Stem Cell Res Ther. 2022 Jan 10;13(1):12. doi: 10.1186/s13287-021-02688-w.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive deadly fibrotic lung disease with high prevalence and mortality worldwide. The therapeutic potential of mesenchymal stem cells (MSCs) in pulmonary fibrosis may be attributed to the strong paracrine, anti-inflammatory, anti-apoptosis and immunoregulatory effects. However, the mechanisms underlying the therapeutic effects of MSCs in IPF, especially in terms of alveolar type 2 (AT2) cells senescence, are not well understood. The purpose of this study was to evaluate the role of MSCs in NAD metabolism and senescence of AT2 cells in vitro and in vivo.

METHODS: MSCs were isolated from human bone marrow. The protective effects of MSCs injection in pulmonary fibrosis were assessed via bleomycin mouse models. The senescence of AT2 cells co-cultured with MSCs was evaluated by SA-β-galactosidase assay, immunofluorescence staining and Western blotting. NAD+ level and NAMPT expression in AT2 cells affected by MSCs were determined in vitro and in vivo. FK866 and NAMPT shRNA vectors were used to determine the role of NAMPT in MSCs inhibiting AT2 cells senescence.

RESULTS: We proved that MSCs attenuate bleomycin-induced pulmonary fibrosis in mice. Senescence of AT2 cells was alleviated in MSCs-treated pulmonary fibrosis mice and when co-cultured with MSCs in vitro. Mechanistic studies showed that NAD+ and NAMPT levels were rescued in AT2 cells co-cultured with MSCs and MSCs could suppress AT2 cells senescence mainly via suppressing lysosome-mediated NAMPT degradation.

CONCLUSIONS: MSCs attenuate AT2 cells senescence by upregulating NAMPT expression and NAD+ levels, thus exerting protective effects in pulmonary fibrosis.

PMID:35012648 | DOI:10.1186/s13287-021-02688-w

J Clin Med. 2021 Dec 24;11(1):79. doi: 10.3390/jcm11010079.

ABSTRACT

Interstitial pneumonia with autoimmune features (IPAF) belongs to a group of diseases called interstitial lung diseases (ILDs), which are disorders of a varied prognosis and course. Finding sufficiently specific and sensitive biomarkers would enable the progression to be predicted, the natural history to be monitored and patients to be stratified according to their treatment. To assess the significance of pulmonary fibrosis biomarkers studied thus far, we searched the PubMed, Medline and Cochrane Library databases for papers published between January 2015 and June 2021. We focused on circulating biomarkers. A primary review of the databases identified 38 articles of potential interest. Overall, seven articles fulfilled the inclusion criteria. This review aims to assess the diagnostic and prognostic value of molecules such as KL-6, SP-A, SP-D, circulating fibrocytes, CCL2, CXCL13, CXCL9, CXCL10 and CXCL11. All of these biomarkers have previously been studied in idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated interstitial lung disease (CTD-ILD). IPAF is a disorder of a heterogeneous nature. It explains the lack of coherent observations in terms of correlations with functional parameters. There is still no meta-analysis of pulmonary fibrosis biomarkers in IPAF. This is mainly due to the heterogeneity of the methodology and groups analysed in the research. More research in this area is needed.

PMID:35011819 | DOI:10.3390/jcm11010079

Cells. 2022 Jan 4;11(1):156. doi: 10.3390/cells11010156.

ABSTRACT

Prior research has implicated the involvement of cell adhesion molecule N-cadherin in tissue fibrosis and remodeling. We hypothesize that anomalies in N-cadherin protein processing are involved in pathological fibrosis. Diseased tissues associated with fibrosis of the heart, lung, and liver were probed for the precursor form of N-cadherin, pro-N-cadherin (PNC), by immunohistochemistry and compared to healthy tissues. Myofibroblast cell lines were analyzed for cell surface pro-N-cadherin by flow cytometry and immunofluorescent microscopy. Soluble PNC products were immunoprecipitated from patient plasmas and an enzyme-linked immunoassay was developed for quantification. All fibrotic tissues examined show aberrant PNC localization. Cell surface PNC is expressed in myofibroblast cell lines isolated from cardiomyopathy and idiopathic pulmonary fibrosis but not on myofibroblasts isolated from healthy tissues. PNC is elevated in the plasma of patients with cardiomyopathy (p ≤ 0.0001), idiopathic pulmonary fibrosis (p ≤ 0.05), and nonalcoholic fatty liver disease with cirrhosis (p ≤ 0.05). Finally, we have humanized a murine antibody and demonstrate that it significantly inhibits migration of PNC expressing myofibroblasts. Collectively, the aberrant localization of PNC is observed in all fibrotic tissues examined in our study and our data suggest a role for cell surface PNC in the pathogenesis of fibrosis.

