Insights into interstitial lung disease pathogenesis

Abstract

This review summarises some of the key features of interstitial lung diseases (ILDs) from a translational science point of view and brings insights into potential therapeutic options. Genetic predisposition and environmental factors like smoking, pollution and infections significantly impact the onset, progression and treatment response in ILDs, highlighting the need for personalised management. Fibroblasts are central to ILD pathology, influencing the tissue microenvironment, immune cell interactions and extracellular matrix (ECM) production, making them critical therapeutic targets. Monocyte-derived M2 macrophages drive fibrosis in idiopathic pulmonary fibrosis by secreting cytokines and remodelling the ECM. Understanding macrophage subtypes and their dynamics offers new therapeutic possibilities. Chronic type 2 immunity contributes to fibrosis, emphasising the need to enhance protective markers in order to even out the balance shift of pathological immune responses in ILD treatments. Serum biomarkers like Krebs von den Lungen-6 (KL-6), surfactant protein (SFTP) D, matrix metalloproteinase-7 (MMP-7), and C-C motif chemokine ligand (CCL)-18 are valuable for diagnosing and predicting ILD progression, although more research is needed for clinical application. Animal models, especially bleomycin-based models, offer insights into ILD pathology, but challenges like lung hyperinflation highlight the need for careful model selection and translational research to bridge preclinical and clinical findings.

FIGURE 1

The major genetic and environmental factors impacting the development and progression of interstitial lung disease. Recently detected genetic predisposition involves mutations in telomere-related genes (TRGs) and in surfactant-related genes (SRGs), as well as single nucleotide polymorphisms (SNPs) in the MUC5B and TOLLIP genes. There are also some ultra rare genetic disorders that are not included in the figure. Environmental factors also influence disease development, including air pollution, exposure to allergens, occupational diseases and inhalation of several particles, but also viral infections, drugs and aspirations mainly associated with gastro-oesophageal reflux (GOR). Figure created using BioRender.

FIGURE 2

Pathogenic fibroblasts arise via multiple cellular and molecular mechanisms in interstitial lung disease (ILD). a) Bidirectional communication between macrophages and fibroblasts via the release of chemokines and pro-fibrotic mediators drives myofibroblast activation and increased deposition of extracellular matrix (ECM). b) Scube2-expressing alveolar fibroblasts are the origin of both inflammatory (CXCL12+) and fibrotic (CTHRC1+) fibroblast subsets in the lung. c) Apoptosis-resistant myofibroblasts accumulate and persist in the injured lung. d) Fibroblast-derived extracellular vesicles (EVs) are released from SFRP1+ transitional fibroblasts and exert pro-fibrotic effects. e) Transforming growth factor-β (TGF-β) increases GLS1 expression driving conversion of intracellular glutamine levels to glutamate, which supports alanine and proline biosynthesis, necessary for the TGF-β–induced collagen response. IL: interleukin. Figure created using BioRender.

FIGURE 3

Representative images from a control group (panel a) and the bleomycin-exposed group (panel b), showing magnetic resonance imaging (MRI) scans and histology assessment by Masson's trichrome stained lung tissue sections. The MRI was acquired in the transversal plane using the Rapid Acquisition with Refocusing Echoes (RARE) sequence combined with the Ultra Short Echo (UTE) sequence of 1 ms, in a chronic bleomycin model with systemic exposure (intraperitoneal) for 4 weeks (scans performed at 6 weeks post-dosing initiation, thus 4 weeks dosing plus 2 weeks rest). The figure was reproduced and modified from [114] with permission.