Eur Respir J. 2022 Jan 20:2102969. doi: 10.1183/13993003.02969-2021. Online ahead of print.

NO ABSTRACT

PMID:35058247 | DOI:10.1183/13993003.02969-2021

BMJ Open Respir Res. 2022 Jan;9(1):e001060. doi: 10.1136/bmjresp-2021-001060.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal interstitial lung disease (ILD); other ILDs have a progressive, fibrotic phenotype (PF-ILD). Antifibrotic agents can slow but not stop disease progression in patients with IPF or PF-ILD. c-Jun N-terminal kinases (JNKs) are stress-activated protein kinases implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarisation of profibrotic macrophages, fibroblast activation and collagen production. CC-90001, an orally administered (PO), one time per day, JNK inhibitor, is being evaluated in IPF and PF-ILD.

METHODS AND ANALYSIS: This is a phase 2, randomised, double-blind, placebo-controlled study evaluating efficacy and safety of CC-90001 in patients with IPF (main study) and patients with PF-ILD (substudy). Both include an 8-week screening period, a 24-week treatment period, up to an 80-week active-treatment extension and a 4-week post-treatment follow-up. Patients with IPF (n=165) will be randomised 1:1:1 to receive 200 mg or 400 mg CC-90001 or placebo administered PO one time per day; up to 25 patients/arm will be permitted concomitant pirfenidone use. Forty-five patients in the PF-ILD substudy will be randomised 2:1 to receive 400 mg CC-90001 or placebo. The primary endpoint is change in per cent predicted forced vital capacity from baseline to Week 24 in patients with IPF.

ETHICS AND DISSEMINATION: This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles and local ethical and legal requirements. Results will be reported in a peer-reviewed publication.

TRIAL REGISTRATION NUMBER: NCT03142191.

PMID:35058236 | DOI:10.1136/bmjresp-2021-001060

Respir Res. 2022 Jan 20;23(1):12. doi: 10.1186/s12931-021-01923-5.

ABSTRACT

BACKGROUND: Fibrotic Interstitial lung diseases (ILD) are a heterogeneous group of chronic lung diseases characterized by diverse degrees of lung inflammation and remodeling. They include idiopathic ILD such as idiopathic pulmonary fibrosis (IPF), and ILD secondary to chronic inflammatory diseases such as connective tissue disease (CTD). Precise differential diagnosis of ILD is critical since anti-inflammatory and immunosuppressive drugs, which are beneficial in inflammatory ILD, are detrimental in IPF. However, differential diagnosis of ILD is still difficult and often requires an invasive lung biopsy. The primary aim of this study is to identify volatile organic compounds (VOCs) patterns in exhaled air to non-invasively discriminate IPF and CTD-ILD. As secondary aim, the association between the IPF and CTD-ILD discriminating VOC patterns and functional impairment is investigated.

METHODS: Fifty-three IPF patients, 53 CTD-ILD patients and 51 controls donated exhaled air, which was analyzed for its VOC content using gas chromatograph- time of flight- mass spectrometry.

RESULTS: By applying multivariate analysis, a discriminative profile of 34 VOCs was observed to discriminate between IPF patients and healthy controls whereas 11 VOCs were able to distinguish between CTD-ILD patients and healthy controls. The separation between IPF and CTD-ILD could be made using 16 discriminating VOCs, that also displayed a significant correlation with total lung capacity and the 6 min' walk distance.

CONCLUSIONS: This study reports for the first time that specific VOC profiles can be found to differentiate IPF and CTD-ILD from both healthy controls and each other. Moreover, an ILD-specific VOC profile was strongly correlated with functional parameters. Future research applying larger cohorts of patients suffering from a larger variety of ILDs should confirm the potential use of breathomics to facilitate fast, non-invasive and proper differential diagnosis of specific ILDs in the future as first step towards personalized medicine for these complex diseases.