PMID:35011717 | DOI:10.3390/cells11010156

Cells. 2022 Jan 2;11(1):143. doi: 10.3390/cells11010143.

ABSTRACT

Antifibrotic agents have been widely used in patients with idiopathic pulmonary fibrosis (IPF). Long-term continuation of antifibrotic therapy is required for IPF treatment to prevent disease progression. However, antifibrotic treatment has considerable adverse events, and the continuation of treatment is uncertain in many cases. Therefore, we examined and compared the continuity of treatment between pirfenidone and nintedanib in patients with IPF. We retrospectively enrolled 261 consecutive IPF patients who received antifibrotic treatment from six core facilities in Gunma Prefecture from 2009 to 2018. Among them, 77 patients were excluded if the antifibrotic agent was switched or if the observation period was less than a year. In this study, 134 patients treated with pirfenidone and 50 treated with nintedanib were analyzed. There was no significant difference in patient background, discontinuation rate of antifibrotic treatment over time, and survival rate between the two groups. However, the discontinuation rate due to adverse events within one year of antifibrotic treatment was significantly higher in the nintedanib group than in the pirfenidone group (76% vs. 37%, p < 0.001). Furthermore, the discontinuation rate due to adverse events in nintedanib was higher than that of pirfenidone treatment throughout the observation period (70.6% vs. 31.2%, p = 0.016). The pirfenidone group tended to be discontinued due to acute exacerbation or transfer to another facility. The results of this study suggest that better management of adverse events with nintedanib leads to more continuous treatment that prevents disease progression and acute exacerbations, thus improving prognosis in patients with IPF.

PMID:35011705 | DOI:10.3390/cells11010143

Int J Mol Sci. 2022 Jan 4;23(1):546. doi: 10.3390/ijms23010546.

ABSTRACT

Epigenetic responses due to environmental changes alter chromatin structure, which in turn modifies the phenotype, gene expression profile, and activity of each cell type that has a role in the pathophysiology of a disease. Pulmonary diseases are one of the major causes of death in the world, including lung cancer, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), lung tuberculosis, pulmonary embolism, and asthma. Several lines of evidence indicate that epigenetic modifications may be one of the main factors to explain the increasing incidence and prevalence of lung diseases including IPF and COPD. Interestingly, isolated fibroblasts and smooth muscle cells from patients with pulmonary diseases such as IPF and PH that were cultured ex vivo maintained the disease phenotype. The cells often show a hyper-proliferative, apoptosis-resistant phenotype with increased expression of extracellular matrix (ECM) and activated focal adhesions suggesting the presence of an epigenetically imprinted phenotype. Moreover, many abnormalities observed in molecular processes in IPF patients are shown to be epigenetically regulated, such as innate immunity, cellular senescence, and apoptotic cell death. DNA methylation, histone modification, and microRNA regulation constitute the most common epigenetic modification mechanisms.

PMID:35008971 | DOI:10.3390/ijms23010546

Int J Mol Sci. 2021 Dec 31;23(1):425. doi: 10.3390/ijms23010425.

ABSTRACT

Telomeres are localized at the end of chromosomes to provide genome stability; however, the telomere length tends to be shortened with each cell division inducing a progressive telomere shortening (TS). In addition to age, other factors, such as exposure to pollutants, diet, stress, and disruptions in the shelterin protein complex or genes associated with telomerase induce TS. This phenomenon favors cellular senescence and genotoxic stress, which increases the risk of the development and progression of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, SARS-CoV-2 infection, and lung cancer. In an infectious environment, immune cells that exhibit TS are associated with severe lymphopenia and death, whereas in a noninfectious context, naïve T cells that exhibit TS are related to cancer progression and enhanced inflammatory processes. In this review, we discuss how TS modifies the function of the immune system cells, making them inefficient in maintaining homeostasis in the lung. Finally, we discuss the advances in drug and gene therapy for lung diseases where TS could be used as a target for future treatments.

