Dataset Information

Small airways pathology in idiopathic pulmonary fibrosis: a retrospective cohort study.

ABSTRACT:

Background

The observation that patients with idiopathic pulmonary fibrosis (IPF) can have higher than normal expiratory flow rates at low lung volumes led to the conclusion that the airways are spared in IPF. This study aimed to re-examine the hypothesis that airways are spared in IPF using a multiresolution imaging protocol that combines multidetector CT (MDCT), with micro-CT and histology.

Methods

This was a retrospective cohort study comparing explanted lungs from patients with severe IPF treated by lung transplantation with a cohort of unused donor (control) lungs. The donor control lungs had no known lung disease, comorbidities, or structural lung injury, and were deemed appropriate for transplantation on review of the clinical files. The diagnosis of IPF in the lungs from patients was established by a multidisciplinary consensus committee according to existing guidelines, and was confirmed by video-assisted thoracic surgical biopsy or by pathological examination of the contralateral lung. The control and IPF groups were matched for age, sex, height, and bodyweight. Samples of lung tissue were compared using the multiresolution imaging approach: a cascade of clinical MDCT, micro-CT, and histological imaging. We did two experiments: in experiment 1, all the lungs were randomly sampled; in experiment 2, samples were selected from regions of minimal and established fibrosis. The patients and donors were recruited from the Katholieke Universiteit Leuven (Leuven, Belgium) and the University of Pennsylvania Hospital (Philadelphia, PA, USA). The study took place at the Katholieke Universiteit Leuven, and the University of British Columbia (Vancouver, BC, Canada).

Findings

Between Oct 5, 2009, and July 22, 2016, explanted lungs from patients with severe IPF (n=11), were compared with a cohort of unused donor (control) lungs (n=10), providing 240 samples of lung tissue for comparison using the multiresolution imaging approach. The MDCT specimen scans show that the number of visible airways located between the ninth generation (control 69 [SD 22] versus patients with IPF 105 [33], p=0·0023) and 14th generation (control 9 [6] versus patients with IPF 49 [28], p<0·0001) of airway branching are increased in patients with IPF, which we show by micro-CT is due to thickening of their walls and distortion of their lumens. The micro-CT analysis showed that compared with healthy (control) lung anatomy (mean 5·6 terminal bronchioles per mL [SD 1·6]), minimal fibrosis in IPF tissue was associated with a 57% loss of the terminal bronchioles (mean 2·4 terminal bronchioles per mL [SD 1·0]; p<0·0001), the appearance of fibroblastic foci, and infiltration of the tissue by inflammatory immune cells capable of forming lymphoid follicles. Established fibrosis in IPF tissue had a similar reduction (66%) in the number of terminal bronchioles (mean 1·9 terminal bronchioles per mL [SD 1·4]; p<0·0001) and was dominated by increased airspace size, Ashcroft fibrosis score, and volume fractions of tissue and collagen.

Interpretation

Small airways disease is a feature of IPF, with significant loss of terminal bronchioles occuring within regions of minimal fibrosis. On the basis of these findings, we postulate that the small airways could become a potential therapeutic target in IPF.

Funding

Katholieke Universiteit Leuven, US National Institutes of Health, BC Lung Association, and Genentech.

SUBMITTER: Verleden SE

PROVIDER: S-EPMC7292784 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale: The diagnosis of idiopathic pulmonary fibrosis (IPF) requires exclusion of an underlying autoimmune disease, as present in interstitial lung diseases associated with connective tissue diseases (CTD-ILD). The prevalence of autoantibodies in IPF patients is currently unknown. Objectives: An unbiased assay for de novo discovery of autoantigens can help characterizing autoreactivities in IPF patients beyond clinically established autoimmune panels. Methods: We developed the proteomic Differential Antigen Capture (DAC) assay, capturing patient antibodies from plasma, followed by affinity purification coupled to mass spectrometry (AP-MS). The DAC assay quantifies the binding capacity of patient antibodies to proteins in a pooled native extract from lung explants (ILD explants n=41; donor controls n=12). Plasma antibodies from patients with IPF (n=35), CTD-ILD (n=24) and age-matched controls (n=32) were analyzed and validated in an independent cohort (IPF: n=40; CTD-ILD: n=20). Plasma antibody binding profiles were associated with clinical meta-data including diagnosis, lung function and transplant free survival. Measurements and Main Results: We identified 586 putative autoantigens in both study cohorts with a broad heterogeneity among disease entities and cohorts. On average, in IPF a mean±SD of 16±40 autoantigens and in CTD-ILD a mean±SD of 9±15 autoantigens were identified per patient. We identified 18 IPF-specific autoantigens validated in the second cohort. Interestingly, there was also a high number of shared autoantigens in IPF and CTD-ILD patients, with 17 being present in IPF and CTD-ILD of both cohorts. Presence of antibodies to Thrombospondin 1 (THBS1) and tubulin beta-1 chain (TUBB1) was associated with a significantly reduced survival in patients with IPF (p=0.002 and p=0.019, respectively). This signature was often associated with autoreactivity against talin-1 (TLN1), latent-transforming growth factor beta-binding protein 1 (LTBP1), epididymis secretory protein Li 112 (HEL-S-112), zyxin (ZYX), the LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1) and caldesmon (CALD1). Conclusions: Unbiased proteomic profiling reveals that the overall prevalence of autoantibodies is similar in IPF and CTD-ILD patients and identifies novel IPF specific autoantigens associated with patient survival.