PMID:35057817 | DOI:10.1186/s12931-021-01923-5

Int J Mol Sci. 2022 Jan 17;23(2):977. doi: 10.3390/ijms23020977.

ABSTRACT

Interstitial lung diseases represent a heterogeneous and wide group of diseases in which factors leading to disease initiation and progression are not fully understood. Recent evidence suggests that the lung microbiome might influence the pathogenesis and progression of interstitial lung diseases. In recent years, the utilization of culture-independent methodologies has allowed the identification of complex and dynamic communities of microbes, in patients with interstitial lung diseases. However, the potential mechanisms by which these changes may drive disease pathogenesis and progression are largely unknown. The aim of this review is to discuss the role of the altered lung microbiome in several interstitial lung diseases. Untangling the host-microbiome interaction in the lung and airway of interstitial lung disease patients is a research priority. Thus, lung dysbiosis is a potentially treatable trait across several interstitial lung diseases, and its proper characterization and treatment might be crucial to change the natural history of these diseases and improve outcomes.

PMID:35055163 | DOI:10.3390/ijms23020977

Cells. 2022 Jan 11;11(2):235. doi: 10.3390/cells11020235.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal degenerative lung disease of unknown etiology. Although in its final stages it implicates, in a reactive manner, all lung cell types, the initial damage involves the alveolar epithelial compartment, in particular the alveolar epithelial type 2 cells (AEC2s). AEC2s serve dual progenitor and surfactant secreting functions, both of which are deeply impacted in IPF. Thus, we hypothesize that the size of the surfactant processing compartment, as measured by LysoTracker incorporation, allows the identification of different epithelial states in the IPF lung. Flow cytometry analysis of epithelial LysoTracker incorporation delineates two populations (Lysohigh and Lysolow) of AEC2s that behave in a compensatory manner during bleomycin injury and in the donor/IPF lung. Employing flow cytometry and transcriptomic analysis of cells isolated from donor and IPF lungs, we demonstrate that the Lysohigh population expresses all classical AEC2 markers and is drastically diminished in IPF. The Lysolow population, which is increased in proportion in IPF, co-expressed AEC2 and basal cell markers, resembling the phenotype of the previously identified intermediate AEC2 population in the IPF lung. In that regard, we provide an in-depth flow-cytometry characterization of LysoTracker uptake, HTII-280, proSP-C, mature SP-B, NGFR, KRT5, and CD24 expression in human lung epithelial cells. Combining functional analysis with extracellular and intracellular marker expression and transcriptomic analysis, we advance the current understanding of epithelial cell behavior and fate in lung fibrosis.

PMID:35053350 | DOI:10.3390/cells11020235

Am J Respir Crit Care Med. 2022 Jan 20. doi: 10.1164/rccm.202106-1485OC. Online ahead of print.

ABSTRACT

RATIONALE: Chronic cough remains a major and often debilitating symptom for patients with idiopathic pulmonary fibrosis (IPF). In a phase 2a study, inhaled RVT-1601 reduced daytime cough and 24-hour average cough counts in patients with IPF.

OBJECTIVES: To determine the efficacy, safety and optimal dose of inhaled RVT-1601 for the treatment of chronic cough in patients with IPF.

METHODS: In this multicenter, randomized, placebo-controlled phase 2b study, patients with IPF and chronic cough for ≥8 weeks were randomized (1:1:1:1) to receive 10, 40, and 80 mg RVT-1601 three times daily or placebo for 12 weeks. The primary endpoint was change from baseline to end of treatment in log-transformed 24-hour cough count. Key secondary endpoints were change from baseline in cough severity and cough specific quality of life. Safety was monitored throughout the study.