PMID:35008850 | DOI:10.3390/ijms23010425

Int J Mol Sci. 2021 Dec 24;23(1):171. doi: 10.3390/ijms23010171.

ABSTRACT

The hedgehog (Hh) pathway is a sophisticated conserved cell signaling pathway that plays an essential role in controlling cell specification and proliferation, survival factors, and tissue patterning formation during embryonic development. Hh signal activity does not entirely disappear after development and may be reactivated in adulthood within tissue-injury-associated diseases, including idiopathic pulmonary fibrosis (IPF). The dysregulation of Hh-associated activating transcription factors, genomic abnormalities, and microenvironments is a co-factor that induces the initiation and progression of IPF.

PMID:35008597 | DOI:10.3390/ijms23010171

Ann Am Thorac Soc. 2022 Jan 10. doi: 10.1513/AnnalsATS.202108-980OC. Online ahead of print.

ABSTRACT

Rationale: Multimorbidity is common and leads to substantial concomitant medication burden in patients with interstitial lung disease (ILD), which may affect tolerability of ILD-targeted medications and health outcomes. Objectives: To determine the associations of concomitant medication burden with tolerability of ILD-targeted medications and survival in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF ILD. Methods: Patients with IPF receiving nintedanib or pirfenidone and patients with non-IPF ILD receiving azathioprine or mycophenolate were identified from two large Australian and Canadian registries. Baseline concomitant medication burden was evaluated using three measures: medication count, polypharmacy (≥5 medications), and the Medication Regimen Complexity Index (MRCI). Medication intolerance and discontinuation were evaluated at six months and one year post-initiation of ILD-targeted medications, respectively. Cox regression models and likelihood ratio tests were used to determine the prognostic significance of medication burden on transplant-free survival. Results: In 645 treated patients with IPF, 43% experienced adverse reactions leading to intolerance (defined as dose reduction, temporary dose interruption, or permanent drug discontinuation) of antifibrotic medications within six months of initiation, with high baseline concomitant medication burden being consistently associated with intolerance (medication count: p=0.005; polypharmacy: p=0.006; MRCI: p=0.004). This association was not observed for immunosuppressive medications in 1255 treated patients with non-IPF ILD, who also had a lower intolerance (18%). Baseline concomitant medication burden was not independently associated with permanent discontinuation of antifibrotic (29%) and immunosuppressive medications (20%) at one year. The MRCI was the only measure of concomitant medication burden associated with transplant-free survival in both cohorts (p<0.01 for both), which improved prognostication beyond common clinical factors and the ILD-GAP index (p<0.001 for both). Conclusions: Concomitant medication burden is associated with intolerance of antifibrotic medications in patients with IPF. Medication regimen complexity is superior to simpler evaluation of concomitant medication burden for predicting prognosis in ILD.

PMID:35007498 | DOI:10.1513/AnnalsATS.202108-980OC

Front Med (Lausanne). 2021 Dec 24;8:802989. doi: 10.3389/fmed.2021.802989. eCollection 2021.

ABSTRACT

Background: Real-world data regarding outcomes of idiopathic pulmonary fibrosis (IPF) are scarce, outside of registries. The claims data from the French National Health System (SNDS) were used to describe outcomes in patients diagnosed with IPF in 2015-2016 but who did not receive antifibrotic therapies. Method: Patients aged <50 years were excluded, as were patients with pulmonary fibrosis other than IPF, patients who had previously received a lung transplant, and those who had received antifibrotic therapies at any time between 2010 and 2016. Patients were followed-up until their last health record, lung transplantation, initiation of antifibrotic therapies, death, or the end of the study period (31 December 2017), whichever occurred first. Results: A total of 5,360 patients (43.2%) not treated with antifibrotic therapies were included. The mean age was 75.5 years, and 57.9% were males. In the year before inclusion, 47.3% of patients had a Charlson score ≥5. During follow-up, 41.2% of patients died. The unadjusted incidence rate was 29.9 per 100 person-years (95%CI = [28.7-31.2]), and the cumulative incidence of death at 3 years was 50.2% (95% CI = [48.3-52.1%]). In the study population, 35.3% of patients experienced an acute respiratory-related hospitalization. The unadjusted incidence rate was 32.1 per 100 person-years (95%CI = [30.6-33.5]) and the cumulative incidence of the event at 3 years was 41.5% (95% CI = [39.7-43.2%]). Interpretation: This observational study showed that, if untreated with antifibrotics, IPF is associated with a 50% all-cause mortality at 3 years. These figures can serve as a historical control of the natural course of the disease.

