American Journal of Respiratory and Critical Care Medicine

We previously reported that oxidative stress drives pseudohypoxic hypoxia-inducible factor (HIF) pathway activation to promote pathogenetic collagen structure-function in human lung fibrosis (Brereton et al., 2022). Here, through bioinformatic studies we investigate HIF pathway activation status in patients with idiopathic pulmonary fibrosis (IPF) and whether this has prognostic significance. Applying a well-established HIF gene expression signature, we classified publicly available datasets int...

AbstractO_ST_ABSRationaleC_ST_ABSIdiopathic pulmonary fibrosis (IPF) is an age-related disorder with common and rare genetic risk factors. It is unknown if the effects of PF genetic risk factors differ by chronologic age. ObjectivesTo assess age-specific effects of genetic risk factors in PF patients and their relatives. MethodsWe identified common and rare genetic risk factors using a Columbia whole genome sequencing (WGS) cohort (777 IPF, 2905 controls) and replicated findings using Trans-Om...

RationaleThe diagnosis of idiopathic pulmonary fibrosis (IPF) requires exclusion of known underlying autoimmunity, as present in interstitial lung diseases associated with connective tissue diseases (CTD-ILD). However, autoantibodies of unknown significance have been repeatedly detected in IPF patients. ObjectivesWe aimed to characterize autoreactivities in IPF patients beyond clinically established autoimmune panels by establishing an unbiased assay for de novo discovery of autoantigens in dif...

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapies and poorly defined cross-tissue immune mechanisms. We performed single-cell RNA sequencing and TCR profiling of paired lung, lymph node, and peripheral blood samples from patients with IPF, combined with functional coculture assays and mouse model. We identified GZMK-high CD8 T cells enriched in fibrotic lungs, displaying inflammatory but low-cytotoxic features. TCR and trajectory analyses indicated t...

BackgroundIdiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia of unknown etiology often leading to respiratory failure. Over half of IPF patients present with discordant features of usual interstitial pneumonia on high-resolution computed tomography at diagnosis which warrants surgical lung biopsy to exclude the possibility of other interstitial lung diseases (ILDs). Therefore, there is a need for non-invasive biomarkers for expediting the differential diagnosis of IPF. Me...

Single cell genomics enables characterization of disease specific cell states, while improvements in mass spectrometry workflows bring the clinical use of body fluid proteomics within reach. The correspondence of cell state changes in diseased organs to peripheral protein signatures is currently unknown. Here, we leverage single cell RNA-seq and proteomic analysis of large pulmonary fibrosis patient cohorts to identify disease specific changes on the cellular level and their corresponding reflec...

ObjectiveCirculating fibrocytes are elevated in idiopathic pulmonary fibrosis, but the relationship between fibrocyte level with lung function decline and outcomes is lacking replication in prospective clinical study. We aim to validate the utility of circulating fibrocyte levels as a prognostic biomarker in idiopathic pulmonary fibrosis. MethodsWe tested associations between circulating fibrocyte levels, mortality, disease progression and longitudinal lung function in a well-defined prospectiv...

RationaleThe association between immune-cell-specific transcriptomic profiles and Idiopathic Pulmonary Fibrosis (IPF) mortality is unknown. ObjectivesTo determine immune-cell-specific transcriptomic profiles associated with IPF mortality. MethodsWe profiled peripheral blood mononuclear cells (PBMC) in 18 participants [University of South Florida: IPF, COVID-19, post-COVID-19 Interstitial Lung Disease (Post-COVID-19 ILD), controls] by single-cell RNA sequencing (scRNA-seq) and identified 16 imm...

Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease where deficiency of the TGF/BMP pathways have causal roles in hereditary and idiopathic forms. It is an attractive candidate for therapeutic intervention but there is an unmet need for clinically-relevant and practical biomarkers that can measure target engagement. A major challenge has been the inaccessibility of lung tissue in disease for molecular profiling. Here we explore the surrogate capacity of peripheral blood BMP pa...

BackgroundOlder age is the main risk factor for chronic lung diseases including idiopathic pulmonary fibrosis (IPF). Halting or reversing progression of IPF remains an unmet clinical need due to limited knowledge of underlying mechanisms. The lung circulatory system, composed of blood (pulmonary and bronchial) and lymphatic vessels networks, has been implicated in IPF pathophysiology in elderly people, based solely on reports of altered density and increased permeability of vessels. AimWe aimed...

