New Chinese Medical Journal Pulmonary and Critical Care Medicine study provides key insights into pathogenesis mechanisms of lung fibrosis

Pulmonary fibrosis (PF), also known as lung fibrosis, refers to the scarring of tissue surrounding alveoli, resulting in respiratory complications. PF is a progressive, terminal disease and has been linked to exposure to hazardous chemicals, smoking, and genetic factors. While previous scientific reports have highlighted the complexity of PF disease, studies on cell-cell interactions (CCIs) between the various cell types can reveal the underlying mechanisms that drive PF.

In this light, a group of researchers conducted a review of literature to assess and evaluate recent research findings on CCIs between epithelial cell and mesenchymal cell in PF. The team comprised Professor Paul Noble, Dr. Ting Xie, and other senior faculty members from the Department of Medicine, Cedars-Sinai Medical Center, USA. Their research findings were published in the Chinese Medical Journal Pulmonary and Critical Care Medicine. This paper was made available online on 18 June 2024 and was published in Volume 2, Issue 2 of the journal.

“The complex interplay among the diverse lung cell types and intricate processes they engage in plays a pivotal role in gas exchange efficiency, immune response modulation, tissue repair mechanisms, and the precise regulation of airway function. Understanding this is especially significant in the context of lung fibrosis, as it sheds light on the underlying mechanisms driving this condition and offers insights into potential avenues for therapeutic intervention,” says Prof. Noble, sharing the motivation and rationale behind the present work.

Initially, the researchers describe the major cell types of epithelial cells in the lungs, namely alveolar epithelial cells, airway epithelial cells, mesenchymal cells, endothelial cells (ECs), and immune cells. “The cellular contribution to PF largely depends on single-cell functions and interactions between cells in the lung,” says Prof. Noble, highlighting the role of CCIs in promoting PF pathogenesis.

Furthermore, they analyzed the crucial interactions between alveolar epithelial type 2 (ATII) cells and mesenchymal cells which enables the smooth functioning of the lungs and air sacs. They found that exposure to stressful conditions can cause the differentiation of ATII cells into alveolar epithelial type 1 (ATI) cells along with ATII cell dysfunction. Subsequently, mesenchymal cells detect ATII cell dysfunction via the increased secretion of certain chemical messenger proteins and contribute to PF pathogenesis by the elevated production of extracellular matrix.

Additionally, analysis of single-cell RNA sequencing datasets revealed the potential ligands involved in ATI cell interactions with other cell types in fibrotic lungs. Tumor necrosis factor, interleukin 1β, and A disintegrin and metalloproteinase 17 (ADAM17) were important ligands for communication and signaling pathways involved in PF.

The researchers found that semaphorin proteins and plexin or neuropilin receptors were key for cell-cell communication between airway epithelial cells and mesenchymal cells in PF.

Explaining the role of basal cells in PF, Prof. Noble says, “Recent research has indicated that basal cells have secretory characteristics that contribute to mesenchymal cell activation in the context of lung fibrosis. Intriguingly, canonical Wnt signalling is central to the orchestration of basal cell activities post-damage.”

Subsequently, the researchers investigated the specific mesenchymal cell-induced interactions with alveolar epithelial cells in lung fibrosis. Presence of leucine-rich repeat-containing G- protein coupled receptor 5 mesenchymal cells and reduced expression of growth hormone receptor was observed in PF lungs.

They conclude by highlighting the various antifibrotic drugs that target CCIs in clinical development and the need for combining computational algorithms with experimental investigations.

The current findings provide a comprehensive overview into the key ligand-receptor interactions and molecular mechanisms driven by specific CCIs in PF disease. Targeting CCIs involved in lung fibrosis may result in novel therapies and strategies, ultimately improving the treatment outcomes of patients with PF.

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Reference

DOI: 10.1016/j.pccm.2024.04.001