MEASUREMENTS AND MAIN RESULTS: The study was prematurely terminated due to the impact of COVID-19 pandemic. Overall, 108 patients (mean age 71.0 years, 62.9% males) received RVT-1601 10 mg (n = 29), 40 mg (n = 25), 80 mg (n = 27), or matching placebo (n = 27); 61.1% (n = 66) completed double-blind treatment. No statistically significant difference was observed in the least-squares mean change from baseline in log-transformed 24-hour average cough count, cough severity, and cough-specific quality of life score between the RVT-1601 groups and placebo. The mean percentage change from baseline in 24-hour average cough count was 27.7% in the placebo group. Treatment was generally well tolerated.

CONCLUSIONS: Treatment with inhaled RVT-1601 (10, 40 and 80 mg TID) did not provide benefit over placebo for the treatment of chronic cough in patients with IPF. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT03864328.

PMID:35050837 | DOI:10.1164/rccm.202106-1485OC

J Cell Physiol. 2022 Jan 19. doi: 10.1002/jcp.30684. Online ahead of print.

ABSTRACT

Pathological fibrosis contributes to progression of various diseases, for which the therapeutic options are limited. Idiopathic pulmonary fibrosis (IPF) is one such progressive and fatal interstitial fibrotic disease that is often characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to stiff lung tissue and impaired gas exchange. However, the molecular mechanisms underlying IPF progression remain largely unknown. In this study, we determined the role of Runt-related transcription factor 1 (RUNX1), an evolutionarily conserved transcription factor, in the differentiation of human lung fibroblasts (HLFs) in vitro and in an animal model of bleomycin (BLM)-induced lung fibrosis. We observed that the expression of RUNX1 was significantly increased in the lungs of BLM-injected mice as compared to saline-treated mice. Furthermore, HLFs stimulated with transforming growth factor β (TGF-β) showed significantly higher RUNX1 expression at both mRNA and protein levels, and compartmentalization in the nucleus. Inhibition of RUNX1 in HLFs (using siRNA) showed a significant reduction in the differentiation of fibroblasts into myofibroblasts as evidenced by reduced expression of alpha-smooth muscle actin (α-SMA), TGF-β and ECM proteins such as fibronectin 1 (FN1), and collagen 1A1 (COL1A1). Mechanistic studies revealed that the increased expression of RUNX1 in TGF-β-stimulated lung fibroblasts is due to enhanced mRNA stability of RUNX1 through selective interaction with the RNA-binding profibrotic protein, human antigen R (HuR). Collectively, our data demonstrate that increased expression of RUNX1 augments processes involved in lung fibrosis including the differentiation of fibroblasts into collagen-synthesizing myofibroblasts. Our study suggests that targeting RUNX1 could limit the progression of organ fibrosis in diseases characterized by abnormal collagen deposition.

PMID:35048404 | DOI:10.1002/jcp.30684

PLoS One. 2022 Jan 19;17(1):e0262737. doi: 10.1371/journal.pone.0262737. eCollection 2022.

ABSTRACT

INTRODUCTION: The coronavirus disease 2019 (COVID-19), emerged in late 2019, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The risk factors for idiopathic pulmonary fibrosis (IPF) and COVID-19 are reported to be common. This study aimed to determine the potential role of differentially expressed genes (DEGs) common in IPF and COVID-19.

MATERIALS AND METHODS: Based on GEO database, we obtained DEGs from one SARS-CoV-2 dataset and five IPF datasets. A series of enrichment analysis were performed to identify the function of upregulated and downregulated DEGs, respectively. Two plugins in Cytoscape, Cytohubba and MCODE, were utilized to identify hub genes after a protein-protein interaction (PPI) network. Finally, candidate drugs were predicted to target the upregulated DEGs.

RESULTS: A total of 188 DEGs were found between COVID-19 and IPF, out of which 117 were upregulated and 71 were downregulated. The upregulated DEGs were involved in cytokine function, while downregulated DEGs were associated with extracellular matrix disassembly. Twenty-two hub genes were upregulated in COVID-19 and IPF, for which 155 candidate drugs were predicted (adj.P.value < 0.01).

