Discussion
In recent years, significant progress has been made in the study of PF
and its related fibrotic mechanisms. PF is generally caused by multiple
pathogenic factors, triggering a wound-healing process that leads to an
inflammatory response in macrophages. Subsequently, dysregulated
epithelial cells interact with various cells, including mesenchymal
cells, immune cells, and endothelial cells, through multiple signaling
mechanisms. This process ultimately recruits fibroblasts and activates
myofibroblasts, resulting in excessive deposition of collagen-rich ECM
and the formation of fibrosis(55). In this review, we focus on the
application and research of in vitro models in PF, specifically
exploring strategies for uncovering disease pathways, repurposing drugs,
and investigating cell-cell interactions.
Throughout our literature review, we found that different cellular
models have been used to study the various pathogenic aspects of PF,
although there is a lack of strict uniform criteria for selecting cell
types in mechanistic studies. Macrophages persist during inflammation
and injury, while monocyte-derived macrophages are recruited to aid in
repair. Researchers commonly employ macrophages to construct
inflammatory models of PF to investigate its pathogenesis in terms of
inflammation and immunity. The repair process driven by airway
epithelial cells leads to epithelial hyperplasia and the emergence of
abnormal basal-like cells around the lungs. Bronchial epithelial cells
are commonly used to construct pathological models of lung fibrosis,
focusing on the pathogenesis of tracheal, bronchial, and fine
bronchial-associated lung fibrosis. Chronic damage to AECs impairs the
effective repair of damaged epithelium by AT2 cells. AECs are often
employed to construct pathological models of PF, primarily studying the
pathogenesis of epithelial-mesenchymal transition (EMT), cellular
senescence, endoplasmic reticulum stress, mitochondrial dysfunction, and
telomere shortening. Abnormally activated fibroblasts and myofibroblasts
contribute to excessive ECM production in the alveolar interstitial
space, ultimately leading to PF. Developing in vitro models of
fibroblasts is crucial for studying excessive ECM deposition and tissue
remodeling in lung fibrosis. Current studies often utilize multiple cell
lines for comparison, enhancing the scientific validity and accuracy of
experiments compared to using a single cell line.
However, the complex and diverse pathogenesis of PF necessitates new
disease models for more intricate mechanism studies. The advent of
co-culture systems enables the study of intercellular relationships and
cell-environment interactions in vitro. Traditional culture systems
consist of single cell types isolated from naturally or complexly
growing in vivo environments, resulting in simplified characteristics.
However, cells require information exchange and substance metabolism
within their survival microenvironment. Intercellular signal
transduction plays a vital role in cellular behaviors. Understanding the
crosstalk mechanisms between different cell types is significant for
investigating the pathogenesis of certain diseases. Thus, comprehending
PF should be based on a multi-organ, multi-level, and multi-perspective
understanding, rather than solely relying on a single cell type or
organ. While the research paradigm traditionally involves studying in
vivo models and extrapolating findings to humans, in vitro co-culture
models offer a simpler and reproducible system for researching PF,
providing a more comprehensive cellular characterization compared to
single-cell models.
In conclusion, this article reviews the construction and application of
in vitro models for PF and their relevance to mechanistic studies. In
the future, optimizing co-culture systems in disease research,
particularly in the early stages, will enable better understanding of
disease mechanisms and support the development of new therapeutic
strategies for PF.