Contemporary Concise Review 2021: Interstitial lung disease

Abstract

The last 2 years have presented previously unforeseen challenges in pulmonary medicine. Despite the significant impact of the SARS-CoV-2 pandemic on patients, clinicians and communities, advances in the care and understanding of interstitial lung disease (ILD) continued unabated. Recent studies have led to improved guidelines, better understanding of the role for antifibrotics in fibrosing ILDs, prognostic indicators and novel biomarkers. In this concise contemporary review, we summarize many of the important studies published in 2021, highlighting their relevance and impact to the management and knowledge of ILD.

Keywords: fibroblast; fibrosis; interstitial lung disease; lung; respiratory.

FIGURE 1

Recently reported pathogenic mechanisms in interstitial lung disease. B cells secrete profibrotic and pro‐inflammatory proteins in response to microbial antigens, and increased IL‐6, IL‐8 and matrix metalloproteinase 7 (MMP7) lead to activated fibroblasts and increased migration. The Notch pathway is involved in myofibroblast differentiation, and reduced Notch3 signalling results in less α‐smooth muscle actin (αSMA), collagen type 1 (Col1a1) and other profibrotic gene expression from fibroblasts. Abnormal extracellular matrix (ECM) in fibrotic lung tissue increases the expression of cellular and extracellular vesicle (EV) expressed miR‐21‐5p from fibrocytes, which exert pro‐fibrotic effects and upregulation of Col1a1 in fibroblasts leading to further ECM

FIGURE 2

Novel potential therapeutic targets in interstitial lung disease. Matrix metalloproteinase 9 (MMP9) blockade with the monoclonal antibody, andecaliximab, led to response in lungs with a type I interferon‐rich environment with increased concentrations of CXCL10 (CXC motif chemokine ligand 10) and by reducing transforming growth factor beta (TGFβ) signalling and decreasing fibrotic extracellular matrix (ECM) deposition. Epithelial–mesenchymal transition (EMT) creates an environment facilitating fibrosis following alveolar epithelial cell injury. IL‐23‐induced EMT is dependent on mammalian target of rapamycin (mTOR) signalling and can be reversed by rapamycin, or potentially targeted blockade by anti‐IL‐23 antibody which can attenuate airway inflammation in acute exacerbations. Stearic acid reduced the TGFβ‐induced expression of α‐smooth muscle actin (αSMA) and collagen type 1 (Col1a1) in fibroblasts, indicating potential novel antifibrotic properties. Recent studies of IL‐13 blockade using the monoclonal antibody, lebrikizumab, was demonstrated to be well tolerated and safe, but lebrikizumab alone or in combination with pirfenidone did not reduce the rate of forced vital capacity

FIGURE 3

Collagen turnover products correlate with survival in pulmonary fibrosis. Neoepitope biomarkers of types III and VI collagen turnover (C3M, C6M, PRO‐C3 and PRO‐C6) were measured in 185 patients with newly diagnosed idiopathic pulmonary fibrosis. High baseline levels of C3M, C6M, PRO‐C3 and PRO‐C6 were associated with more advanced disease at the time of diagnosis. Figures show Kaplan–Meier curves of survival of participants in the Pulmonary Fibrosis Biomarker (PFBIO) cohort followed up for 3 years. Patients are divided according to the number of high neoepitope biomarkers (C3M, C6M, PRO‐C3 and PRO‐C6) at baseline. Reproduced from Hoyer et al., with permission

FIGURE 4

Serum KL‐6 and CYFRA 21‐1 are associated with the presence and extent of systemic sclerosis‐associated interstitial lung disease (SSc‐ILD). KL‐6 is a mucin‐like glycoprotein (MUC1) that is expressed by type II pneumocytes, and CYFRA 21‐1 is expressed by alveolar and bronchiolar epithelial cells. Serum KL‐6 and CYFRA 21‐1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc‐ILD patients. Serum KL‐6 and CYFRA 21‐1 correlated with the presence and severity of ILD, with higher levels in SSc‐ILD compared to SSc‐no ILD, and in extensive compared to limited ILD. Serum KL‐6 levels in no‐ILD, limited ILD and extensive ILD in the (A) retrospective and (B) prospective cohorts. Serum CYFRA 21‐1 levels in no‐ILD, limited ILD and extensive ILD in the (C) retrospective and (D) prospective cohorts. Central lines indicate median values with boxes showing the 25th and 75th percentiles, whiskers indicate upper and lower quartile + 1.5 × interquartile range. Reproduced from Stock et al., with permission