PMID:35004781 | PMC:PMC8739228 | DOI:10.3389/fmed.2021.802989

Front Med (Lausanne). 2021 Dec 23;8:729203. doi: 10.3389/fmed.2021.729203. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare lung disease with poor prognosis. The diagnosis and treatment possibilities are dependent on the health systems of countries. Hence, comparison among countries is difficult due to data heterogeneity. Our aim was to analyse patients with IPF in Central and Eastern Europe using the uniform data from the European Multipartner IPF registry (EMPIRE), which at the time of analysis involved 10 countries. Newly diagnosed IPF patients (N = 2,492, between March 6, 2012 and May 12, 2020) from Czech Republic (N = 971, 39.0%), Turkey (N = 505, 20.3%), Poland (N = 285, 11.4%), Hungary (N = 216, 8.7%), Slovakia (N = 149, 6.0%), Israel (N = 120, 4.8%), Serbia (N = 95, 3.8%), Croatia (N = 87, 3.5%), Austria (N = 55, 2.2%), and Bulgaria (N = 9, 0.4%) were included, and Macedonia, while a member of the registry, was excluded from this analysis due to low number of cases (N = 5) at this timepoint. Baseline characteristics, smoking habit, comorbidities, lung function values, CO diffusion capacity, high-resolution CT (HRCT) pattern, and treatment data were analysed. Patients were significantly older in Austria than in the Czech Republic, Turkey, Hungary, Slovakia, Israel, and Serbia. Ever smokers were most common in Croatia (84.1%) and least frequent in Serbia (39.2%) and Slovakia (42.6%). The baseline forced vital capacity (FVC) was >80% in 44.6% of the patients, between 50 and 80% in 49.3%, and <50% in 6.1%. Most IPF patients with FVC >80% were registered in Poland (63%), while the least in Israel (25%). A typical usual interstitial pneumonia (UIP) pattern was present in 67.6% of all patients, ranging from 43.5% (Austria) to 77.2% (Poland). The majority of patients received antifibrotic therapy (64.5%); 37.4% used pirfenidone (range 7.4-39.8% between countries); and 34.9% nintedanib (range 12.6-56.0% between countries) treatment. In 6.8% of the cases, a therapy switch was initiated between the 2 antifibrotic agents. Significant differences in IPF patient characteristics and access to antifibrotic therapies exist in EMPIRE countries, which needs further investigation and strategies to improve and harmonize patient care and therapy availability in this region.

PMID:35004713 | PMC:PMC8733326 | DOI:10.3389/fmed.2021.729203

Cureus. 2022 Jan 4;14(1):e20916. doi: 10.7759/cureus.20916. eCollection 2022 Jan.

ABSTRACT

We describe a case of a 77-year-old male with idiopathic pulmonary fibrosis (IPF) complicated by lung adenocarcinoma and organizing pneumonia (OP). On initial examination, physical examination revealed fine crackles in both sides of his chest. There were no physical findings suggestive of collagen disease. Blood tests showed no elevation of C-reactive protein, and lactate dehydrogenase and Krebs von den Lungen-6 (KL-6) were within normal limits. A high-resolution CT (HRCT) of the chest showed multiple ground-glass opacities (GGOs) in both lungs, with consolidation and traction bronchiectasis in the left lower lobe. Although a bronchoscopy was performed, no diagnosis could be made. Bronchoalveolar lavage showed elevated lymphocytes, and treatment with prednisolone was started for the possibility of OP. Subsequent chest X-ray and chest CT showed worsening of the shadows over time, and shortness of breath on exertion progressed. Surgical lung biopsy revealed IPF complicated by adenocarcinoma and OP. Although the patient was treated with pemetrexed and carboplatin combination therapy, respiratory failure progressed, and palliative care was decided. There is no report of IPF complicated by adenocarcinoma and OP, and early surgical lung biopsy may be important for diagnosis.

PMID:35004080 | PMC:PMC8727334 | DOI:10.7759/cureus.20916

Front Pharmacol. 2021 Dec 24;12:788714. doi: 10.3389/fphar.2021.788714. eCollection 2021.