BackgroundChronic lung allograft dysfunction (CLAD) leads to declining respiratory function and high mortality, representing the main barrier to long-term survival in lung transplantation (LT). We performed the first genome-wide association study (GWAS) investigating donors and recipients genetic factors associated with CLAD. MethodWe genotyped 392 donor-recipient pairs from the multicentric Cohort in Lung Transplantation. We tested 4.5 million SNPs for association with CLAD using multivariable...

BackgroundIdiopathic pulmonary fibrosis (IPF) leads to progressive loss of lung function and mortality. Understanding mechanisms and markers of lung injury in IPF is paramount to improving outcomes for these patients. Despite the lack of systemic involvement in IPF, many analyses focus on identifying circulating prognostic markers. Using a proteomic discovery method followed by ELISA validation in multiple IPF lung compartments and cohorts we explored novel markers of IPF survival. MethodsIn ou...

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options. Although macrophages have been implicated in pathogenesis in murine models, their role in human disease remains unclear. Here, we present a comprehensive, unbiased single-cell transcriptomic and regulon atlas of myeloid cells from the alveolar barrier and lung tissue. We demonstrate that alveolar barrier macrophages are transcriptionally distinct from their lung tissue counterparts, exhi...

Sarcoidosis is a multisystem granulomatous disease of unknown origin with a variable and often unpredictable course and pattern of organ involvement. In this study we sought to identify specific bronchoalveolar lavage (BAL) cell gene expression patterns indicative of distinct disease phenotypic traits. RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well characterized patients with pulmonary sarcoidosis enrolled in the multicenter Genomic Research in Alpha-1 An...

AbstractHealthy repair of the alveoli requires alveolar stem cells to differentiate into cells designed for gas exchange. In chronic lung fibrotic disease like idiopathic pulmonary fibrosis (IPF), alveolar epithelial cells regenerate abnormally. The cause of this is unknown but its highly cellular, inflamed and structurally altered regenerating niche is likely to be relevant. Here, in unique sets of human lung tissues capturing advancing fibrosis, and with a 33-plex single cell imaging mass cyto...

Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with limited therapeutic options. We carried out genome-wide association (GWAS), post-GWAS and rare variant analyses utilising the whole genome sequencing data (WGS) from the 100,000 Genomes Project (100kGP) of a cohort of IPF participants (n=586) to identify novel associations and potential drug targets. Meta-analysis combining 100kGP and published GWASs of IPF (total 11,746 cases and 1,416,493 controls) i...

Interstitial lung diseases (ILD) are heterogeneous conditions that may lead to progressive fibrosis and death of affected individuals. Despite diversity in clinical manifestations, enlargement of lung-associated lymph nodes (LLN) in fibrotic ILD patients predicts worse survival. Herein, we revealed a common adaptive immune landscape in LLNs of all ILD patients, characterized by highly activated germinal centers and antigen-activated T cells including regulatory T cells (Tregs). In support of the...

Radiomic features are quantitative data calculated from routine medical images and have shown great potential for disease phenotyping and risk stratification in cancer. Patients with systemic sclerosis (SSc), a multi-organ autoimmune disorder, have a similarly poor prognosis (10-year survival of 66%), due to interstitial lung disease (ILD) as the primary cause of death. Here, we present the analysis of 1,355 stable radiomic features extracted from computed tomography scans from 156 SSc-ILD patie...

RationaleIdiopathic pulmonary fibrosis (IPF) is a rare, chronic, progressive lung disease with high mortality and few treatment options. Using an additive genetic model, genome-wide association studies (GWAS) have identified multiple risk loci highlighting new genes and pathways of interest. Since IPF risk could also be influenced by non-additive effects, we hypothesised that association analyses using alternative genetic models may provide additional mechanistic insight. ObjectivesTo perform G...

BackgroundLung microbiota profiles in patients with early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression; however, the topographic heterogeneity of lung microbiota and their roles in advanced IPF are unknown. MethodsWe sampled subpleural tissue from up to three lobes as well as airway-based specimens (bronchial washings and airway tissue) in patients with IPF, connective tissue disease-associated interstitial lung disease (CTD-ILD), cystic fibrosis (CF), and c...