CONCLUSION: Identifying the hub genes aberrantly regulated in both COVID-19 and IPF may enable development of molecules, encoded by those genes, as therapeutic targets for preventing IPF progression and SARS-CoV-2 infections.

PMID:35045126 | DOI:10.1371/journal.pone.0262737

Sci Transl Med. 2022 Jan 19;14(628):eabn9849. doi: 10.1126/scitranslmed.abn9849. Epub 2022 Jan 19.

ABSTRACT

[Figure: see text].

PMID:35044786 | DOI:10.1126/scitranslmed.abn9849

Cell Death Dis. 2022 Jan 17;13(1):60. doi: 10.1038/s41419-021-04365-5.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with increasing occurrence, high death rates, and unfavorable treatment regimens. The pathogenesis underlying IPF is complex and the epigenetic contributions to IPF are largely unknown. Recent studies have shown that DOT1L (Disruptor of telomeric silencing-1 like), a histone H3K79 methyltransferase, contributes to fibrosis response, but its role in IPF remains unclear. DOT1L, H3K79me3, and the profibrotic proteins levels were upregulated in the pulmonary fibrosis models both in vivo and in vitro. Lentivirus-mediated DOT1L knockdown or DOT1L-specific inhibitor EPZ5676 alleviated the pathogenesis of bleomycin-induced mouse pulmonary fibrosis. Furthermore, heterozygous DOT1L-deficient mice (Dot1l+/-) showed less sensitive to pulmonary fibrosis, as shown by decreased lung fibrosis phenotypes in vivo. Mechanically, DOT1L regulated TGF-β1-induced fibroblasts fibrosis by increasing enrichments of H3K79me3 on the promoter of Jag1 gene (encoding the Notch ligand Jagged1), enhancing the expression of Jagged1, which in turn stimulated exuberant Notch signaling and actuated the fibrosis response. In conclusion, our study confirmed DOT1L to be an epigenetic modifier in the pathogenesis of lung fibrosis, revealed a counterbalancing mechanism governing Jag1 transcription by modulating H3K79 trimethylation at the Jag1 promoter, activating the Notch signaling, and affecting the expression of profibrotic proteins to accelerate the lung fibrosis.

PMID:35039472 | DOI:10.1038/s41419-021-04365-5

Respirology. 2022 Jan 17. doi: 10.1111/resp.14209. Online ahead of print.

NO ABSTRACT

PMID:35037339 | DOI:10.1111/resp.14209

ERJ Open Res. 2022 Jan 10;8(1):00505-2021. doi: 10.1183/23120541.00505-2021. eCollection 2022 Jan.

ABSTRACT

In this study using a large database of US decedents, the overall presence of lung cancer was lower in those with idiopathic pulmonary fibrosis compared to those without idiopathic pulmonary fibrosis https://bit.ly/30d6dC4.

PMID:35036421 | PMC:PMC8752943 | DOI:10.1183/23120541.00505-2021

Expert Rev Respir Med. 2022 Jan 15. doi: 10.1080/17476348.2022.2030710. Online ahead of print.

ABSTRACT

INTRODUCTION: A major focus of interstitial lung disease (ILD) has centered on disorders termed idiopathic interstitial pneumonias (IIPs) which include, among others, idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, and respiratory bronchiolitis-interstitial lung disease.

AREAS COVERED: We review the radiologic and histologic patterns for the nine disorders classified by multidisciplinary approach as IIP, and describe the remarkable amount of published epidemiologic, translational, and molecular studies demonstrating their associations with numerous yet definitive environmental exposures, occupational exposures, pulmonary diseases, systemic diseases, medication toxicities, and genetic variants.