ABSTRACT

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. The aberrantly activated lung myofibroblasts, predominantly emerging through fibroblast-to-myofibroblast differentiation, are considered to be the key cells in PF, resulting in excessive accumulation of extracellular matrix (ECM). Latent transforming growth factor-β (TGFβ) binding protein-2 (LTBP2) has been suggested as playing a critical role in modulating the structural integrity of the ECM. However, its function in PF remains unclear. Here, we demonstrated that lungs originating from different types of patients with PF, including idiopathic PF and rheumatoid arthritis-associated interstitial lung disease, and from mice following bleomycin (BLM)-induced PF were characterized by increased LTBP2 expression in activated lung fibroblasts/myofibroblasts. Moreover, serum LTBP2 was also elevated in patients with COVID-19-related PF. LTBP2 silencing by lentiviral shRNA transfection protected against BLM-induced PF and suppressed fibroblast-to-myofibroblast differentiation in vivo and in vitro. More importantly, LTBP2 overexpression was able to induce differentiation of lung fibroblasts to myofibroblasts in vitro, even in the absence of TGFβ1. By further mechanistic analysis, we demonstrated that LTBP2 silencing prevented fibroblast-to-myofibroblast differentiation and subsequent PF by suppressing the phosphorylation and nuclear translocation of NF-κB signaling. LTBP2 overexpression-induced fibroblast-to-myofibroblast differentiation depended on the activation of NF-κB signaling in vitro. Therefore, our data indicate that intervention to silence LTBP2 may represent a promising therapy for PF.

PMID:35002722 | PMC:PMC8740300 | DOI:10.3389/fphar.2021.788714

Clin Respir J. 2022 Jan 10. doi: 10.1111/crj.13466. Online ahead of print.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease characterized by dry cough, fatigue, and progressive exertional dyspnea. Lung parenchyma and architecture is destroyed, compliance is lost, and gas exchange is compromised in this debilitating condition that leads inexorably to respiratory failure and death within 3-5 years of diagnosis. This review discusses treatment approaches to IPF in current use and those that appear promising for future development.

DATA SOURCE: The data were obtained from the Randomized Controlled Trials and scientific studies published in English literature. We used search terms related to IPF, antifibrotic treatment, lung transplant, and management.

RESULTS: Etiopathogenesis of IPF is not fully understood, and treatment options are limited. Pathological features of IPF include extracellular matrix remodeling, fibroblast activation and proliferation, immune dysregulation, cell senescence, and presence of aberrant basaloid cells. The mainstay therapies are the oral antifibrotic drugs pirfenidone and nintedanib, which can improve quality of life, attenuate symptoms, and slow disease progression. Unilateral or bilateral lung transplantation is the only treatment for IPF shown to increase life expectancy.

CONCLUSION: Clearly, there is an unmet need for accelerated research into IPF mechanisms so that progress can be made in therapeutics toward the goals of increasing life expectancy, alleviating symptoms, and improving well-being.

PMID:35001525 | DOI:10.1111/crj.13466

BMC Pulm Med. 2022 Jan 10;22(1):18. doi: 10.1186/s12890-021-01811-0.

ABSTRACT

BACKGROUND: The anti-fibrotic medications nintedanib and pirfenidone were approved in the United States for use in patients with idiopathic pulmonary fibrosis several years ago. While there is a growing body of evidence surrounding their clinical effectiveness, these medications are quite expensive and no prior cost-effectiveness analysis has been performed in the United States.

METHODS: A previously published Markov model performed in the United Kingdom was replicated using United States data to project the lifetime costs and health benefits of treating idiopathic pulmonary fibrosis with: (1) symptom management; (2) pirfenidone; or (3) nintedanib. For the cost-effectiveness analysis, strategies were ranked by increasing costs and then checked for dominating treatment strategies. Then an incremental cost-effectiveness ratio was calculated for the dominant therapy.

RESULTS: The anti-fibrotic medications were found to cost more than $110,000 per year compared to $12,291 annually for symptom management. While pirfenidone was slightly more expensive than nintedanib and provided the same amount of benefit, neither medication was found to be cost-effective in this U.S.-based analysis, with an average cost of $1.6 million to gain one additional quality-adjusted life year over symptom management.

