prioritization of membrane-associated biomarkers for idiopathic pulmonary fibrosis (IPF) by bioinformatics approach.

Idiopathic pulmonary fibrosis (IPF) is a rare yet crucial persistent lung disorder that actuates scarring of lung tissues, which makes breathing difficult. Smoking, environmental pollution, and certain viral infections could initiate lung scarring. However, the molecular mechanism involved in IPF remains elusive. To develop an efficient therapeutic arsenal against IPF, it is vital to understand the pathology and deviations in biochemical pathways that lead to disorder. In this study, we availed network analysis and other computational pipelines to delineate the prominent membrane proteins as diagnostic biomarkers and therapeutic targets for IPF. This study yielded a significant role of glycosaminoglycan binding, endothelin, and GABA-B receptor signaling pathway in IPF pathogenesis. Furthermore, ADCY8, CRH, FGB, GPR17, MCHR1, NMUR1, and SAA1 genes were found to be immensely involved with IPF, and the enrichment pathway analysis suggests that most of the pathways were corresponding to membrane transport and signal transduction functionalities. This analysis could help in better understanding the molecular mechanism behind IPF to develop an efficient therapeutic target or biomarkers for IPF.

Integrated analysis of the molecular mechanisms in idiopathic pulmonary fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonia. Some miRNAs may be associated with IPF and may affect the occurrence and development of IPF in various pathways. Many miRNAs and genes that may be involved in the development of IPF have been discovered using chip and high throughput technologies.Methods: We analyzed one miRNA and four mRNA databases. We identified hub genes and pathways related to IPF using GO, KEGG enrichment analysis, gene set variation analysis (GSVA), PPI network construction, and hub gene analysis. A comprehensive analysis of differentially expressed miRNAs (DEMs), predicted miRNA target genes, and differentially expressed genes (DEGs) led to the creation of a miRNA-mRNA regulatory network in IPF.Results: We found 203 DEGs and 165 DEMs that were associated with IPF. The findings of enrichment analyses showed that these DEGs were mainly involved in antimicrobial humoral response, antimicrobial humoral immune response mediated by antimicrobial peptide, extracellular matrix organization, cell killing, and organ or tissue specific immune response. The VEGFA, CDH5, and WNT3A genes overlapped between hub genes and the miRNA-mRNA regulatory network. The miRNAs including miR-199b-5p, miR-140-5p, miR-199a-5p, miR-125A-5p, and miR-107 that we predicted would regulate the VEGFA, CDH5, and WNT3A genes, which were also associated with IPF or other fibrosis-related diseases. GSVA indicated that metabolic processes of UTP and IMP, immune response, regulation of Th2 cell cytokine production, and positive regulation of NK cell-mediated immunity are associated with the pathogenesis and treatment of IPF. These pathways also interact with VEGFA, CDH5, and WNT3A.Conclusion: These findings provide a new research direction for the diagnosis and treatment of IPF.

Serum calprotectin as new biomarker for disease severity in idiopathic pulmonary fibrosis: a cross-sectional study in two independent cohorts

BackgroundNon-invasive biomarkers for the assessment of disease severity in idiopathic pulmonary fibrosis (IPF) are urgently needed. Calprotectin belongs to the S-100 proteins produced by neutrophils, which likely contribute to IPF...

