Risk Factor For Idiopathic Pulmonary Fibrosis Research Articles

Smoking and idiopathic pulmonary fibrosis: A meta-analysis.

In this study, we aimed to systematically explore the relationship between smoking and idiopathic pulmonary fibrosis (IPF). The PubMed, Web of Science and Embase databases were searched to systematically identify eligible studies. The Newcastle‒Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of the selected studies. The pooled odds ratio (OR) and survival hazard ratio (HR) were calculated with a random effects model using Stata 16.0 software. Thirty studies were enrolled. All of the included studies were considered to have intermediate or high quality. Nine studies were suitable for meta-analysis of ORs, and twenty-one studies were suitable for meta-analysis of survival HR. The pooled analysis revealed a significant difference in the risk of IPF between the smoking group and the never smoking group (OR 1.71, 95% CI 1.27-2.30, P < 0.001), indicating that smoking is a risk factor for IPF. When analyzing pooled survival HRs, never smoking was compared to former smoking or current smoking. Former smoking was shown to be a poor prognostic factor for IPF (HR 1.43, 95% CI 1.18-1.74, P < 0.001), but current smoking was not a significant factor. Our results indicated that smoking is a risk factor for IPF patients. In this study, we mainly concluded that smoking is a risk factor for IPF and that former smoking is a poor prognostic factor for IPF. To our knowledge, this is the first meta-analysis report focusing on the association between smoking per se and IPF. Through our current study, we hope to further raise awareness of the relationship between smoking and IPF.

INCREASED SUSCEPTIBILITY TO HERPESVIRUS COMPLICATIONS IN PULMONARY FIBROSIS LUNG TRANSPLANT RECIPIENTS WITH SHORT TELOMERES

SESSION TITLE: Late Breaking Pulmonary Fibrosis SESSION TYPE: Original Investigations PRESENTED ON: 10/22/2019 08:45 AM - 09:45 AM PURPOSE: Idiopathic Pulmonary Fibrosis (IPF) is the leading indication for lung transplantation in North America, however transplant survival rates in this population lag behind all other end-stage lung diseases. Herpesvirus infectious complications are common causes of morbidity and mortality among lung transplant recipients (LTRs). We recently demonstrated that a high percentage of IPF lung transplant recipients (IPF-LTRs) have short lymphocyte telomere length (short TL) using flow cytometry and fluorescence in situ hybridization. Cytomegalovirus (CMV) infection continues to be one of the most common opportunistic infections in LTRs and is associated with chronic lung allograft dysfunction (CLAD). Epstein Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is a herpesvirus transplant complication that is associated with significant mortality. METHODS: We performed retrospective outcomes analyses combined with genetic analyses in a single institution LTR cohort. RESULTS: We have shown that IPF-LTRs with short TL have increased susceptibility to CMV viremia and other CMV complications post-transplant, compared to age-matched non-IPF-LTRs (P < 0.01). In addition, we find that IPF-LTRs with short TL demonstrate impaired CMV-specific T cell immunity compared to non-IPF-LTRs. We evaluated a cohort of 611 LTRs at our institution from 2010-2016 for EBV-associated post-transplant lymphoproliferative disorder (PTLD) and found 28 cases of PTLD (4.6% incidence). Of these, 12/28 patients (43%) were IPF-LTRs and IPF was a risk factor associated with PTLD (Odds ratio: 2.9; 95% CI: 1.2-6.9; P<0.02). Kaplan Meier analyses demonstrated a significant decreased freedom from EBV-associated PTLD among IPF-LTRs (P<0.02), as well as decreased survival with PTLD in IPF-LTRs with PTLD (P<0.05). In addition, EBV mismatch (donor+/recipient-), a known risk factor for PTLD, carried an increased risk (Odds ratio: 6.9; 95% CI 2.3-20.9; P<0.001), while other factors such as male sex or age (risk factors for IPF) were not associated with increase risk for PTLD. Using both targeted exome sequencing and whole genome sequencing approaches, we found genetic mutations in either telomere or telomere-maintenance genes associated with the short telomere syndrome among both the CMV cohort and IPF-LTRs with EBV-PTLD. CONCLUSIONS: Together, these data highlight a predominance of short TL among current IPF-LTRs, along with increased susceptibility to herpesvirus complications in IPF-LTRs as manifestations of the short telomere syndrome. The identification of IPF-LTRs at increased risk for herpesvirus complications using telomere length and genome sequencing, may allow the development of clinical strategies to mitigate these post-transplant complications. CLINICAL IMPLICATIONS: Short telomeres are common in IPF LTRs. Stratification of risk for CMV and EBV-PTLD can advance strategies to mitigate adverse clinical outcomes. DISCLOSURES: No relevant relationships by Jonathan Alder, source=Web Response No relevant relationships by Stefanie Hannan, source=Web Response No relevant relationships by Carlo Iasella, source=Web Response No relevant relationships by Ritchie Koshy, source=Web Response No relevant relationships by John McDyer, source=Web Response No relevant relationships by Matthew Morrell, source=Web Response No relevant relationships by Seyed Mehdi Nouraie, source=Web Response No relevant relationships by Joseph Pilewski, source=Web Response No relevant relationships by Iulia Popescu, source=Web Response No relevant relationships by Pablo Sanchez, source=Web Response no disclosure on file for Fernanda Silveira; No relevant relationships by Spencer Winters, source=Web Response