EXPERT OPINION: : In the 21st century, these disorders termed IIPs are rarely idiopathic, but rather are well-described radiologic and histologic patterns of lung injury that are associated with a wide array of diverse etiologies. Accordingly, the idiopathic nomenclature is misleading and confusing, and may also promote a lack of inquisitiveness, suggesting the end rather than the beginning of a thorough diagnostic process to identify ILD etiology and initiate patient-centered management. A shift towards more etiology-focused nomenclature will be beneficial to all, including patients hoping for better life quality and disease outcome, general medicine and pulmonary physicians furthering their ILD knowledge, and expert ILD clinicians and researchers who are advancing the ILD field.

PMID:35034567 | DOI:10.1080/17476348.2022.2030710

Nanomedicine. 2022 Jan 12:102517. doi: 10.1016/j.nano.2022.102517. Online ahead of print.

ABSTRACT

Mesenchymal stem cells (MSCs) are promising in idiopathic pulmonary fibrosis (IPF) therapy. However, low survival rate and ambiguous behavior of MSCs after transplantation impede their clinical translation. To this end, we have developed a new strategy to improve the survival rate and monitor the behavior of the transplanted MSCs simultaneously. In our strategy, nintedanib, a tyrosine kinase inhibitor, is employed to protect the human MSCs (hMSCs) from excessive oxidative stress responses and inflammatory environment in the damaged lung. Moreover, by labeling of the transplanted hMSCs with a computed tomography (CT) nanotracer, Au nanoparticles functionalized with polyethylenimine (PEI) and polyethylene glycol (PEG) (Au@PEI@PEG), in combination with red-emitting firefly luciferase (RfLuc), in vivo CT/bioluminescence (BL) dual-modal imaging tracking of the location, distribution, and survival of the transplanted hMSCs in presence of nintedanib were achieved, which facilitates the profound understanding of the role the stem cells play in IPF therapy.

PMID:35032629 | DOI:10.1016/j.nano.2022.102517

Eur Radiol. 2022 Jan 14. doi: 10.1007/s00330-021-08482-9. Online ahead of print.

ABSTRACT

OBJECTIVES: To compare the lung CT volume (CTvol) and pulmonary function tests in an interstitial lung disease (ILD) population. Then to evaluate the CTvol loss between idiopathic pulmonary fibrosis (IPF) and non-IPF and explore a prognostic value of annual CTvol loss in IPF.

METHODS: We conducted in an expert center a retrospective study between 2005 and 2018 on consecutive patients with ILD. CTvol was measured automatically using commercial software based on a deep learning algorithm. In the first group, Spearman correlation coefficients (r) between forced vital capacity (FVC), total lung capacity (TLC), and CTvol were calculated. In a second group, annual CTvol loss was calculated using linear regression analysis and compared with the Mann-Whitney test. In a last group of IPF patients, annual CTvol loss was calculated between baseline and 1-year CTs for investigating with the Youden index a prognostic value of major adverse event at 3 years. Univariate and log-rank tests were calculated.

RESULTS: In total, 560 patients (4610 CTs) were analyzed. For 1171 CTs, CTvol was correlated with FVC (r: 0.86) and TLC (r: 0.84) (p < 0.0001). In 408 patients (3332 CT), median annual CTvol loss was 155.7 mL in IPF versus 50.7 mL in non-IPF (p < 0.0001) over 5.03 years. In 73 IPF patients, a relative annual CTvol loss of 7.9% was associated with major adverse events (log-rank, p < 0.0001) in univariate analysis (p < 0.001).

CONCLUSIONS: Automated lung CT volume may be an alternative or a complementary biomarker to pulmonary function tests for the assessment of lung volume loss in ILD.

KEY POINTS: • There is a good correlation between lung CT volume and forced vital capacity, as well as for with total lung capacity measurements (r of 0.86 and 0.84 respectively, p < 0.0001). • Median annual CT volume loss is significantly higher in patients with idiopathic pulmonary fibrosis than in patients with other fibrotic interstitial lung diseases (155.7 versus 50.7 mL, p < 0.0001). • In idiopathic pulmonary fibrosis, a relative annual CT volume loss higher than 9.4% is associated with a significantly reduced mean survival time at 2.0 years versus 2.8 years (log-rank, p < 0.0001).