CONCLUSIONS: Though the anti-fibrotics remain the only effective treatment option for patients with idiopathic pulmonary fibrosis and the data surrounding their clinical effectiveness continues to grow, they are not considered cost-effective treatment strategies in the United States due to their high price.

PMID:35000589 | DOI:10.1186/s12890-021-01811-0

Zhonghua Jie He He Hu Xi Za Zhi. 2022 Jan 12;45(1):95-99. doi: 10.3760/cma.j.cn112147-20211020-00729.

ABSTRACT

The significant scientific advances about interstitial lung disease from November 2020 to October 2021 which were published in the Chinese and international journals were systematically reviewed in this paper. The year 2021 brought advances in our understanding of the real-world adoption of the antifibrotic medications pirfenidone and nintedanib for US idiopathic pulmonary fibrosis patients, the European statement on the diagnosis and evaluation and treatment of pulmonary fibrosis, the CHEST guideline on the diagnosis and evaluation of hypersensitivity pneumonitis, Chinese expert viewpoints on the progressive fibrosing interstitial lung disease, and international updates on the diagnosis and management of connective tissue disease-associated interstitial lung diseases.

PMID:35000313 | DOI:10.3760/cma.j.cn112147-20211020-00729

Am J Kidney Dis. 2022 Jan 6:S0272-6386(21)01051-9. doi: 10.1053/j.ajkd.2021.11.010. Online ahead of print.

ABSTRACT

Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and a potential therapeutic target. However, there are conceptual and practical challenges to directly targeting kidney fibrosis. Whether fibrosis is mainly a cause or a consequence of CKD progression has been disputed. It is unclear whether specifically targeting fibrosis is feasible in clinical practice as most drugs that decrease fibrosis in preclinical models also target additional and often multiple pathogenic pathways (e.g. renin-angiotensin-aldosterone system blockade). Finally, tools to assess whole kidney fibrosis in routine clinical practice are lacking. Pirfenidone, a drug used for idiopathic pulmonary fibrosis (IPF), is undergoing a phase 2 trial for kidney fibrosis. Other drugs in use or being tested for IPF (e.g. nintedanib, PRM-151, epigallocatechin gallate) are also potential candidates to treat kidney fibrosis. Novel therapeutic approaches may include antagomirs (e.g. lademirsen) or drugs targeting IL-11 or NKD2. Reversing dysfunctional tubular cell metabolism that leads to kidney fibrosis offers additional therapeutic opportunities. However, any future drug targeting fibrosis of the kidneys should demonstrate added benefit to a novel standard of care combining renin-angiotensin system with mineralocorticoid receptor (e.g. finerenone) blockade or with SGLT2 inhibitors.

PMID:34999158 | DOI:10.1053/j.ajkd.2021.11.010

Life Sci. 2022 Jan 5:120283. doi: 10.1016/j.lfs.2021.120283. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with unknown etiological factors that can progress to other dangerous diseases like lung cancer. Environmental and genetic predisposition are the two major etiological or risk factors involved in the pathology of the IPF. Among the environmental risk factors, smoking is one of the major causes for the development of IPF. Epigenetic pathways like nucleosomes remodeling, DNA methylation, histone modifications and miRNA mediated genes play a crucial role in development of IPF. Mutations in the genes make the epigenetic factors as important drug targets in IPF. Transcriptional changes due to environmental factors are also involved in the progression of IPF. The mutations in human telomerase reverse transcriptase (hTERT) have shown decreased life expectancy in IPF patients. The TERT-gene is highly expressed in chronic smokers and makes the role of epigenetics evident. Drug like nintedanib acts through vascular endothelial growth factor receptors (VEGFR), while drug pirfenidone acts through transforming growth factor (TGF), which is useful in IPF. Gefitinib, a tyrosine kinase inhibitor of EGFR, is useful as an anti-fibrosis agent in preclinical models. Newer drugs such as Celgene-CC90001 and Fibrogen FG-3019 are currently under investigations acts through the modulating epigenetic mechanisms. Thus, the study on epigenetics opens a wide window for the discovery of newer drugs. This study provides an elementary analysis of multiple regulators of epigenetics and their roles associated with the pathology of IPF. Further, this review also includes epigenetic drugs under development in preclinical and clinical stages.

PMID:34998839 | DOI:10.1016/j.lfs.2021.120283

Lung. 2022 Jan 7. doi: 10.1007/s00408-021-00506-x. Online ahead of print.