Cigarette Smoke Extract Promotes Human Lung Myofibroblast Differentiation by the Induction of Endoplasmic Reticulum Stress

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal fibrotic lung disease with an unknown aetiology. Persistent myofibroblast differentiation is a prominent feature of IPF. Cigarette smoking is a risk factor for IPF and an indicator of poor prognosis. Cigarette smoking induces endoplasmic reticulum (ER) stress, and it has been shown that ER stress promotes fibroblast-to-myofibroblast differentiation in lung fibrosis. In this study, we investigated whether cigarette smoke extract (CSE) promotes lung myofibroblast differentiation via the induction of ER stress. Objectives: Our study concentrates on exploring the relationship between smoking and ER stress in the differentiation of lung fibroblasts to myofibroblasts. Methods: Human embryonic lung fibroblasts (MRC-5 fibroblasts) were stimulated with various doses of CSE. Levels of α-smooth muscle actin (α-SMA) protein were evaluated by immunofluorescence and western blot analyses. ER stress was induced by thapsigargin (TG) and inhibited by 4-phenyl butyric acid (4-PBA). Protein levels of glucose-regulated protein-78 (GRP78), inositol-requiring enzyme 1 (IRE1), X box-binding protein-1 (XBP-1) and activating transcription factor 6 (ATF6) were determined by western blotting. GRP78 siRNA was transfected into MRC-5 cells using Lipofectamine RNAiMAX Reagent. Results: CSE at a concentration of 1.0% significantly increased α-SMA expression in MRC-5 cells. There was no significant cell apoptosis after cells were exposed to CSE. CSE treatment significantly increased the expression of GRP78, IRE1, XBP-1 and ATF6 at the protein level at 48 h. Pretreatment with TG enhanced, whereas pretreatment with 4-PBA inhibited, the CSE-induced expression of α-SMA, GRP78 and XBP-1. Furthermore, knockdown of GRP78 blocked α-SMA expression in MRC-5 cells exposed to CSE. Conclusion: Our data suggested that CSE promotes lung fibroblast-to-myofibroblast differentiation by the induction of ER stress.

Autophagy inhibition-mediated epithelial\u2013mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here, we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial–mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (SNAI2), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. Our data suggest that reduced autophagy induces EMT of alveolar epithelial cells and can contribute to fibrosis via aberrant epithelial–fibroblast crosstalk.

Impact of ergothioneine on idiopathic pulmonary fibrosis markers in human lung epithelial cells in vitro

The pathology of idiopathic pulmonary fibrosis (IPF) remains unknown. Tobacco smoking is a risk factor for IPF and tobacco smoke‐induced oxidative stress can initiate/worsen epithelial‐mesenchymal transition (EMT) in pulmonary epithelial cells, leading to IPF. Ergothioneine (ET) is an antioxidant amino acid available exclusively from the diet. ET requires its physiological transporter OCTN1 (SLC22A4) for cellular uptake and accumulation. Genetic variants of SLC22A4 have been associated with inflammatory bowel diseases and COPD, diseases with fibrotic phenotype. In this study, we tested the hypothesis that ET protects lung epithelial cells in vitro from factors implicated with EMT.NCl‐H441 and A549 cells were cultured in RPMI‐1640 medium supplemented with 5% FBS and 1% sodium pyruvate, at 37°C and in 5% CO2 atmosphere. In some experiments, the medium was supplemented with 250 or 500 μM ET. To assess the impact of tobacco smoke, cells were cultured in the presence of 5 or 10% cigarette smoke extract (CSE) for 24h. CSE was generated by bubbling one Kentucky 3R4F research cigarette through 10ml of medium. The CSE was filtered and diluted before use. To initiate EMT, cells were exposed to 5ng/mL TGF‐β1 in serum‐free medium for 3 days in the respective experiments.Cell proliferation was determined by CyQUANT® NF assay. Cell shape investigation was performed by phase‐contrast microscopy and ImageJ software. A scratch wound assay was carried out to measure wound closure. Before the assay, cells were subjected to serum‐deprivation for 24h. Monolayers were wounded with a pipette tip, followed by 1‐day of serum‐free culture. The wound area was measured by phase‐contrast microscopy using the Cell^A software.The cell proliferation assay showed that CSE‐attenuated cell proliferation rate was significantly reduced by ET in NCl‐H441 cells. However, in A549 cells, their rapid proliferation rate might have compromised the sensitivity of the assay. In A549 cells, decreased circularity and increased aspect ratio were measured after TGF‐β1 treatment. These effects were significantly reduced when cultured in the presence of ET. In the scratch assay, increased cell migration was observed in CSE‐treated NCl‐H441 cells, but the effect was diminished after ET treatment. These data suggest that ET not only protects lung epithelial cells from CSE‐induced cell death, but also prevent CSE‐induced cell migration, thereby ameliorating EMT. Of note, in NCl‐H441 cells, TGF‐β1 failed to establish signs of EMT.Future research will investigate the effect of ET on molecular markers of EMT such as α‐SMA, vimentin and collagen.Support or Funding InformationThis work has been financially supported by a Clinical Investigator Award from the Flight Attendant Medical Research Institute (FAMRI CIA 130016). M.A.S. is the recipient of a PhD bursary from the Iraqi Ministry of Higher Education and Scientific Research (MOHESR). A.K. is the recipient of a Laidlaw Undergraduate Research and Leadership Programme.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Oxidation of extracellular cysteine/cystine redox state in bleomycin-induced lung fibrosis