PMID:35029730 | DOI:10.1007/s00330-021-08482-9

Am J Respir Crit Care Med. 2022 Jan 12. doi: 10.1164/rccm.202109-2091OC. Online ahead of print.

ABSTRACT

Rationale Novel therapies for idiopathic pulmonary fibrosis (IPF) are in development, but there remains uncertainty about the optimal trial endpoint. An earlier endpoint would enable assessment of a greater number of therapies in adaptive trial designs. Objectives To determine whether short-term changes in forced vital capacity (FVC), gas transfer for carbon monoxide (DLCO) and six-minute walk distance (6MWD) could act as surrogate endpoints to accelerate early-phase trials in IPF. Methods Individual participant data (IPD) from IPF clinical trials were included in two-step random effects meta-analysis to determine whether baseline or three-month changes in FVC, DLCO, 6MWD associated with mortality or disease progression in placebo arms. Three-month and twelve-month FVC decline endpoints were compared to treatment arm data from antifibrotic studies by meta-regression. Measurements and main results IPD were available from twelve placebo cohorts totalling 1819 participants, with baseline and three-month change in all physiological variables independently associated with poorer outcomes. Treatment data were available from six cohorts with 1684 participants. For each 2.5% relative decline in FVC over three-months there was an associated 15% [adjusted hazard ratio (aHR) 1.15,95%CI 1.06;1.24,I2=59.4%] and 20% (aHR 1.20,95%CI 1.12;1.28,I2=18.0%) increased risk of mortality in untreated and treated individuals respectively. An FVC change treatment effect was observed between treatment and placebo arms at three-months (difference in FVC change of 42.9ml,95%CI 24.0;61.8;p<0.001). Conclusions IPD meta-analysis demonstrated three-month change in physiological variables, particularly FVC, were associated with mortality among individuals with IPF. FVC change over three-months may hold potential as a surrogate endpoint in IPF adaptive trials.

PMID:35020580 | DOI:10.1164/rccm.202109-2091OC

Sleep Breath. 2022 Jan 12. doi: 10.1007/s11325-021-02560-4. Online ahead of print.

NO ABSTRACT

PMID:35020132 | DOI:10.1007/s11325-021-02560-4

Ann Am Thorac Soc. 2022 Jan 11. doi: 10.1513/AnnalsATS.202102-222OC. Online ahead of print.

ABSTRACT

RATIONALE: Chronic fibrosing interstitial lung disease (ILD) with a progressive phenotype is a clinical concept describing the broad group of interstitial lung diseases characterized by progressive pulmonary fibrosis. The prevalence of progressive fibrotic ILDs other than idiopathic pulmonary fibrosis (IPF) is not well understood.

OBJECTIVES: We utilized a novel algorithm to estimate the prevalence range of disease progression among patients with non-IPF fibrotic ILD in a US claims database.

METHODS: This was a retrospective study including adults with commercial or Medicare Advantage with Part D (MAPD) insurance using administrative claims data from October 2015 - September 2019. Patients likely to have non-IPF fibrosing ILDs with a progressive phenotype were identified via an algorithm that incorporated ILD-related diagnosis codes (excluding IPF) and claims-based proxies for fibrotic ILD progression, including pulmonary function tests, chest imaging, oral corticosteroid (OCS) medications, immunosuppressive medications, lung transplant, oxygen therapy, palliative care, and respiratory hospitalization. The prevalence range of non-IPF fibrotic ILD with progressive disease behavior was calculated using strict and lenient case definitions to account for potential imprecision in the progression proxies.