ABSTRACT

PURPOSE: To assess the impact of concomitant emphysema on outcomes in patients with idiopathic pulmonary fibrosis (IPF).

METHODS: The IPF-PRO Registry is a US registry of patients with IPF. The presence of combined pulmonary fibrosis and emphysema (CPFE) at enrollment was determined by investigators' review of an HRCT scan. Associations between emphysema and clinical outcomes were analyzed using Cox proportional hazards models.

RESULTS: Of 934 patients, 119 (12.7%) had CPFE. Compared with patients with IPF alone, patients with CPFE were older (median 72 vs 70 years); higher proportions were current/former smokers (88.2% vs 63.7%), used oxygen with activity (49.6% vs 31.9%) or at rest (30.8% vs 18.4%), had congestive heart failure (13.6% vs 4.8%) and had prior respiratory hospitalization (25.0% vs 16.7%); they had higher FVC (median 71.8 vs 69.4% predicted) and lower DLco (median 35.3 vs 43.6% predicted). In patients with CPFE and IPF alone, respectively, at 1 year, rates of death or lung transplant were 17.5% (95% CI: 11.7, 25.8) and 11.2% (9.2, 13.6) and rates of hospitalization were 21.6% (14.6, 29.6) and 20.6% (17.9, 23.5). There were no significant associations between emphysema and any outcome after adjustment for baseline variables. No baseline variable predicted outcomes better in IPF alone than in CPFE.

CONCLUSION: Approximately 13% of patients in the IPF-PRO Registry had CPFE. Physiologic characteristics and comorbidities of patients with CPFE differed from those of patients with IPF alone, but the presence of emphysema did not drive outcomes after adjustment for baseline covariates.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT01915511; registered August 5, 2013.

PMID:34997268 | DOI:10.1007/s00408-021-00506-x

Thorax. 2022 Jan 7:thoraxjnl-2021-217693. doi: 10.1136/thoraxjnl-2021-217693. Online ahead of print.

ABSTRACT

A subset of patients with hypersensitivity pneumonitis (HP) develop lung fibrosis that is clinically similar to idiopathic pulmonary fibrosis (IPF). To address the aetiological determinants of fibrotic HP, we investigated whether the common IPF genetic risk variants were also relevant in study subjects with fibrotic HP. Our findings indicate that common genetic variants in TERC, DSP, MUC5B and IVD were significantly associated with fibrotic HP. These findings provide support for a shared etiology and pathogenesis between fibrotic HP and IPF.

PMID:34996848 | DOI:10.1136/thoraxjnl-2021-217693

Respir Res. 2022 Jan 7;23(1):3. doi: 10.1186/s12931-021-01921-7.

ABSTRACT

BACKGROUND: Performance benchmarks for the management of idiopathic pulmonary fibrosis (IPF) have not been established. We used data from the IPF-PRO Registry, an observational registry of patients with IPF managed at sites across the US, to examine associations between the characteristics of the enrolling sites and patient outcomes.

METHODS: An online survey was used to collect information on the resources, operations, and self-assessment practices of IPF-PRO Registry sites that enrolled ≥ 10 patients. Site variability in 1-year event rates of clinically relevant outcomes, including death, death or lung transplant, and hospitalization, was assessed. Models were adjusted for differences in patient case mix by adjusting for known predictors of each outcome. We assessed whether site-level heterogeneity existed for each patient-level outcome, and if so, we investigated potential drivers of the heterogeneity.

RESULTS: All 27 sites that enrolled ≥ 10 patients returned the questionnaire. Most sites were actively following > 100 patients with IPF (70.4%), had a lung transplant program (66.7%), and had a dedicated ILD nurse leader (77.8%). Substantial heterogeneity was observed in the event rates of clinically relevant outcomes across the sites. After controlling for patient case mix, there were no outcomes for which the site variance component was significantly different from 0, but the p-value for hospitalization was 0.052. Starting/completing an ILD-related quality improvement project in the previous 2 years was associated with a lower risk of hospitalization (HR 0.60 [95% CI 0.44, 0.82]; p = 0.001).

CONCLUSIONS: Analyses of data from patients with IPF managed at sites across the US found no site-specific characteristics or practices that were significantly associated with clinically relevant outcomes after adjusting for patient case mix. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511.

PMID:34996465 | DOI:10.1186/s12931-021-01921-7