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Histologic features suggesting connective tissue disease in idiopathic pulmonary fibrosis.

ABSTRACT: Some patients with idiopathic pulmonary fibrosis (IPF) have histopathologic features suggesting connective tissue disease (CTD); however, their clinical course and prognosis remain unclear. Thus, we aimed to investigate the clinical course and prognosis of these patients with histologic autoimmune features. Among 114 patients with biopsy-proven IPF, the histologic features were semi-quantitatively graded, and CTD scores (range: 0-9) were calculated as the sum of each score of plasma cell infiltration, lymphoid aggregates, and germinal centres. Patients with high CTD scores (??4) were classified into the interstitial pneumonia with histologic autoimmune features (IP-hAF) group. The mean age of the patients was 60.0 years; 74.6% were men, 69.3% were ever-smokers, and 35.1% had IP-hAF. During follow-up, the IP-hAF group showed slower decline in lung function, and better prognosis (median survival, 48.7 vs. 40.4 months; p?=?0.015) than the no-IP-hAF group. On multivariate Cox analysis, IP-hAF was an independent prognostic factor (hazard ratio, 0.522; p?=?0.016), along with the lower diffusing capacity for carbon monoxide, higher scores of reticulation and honeycombing, and usual interstitial pneumonia pattern on high-resolution computed tomography. Patients with IPF having histologic autoimmune features show distinct clinical characteristics and better outcome than those without histologic autoimmune features.

SUBMITTER: Kim HC

PROVIDER: S-EPMC7713371 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Histologic features suggesting connective tissue disease in idiopathic pulmonary fibrosis.

Kim Ho Cheol HC Song Joon Seon JS Park Sojung S Yoon Hee-Young HY Lim So Yun SY Chae Eun Jin EJ Jang Se Jin SJ Song Jin Woo JW

Scientific reports 20201203 1

Some patients with idiopathic pulmonary fibrosis (IPF) have histopathologic features suggesting connective tissue disease (CTD); however, their clinical course and prognosis remain unclear. Thus, we aimed to investigate the clinical course and prognosis of these patients with histologic autoimmune features. Among 114 patients with biopsy-proven IPF, the histologic features were semi-quantitatively graded, and CTD scores (range: 0-9) were calculated as the sum of each score of plasma cell infiltr ...[more]

PMID: 33273612

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Project description:BackgroundIn the aftermath of Covid-19, some patients develop a fibrotic lung disease, i.e., post-COVID-19 lung disease (PCLD), for which we currently lack insights into pathogenesis, disease models, or treatment options.MethodsUsing an AI-guided approach, we analyzed > 1000 human lung transcriptomic datasets associated with various lung conditions using two viral pandemic signatures (ViP and sViP) and one covid lung-derived signature. Upon identifying similarities between COVID-19 and idiopathic pulmonary fibrosis (IPF), we subsequently dissected the basis for such similarity from molecular, cytopathic, and immunologic perspectives using a panel of IPF-specific gene signatures, alongside signatures of alveolar type II (AT2) cytopathies and of prognostic monocyte-driven processes that are known drivers of IPF. Transcriptome-derived findings were used to construct protein-protein interaction (PPI) network to identify the major triggers of AT2 dysfunction. Key findings were validated in hamster and human adult lung organoid (ALO) pre-clinical models of COVID-19 using immunohistochemistry and qPCR.FindingsCOVID-19 resembles IPF at a fundamental level; it recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric), and the AT2 cytopathic changes, e.g., injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP). These immunocytopathic features were induced in pre-clinical COVID models (ALO and hamster) and reversed with effective anti-CoV-2 therapeutics in hamsters. PPI-network analyses pinpointed ER stress as one of the shared early triggers of both diseases, and IHC studies validated the same in the lungs of deceased subjects with COVID-19 and SARS-CoV-2-challenged hamster lungs. Lungs from tg-mice, in which ER stress is induced specifically in the AT2 cells, faithfully recapitulate the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.InterpretationLike IPF, COVID-19 may be driven by injury-induced ER stress that culminates into progenitor state arrest and SASP in AT2 cells. The ViP signatures in monocytes may be key determinants of prognosis. The insights, signatures, disease models identified here are likely to spur the development of therapies for patients with IPF and other fibrotic interstitial lung diseases.FundingThis work was supported by the National Institutes for Health grants R01- GM138385 and AI155696 and funding from the Tobacco-Related disease Research Program (R01RG3780).

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, eventually fatal disease. IPF is characterized by excessive accumulation of the extracellular matrix (ECM) in the alveolar parenchyma and progressive lung scarring. The pathogenesis of IPF and whether the ECM involved in the process remain unknown.MethodsTo identify potential treatment target and ECM associated proteins that may be involved in the development of IPF, we employed isobaric tag for relative and absolute quantitation (iTRAQ) combined liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach to examine protein expression in lung tissues from IPF patients.ResultsA total of 662 proteins with altered expression (455 upregulated proteins and 207 downregulated proteins) were identified in lung tissue of IPF patients compared with control. KEGG pathway enrichment analysis showed that the altered proteins in lung tissue mainly belonged to the PI3K-Akt signaling, focal adhesion, ECM-receptor interaction, and carbon metabolism pathways. According to the bioinformatic definition of the matrisome, 229 matrisome proteins were identified in lung tissue. These proteins comprised the ECM of lung, of which 104 were core matrisome proteins, and 125 were matrisome-associated proteins. Of the 229 ECM quantified proteins, 56 significantly differentially expressed proteins (19 upregulated proteins and 37 downregulated proteins) were detected in IPF lung tissue samples. In addition to proteins with well-known functions such as COL1A1, SCGB1A1, TAGLN, PSEN2, TSPAN1, CTSB, AGR2, CSPG2, and SERPINB3, we identified several novel ECM proteins with unknown function deposited in IPF lung tissue including LGALS7, ASPN, HSP90AA1 and HSP90AB1. Some of these differentially expressed proteins were further verified using Western blot analysis and immunohistochemical staining.ConclusionsThis study provides a list of proteomes that were detected in IPF lung tissue by iTRAQ technology combined with LC-MS/MS. The findings of this study will contribute better understanding to the pathogenesis of IPF and facilitate the development of therapeutic targets.

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Histologic features suggesting connective tissue disease in idiopathic pulmonary fibrosis.

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Histologic features suggesting connective tissue disease in idiopathic pulmonary fibrosis.

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