RESULTS: Of nearly 9 million study-eligible patients, 17,136 were identified with non-IPF fibrosing ILD. The prevalence of disease progression per 10,000 (95% CI) ranged from 12.14 (11.74-12.54) to 29.05 (28.43-29.67) over a mean observation time of 1.44 years for MAPD enrollees (n = 14,686), and from 0.89 (0.81-0.97) to 2.36 (2.24-2.48) over a mean observation time of 1.29 years for commercial enrollees (n = 2,450). Prevalence estimates increased with age for both insurance types. Among patients with progression, 4,097 met ≥ 2 progression proxies not considering OCS (strict case definition) and 9,946 met ≥ 1 progression proxy (lenient case definition). The mean (SD) number of proxies met was 2.1 (1.3) and the most common individual proxies met (alone or in combination with other proxies) were OCS use (48.9%), respiratory hospitalization (44.2%), and oxygen therapy (44.1%).

CONCLUSIONS: This is among the first claims-based estimates of the prevalence of non-IPF chronic fibrosing ILD with a progressive phenotype. Our analysis indicates that this phenotype is rare in the overall population but increases substantially with increasing age.

PMID:35015982 | DOI:10.1513/AnnalsATS.202102-222OC

Cell Mol Life Sci. 2022 Jan 11;79(1):66. doi: 10.1007/s00018-021-04094-0.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by chronic progressive pulmonary fibrosis and a poor prognosis. Genetic studies, including transcriptomic and proteomics, have provided new insight into revealing mechanisms of IPF. Herein we provided a novel strategy to identify biomarkers by integrative analysis of transcriptomic and proteomic profiles of IPF patients. We examined the landscape of IPF patients' gene expression in the transcription and translation phases and investigated the expression and functions of two new potential biomarkers. Differentially expressed (DE) mRNAs were mainly enriched in pathways associated with immune system activities and inflammatory responses, while DE proteins are related to extracellular matrix production and wound repair. The upregulated genes in both phases are associated with wound repair and cell differentiation, while the downregulated genes in both phases are associated with reduced immune activities and the damage of the alveolar tissues. On this basis, we identified thirteen potential marker genes. Among them, we validated the expression changes of butyrophilin-like 9 (BTNL9) and plasmolipin (PLLP) and investigated their functional pathways in the IPF mechanism. Both genes are downregulated in the tissues of IPF patients and Bleomycin-induced mice, and co-expression analysis indicates that they have a protective effect by inhibiting extracellular matrix production and promoting wound repair in alveolar epithelial cells.

PMID:35015148 | DOI:10.1007/s00018-021-04094-0

Nat Commun. 2022 Jan 10;13(1):114. doi: 10.1038/s41467-021-27684-9.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tartrate-resistant acid phosphatase 5 (ACP5) performs a variety of functions. However, its role in IPF remains unclear. Here, we demonstrate that the levels of ACP5 are increased in IPF patient samples and mice with bleomycin (BLM)-induced pulmonary fibrosis. In particular, higher levels of ACP5 are present in the sera of IPF patients with a diffusing capacity of the lungs for carbonmonoxide (DLCO) less than 40% of the predicted value. Additionally, Acp5 deficiency protects mice from BLM-induced lung injury and fibrosis coupled with a significant reduction of fibroblast differentiation and proliferation. Mechanistic studies reveal that Acp5 is upregulated by transforming growth factor-β1 (TGF-β1) in a TGF-β receptor 1 (TGFβR1)/Smad family member 3 (Smad3)-dependent manner, after which Acp5 dephosphorylates p-β-catenin at serine 33 and threonine 41, inhibiting the degradation of β-catenin and subsequently enhancing β-catenin signaling in the nucleus, which promotes the differentiation, proliferation and migration of fibroblast. More importantly, the treatment of mice with Acp5 siRNA-loaded liposomes or Acp5 inhibitor reverses established lung fibrosis. In conclusions, Acp5 is involved in the initiation and progression of pulmonary fibrosis and strategies aimed at silencing or suppressing Acp5 could be considered as potential therapeutic approaches against pulmonary fibrosis.

PMID:35013220 | DOI:10.1038/s41467-021-27684-9