Several lines of evidence indicate that depletion of glutathione (GSH), a critical thiol antioxidant, is associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, GSH synthesis depends on the amino acid cysteine (Cys), and relatively little is known about the regulation of Cys in fibrosis. Cys and its disulfide, cystine (CySS), constitute the most abundant low-molecular weight thiol/disulfide redox couple in the plasma, and the Cys/CySS redox state (E(h) Cys/CySS) is oxidized in association with age and smoking, known risk factors for IPF. Furthermore, oxidized E(h) Cys/CySS in the culture media of lung fibroblasts stimulates proliferation and expression of transitional matrix components. The present study was undertaken to determine whether bleomycin-induced lung fibrosis is associated with a decrease in Cys and/or an oxidation of the Cys/CySS redox state and to determine whether these changes were associated with changes in E(h) GSH/glutathione disulfide (GSSG). We observed distinct effects on plasma GSH and Cys redox systems during the progression of bleomycin-induced lung injury. Plasma E(h) GSH/GSSG was selectively oxidized during the proinflammatory phase, whereas oxidation of E(h) Cys/CySS occurred at the fibrotic phase. In the epithelial lining fluid, oxidation of E(h) Cys/CySS was due to decreased food intake. Thus the data show that decreased precursor availability and enhanced oxidation of Cys each contribute to the oxidation of extracellular Cys/CySS redox state in bleomycin-induced lung fibrosis.

Occupational Risks for Idiopathic Pulmonary Fibrosis Mortality in the United States

Metal and wood dust exposures have been identified as possible occupational risk factors for idiopathic pulmonary fibrosis (IPF). We analyzed mortality data using ICD-10 code J84.1--"Other interstitial pulmonary diseases with fibrosis," derived age-adjusted mortality rates for 1999-2003, and assessed occupational risks for 1999, by calculating proportionate mortality ratios (PMRs) and mortality odds ratios (MORs) using a matched case-control approach. We identified 84,010 IPF deaths, with an age-adjusted mortality rate of 75.7 deaths/million. Mortality rates were highest among males, whites, and those aged 85 and older. Three industry categories with potential occupational exposures recognized as risk factors for IPF were identified: "Wood buildings and mobile homes" (PMR = 4.5, 95% confidence interval (CI) 1.2-11.6 and MOR = 5.3, 95% CI 1.2-23.8), "Metal mining" (PMR = 2.4, 95% CI 1.3-4.0 and MOR = 2.2, 95% CI 1.1-4.4), and "Fabricated structural metal products" (PMR = 1.9, 95% CI 1.1-3.1 and MOR = 1.7, 95% CI 1.0-3.1). Workers in these industry categories may benefit from toxicological studies and improved surveillance for this disease.

Diabetes Mellitus May Increase Risk for Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. The incidence of IPF increases with age. Aging contributes to lifestyle-related diseases, including diabetes mellitus (DM); therefore, it is possible that lifestyle-related diseases may affect either the initiation or progression of IPF. Case-control study. Nippon Medical School and Omiya City Clinic. Sixty-five consecutive patients with IPF who were admitted to Nippon Medical School Hospital from 1995 to 2000, and 184 control subjects selected from 15,798 subjects who were admitted to Omiya City Clinic for routine medical examination between September 1999 and August 2000. Age, sex, smoking history, and results of physical examinations, blood examinations, and lung function testing were extracted from medical records and were compared with the diagnostic criteria for lifestyle-related diseases. The adjusted odds ratios for cigarette smoking were 5.40 (95% confidence interval [CI], 2.30 to 12.66) and 4.06 (95% CI, 1.80 to 9.15) for diabetes. There were no differences in clinical characteristics of patients with IPF that could be related to the presence of DM. DM may be a risk factor for IPF.