ЕВОЛЮЦІЯ ПРИНЦИПІВ ДІАГНОСТИКИ І ТЕРАПІЇ ІДІОПАТИЧНОГО ЛЕГЕНЕВОГО ФІБРОЗУ У ПОЛОЖЕННЯХ МІЖНАРОДНИХ КЛІНІЧНИХ НАСТАНОВ

EVOLUTION OF PRINCIPLES OF DIAGNOSIS AND TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS IN THE INTERNATIONAL GUIDELINE STATEMENTS Y. I. Feshchenko, V. K. Gavrysyuk, N. G. Gorovenko, Y. A. Dziublyk, I. V. Liskina Abstract Idiopathic pulmonary fibrosis (IPF) is specific form of chronic progressive interstitial fibrosing pneumonia of unknown nature, mainly occurring in patients > 50 years of age, limited to the lungs and associated with histological and/or radiological pattern of usual interstitial pneumonia. Epidemiological studies estimate that prevalence of ILF in different countries varies between 1,25 and 63 cases per 100 000 persons. Along with that, ILF is characterized by unfavorable prognosis — median survival time ranges within 2,5−3,5 years from the time of diagnosis. In 2000 American thoracic society (ATS) and European respiratory society (ERS) published first international statement on diagnosis and treatment of ILF — American Thoracic Society, European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Data from studies, accumulated during next 10 years of research, determined the necessity of update of certain diagnostic criteria and principles of therapy. In this regard, a new guideline for diagnosis and treatment of IPF was published in 2011 and approved by ATS, ERS, Japanese Respiratory Society (JRS) and Latin American Thoracic Association (ALAT) — An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. A new update on “Treatment of IPF” was published in 2015, and chapter “Diagnosis” was updated later in 2018. Current literature review focuses on the principles and algorithms of IPF treatment and the changes in guidelines, occurred from the time of first Statement published. Summarizing review results, we can conclude, that evolution of diagnostics principles, which limited the indications for surgical lung biopsy for the purpose of diagnosis verification, is caused by explosive technological advances in the field of chest computed tomography. The capability of computed tomography has grown to such an extent, that in terms of morphological diagnosing this method can compete with histological examination. The changes in management principles were evoked by the revision of IPF pathogenesis mechanisms. Since 2000, most of the experts concluded, that fibrosis, rather than inflammation, was the leading link of pathogenesis. A fibrosing process, initially playing a reparative role, further due to unknown reasons, gains an uncontrolled progressive character. Accordingly, antifibrotic compounds, such as pirfenidone and nintedanib, came to substitute glucocorticosteroids, known for their powerful antiinflammatory potential. The publication also presents the review of most relevant randomized clinical trials on safety and efficacy of antifibrotic drugs — pirfenidone and nintedanib. Key words: idiopathic pulmonary fibrosis, diagnostics, treatment, algorithms, pirfenidone, nintedanib. Ukr. Pulmonol. J. 2021;29(3):5–23.

Non-coding RNAs as Regulators of Cellular Senescence in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease.

Cellular senescence is a cell fate implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Cellular senescence occurs in response to cellular stressors such as oxidative stress, DNA damage, telomere shortening, and mitochondrial dysfunction. Whether these stresses induce cellular senescence or an alternative cell fate depends on the type and magnitude of cellular stress, but also on intrinsic factors regulating the cellular stress response. Non-coding RNAs, including both microRNAs and long non-coding RNAs, are key regulators of cellular stress responses and susceptibility to cellular senescence. In this review, we will discuss cellular mechanisms that contribute to senescence in IPF and COPD and highlight recent advances in our understanding of how these processes are influenced by non-coding RNAs. We will also discuss the potential therapeutic role for targeting non-coding RNAs to treat these chronic lung diseases.

Fisetin Alleviated Bleomycin-Induced Pulmonary Fibrosis Partly by Rescuing Alveolar Epithelial Cells From Senescence.

Idiopathic pulmonary fibrosis is an aging-associated disease, satisfactory therapies are not yet available. Accelerated senescence of alveolar epithelial cells plays an important part in Idiopathic pulmonary fibrosis pathogenesis. Fisetin (FIS) is a natural non-toxic flavonoid, which has many pharmacological functions. However, the role of FIS in pulmonary fibrosis has not been established. In this study, we found that FIS treatment apparently alleviated BLM-induced weight loss, inflammatory cells infiltration, inflammatory factors expression, collagen deposition and alveolar epithelial cell senescence, along with AMPK activation and the down regulation of NF-κB and TGF-β/Smad3 in vivo. In vitro, FIS administration significantly inhibited the senescence of alveolar epithelial cells and senescence-associated secretory phenotype, followed by reduced transdifferentiation of fibroblasts to myofibroblasts as well as collagen deposition in fibroblasts, which was blocked by an AMPK inhibitor, Compound C. Together, these results suggest that FIS can alleviate the development of BLM-induced pulmonary fibrosis, which is related to the inhibition of TGF-β/Smad3 signaling and the reduction of alveolar epithelium cell senescence by regulating AMPK/NF-κB signaling pathway. FIS may be a promising candidate for patients with pulmonary fibrosis.

Extracellular Vesicles from Fibroblasts Induce Epithelial-Cell Senescence in Pulmonary Fibrosis.

Aberrant epithelial-mesenchymal interactions have critical roles in regulating fibrosis development. The involvement of extracellular vesicles (EVs), including exosomes, remains to be elucidated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we found that lung fibroblasts (LFs) from patients with IPF induce cellular senescence via EV-mediated transfer of pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF-derived EVs increased mitochondrial reactive oxygen species and associated mitochondrial damage in lung epithelial cells, leading to activation of the DNA damage response and subsequent epithelial-cell senescence. We showed that IPF LF-derived EVs contain elevated levels of microRNA-23b-3p (miR-23b-3p) and miR-494-3p, which suppress SIRT3, resulting in the epithelial EV-induced phenotypic changes. Furthermore, the levels of miR-23b-3p and miR-494-3p found in IPF LF-derived EVs correlated positively with IPF disease severity. These findings reveal that the accelerated epithelial-cell mitochondrial damage and senescence observed during IPF pathogenesis are caused by a novel paracrine effect of IPF fibroblasts via microRNA-containing EVs.

Mitochondrial antiviral signaling protein is crucial for the development of pulmonary fibrosis.

Danger signals, or damage-associated molecular patterns (DAMPs), instigate mitochondrial innate immune responses wherein mitochondrial antiviral signaling protein (MAVS) functions as a key platform molecule to mediate them. The role of MAVS in the pathogenesis of idiopathic pulmonary fibrosis (IPF), however, has not yet been identified. Whether MAVS signalling can be modulated by currently existing drugs has also not been explored.We used an established model of pulmonary fibrosis to demonstrate that MAVS is a critical mediator of multiple DAMP signalling pathways and the consequent lung fibrosis after bleomycin-induced injury in vivoAfter bleomycin injury, MAVS expression was mainly observed in macrophages. Multimeric MAVS aggregation, a key event of MAVS signalling activation, was significantly increased and persisted in bleomycin-injured lungs. A proapoptotic BH3 mimetic, ABT-263, attenuated the expression of MAVS and its signalling and, consequently, the development of experimental pulmonary fibrosis. In contrast, the therapeutic effects of nintedanib and pirfenidone, two drugs approved for IPF treatment, were not related to the modulation of MAVS or its signalling. Multimeric MAVS aggregation was significantly increased in lungs from IPF patients as well.MAVS may play an important role in the development of pulmonary fibrosis, and targeting MAVS with BH3 mimetics may provide a novel and much needed therapeutic strategy for IPF.

THE CASE OF ASCENDING PARAPARESIS FOLLOWING NINTEDANIB

SESSION TITLE: Fellows Diffuse Lung Disease SESSION TYPE: Fellow Case Reports PRESENTED ON: October 18-21, 2020 INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is an incurable, progressive fibrosing interstitial lung disease reflected by a decline in lung function, worsening dyspnea, exercise capacity, and overall poor prognosis. Nintedanib is one of two anti-fibrotic therapies approved for the treatment of IPF. We present the case of a patient who presented with ascending paraparesis following Nintedanib and here by hope to shed light on treatment of IPF and potential but unproven side effects of Nintedanib. CASE PRESENTATION: 39-year-old male with history of familial IPF secondary to short telomere syndrome who presented with bilateral progressive upper and lower extremity paresthesia and weakness which started shortly after he was commenced on Nintedanib for pulmonary fibrosis. This progressed to numbness and weakness till he could barely walk or lift his arms against gravity by day 5. He denied any preceding upper respiratory tract or gastrointestinal symptoms. Physical exam was significant for bibasilar fine velcro crackles in the lungs, hyporeflexia and flaccid tone with power of 3/5 in all extremities. He had negative autoimmune work up. Cerebro-spinal fluid analysis, Pan spinal MRI and MRI of the brain were unrevealing. Electromyogram was significant for motor polyneuropathy with limited demyelinating features. Management was mainly supportive with physical therapy and patient gradually regained his strength back to baseline. DISCUSSION: Nintedanib inhibits multiple tyrosine kinases and targets growth factors like vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor which have been implicated in the pathogenesis of idiopathic pulmonary fibrosis. It is important to monitor potential adverse effects aside from what was noted in the relevant trials of which diarrhea was the commonest. Other side effects were bronchitis, upper respiratory tract symptoms, nausea, vomiting, cough weight loss and back ache. Our patient presented with paresthesias and ascending paresis after taking Nintadenib. He had negative extensive work up for other causes of ascending paralysis and his weakness gradually improved after stopping the medication and with Physical therapy. He was initially offered Intravenous immunoglobulin but was already improving clinically with supportive therapy and physical therapy, so after weighing risk to benefit, decided against it. CONCLUSIONS: With the widening use of Nintedanib, more patients will undoubtedly be exposed to it, and providers should be aware of this unlikely, but serious, potential side effect of Guillain-Barre like presentation which has been associated with other tyrosine kinase inhibitors. To the best of our knowledge, this is the first reported case of ascending paresis following the use of Nintedanib in particular. Reference #1: Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. (2015). New England Journal Of Medicine, 373(8), 782-782. doi: 10.1056/nejmx150012 Reference #2: "Human Medicines European Public Assessment Report (EPAR): Ofev, Nintedanib, Idiopathic Pulmonary Fibrosis, Date Of Authorisation: 14/01/2015, Revision: 10, Status: Authorised". 2019. Case Journals, doi:10.31525/cmr-587247. Reference #3: Lehky, T. J. et al. "Neuromuscular Junction Toxicity With Tandutinib Induces A Myasthenic-Like Syndrome". Neurology, vol 76, no. 3, 2011, pp. 236-241. Ovid Technologies (Wolters Kluwer Health), doi:10.1212/wnl.0b013e3182074a69. DISCLOSURES: No relevant relationships by Shehabaldin Alqalyoobi, source=Web Response No relevant relationships by Afua Kunadu, source=Web Response No relevant relationships by Ogugua Obi, source=Web Response