Table 1.

Novel Models and Tools to Study Pulmonary Fibrosis

Model/Tool	Advantages	Limitations
Ferret model	Pathology recapitulates characteristic key features of pulmonary fibrosis, including persistent fibrosis, prominent MUC5B expression in distal airways, and aberrant repair	Cost and complexity of ferret model Lifespan 5–10 yr with onset of geriatric diseases between 3 and 4 yr Fewer ferret-specific reagents available to characterize the model Requires more compound for drug testing than mouse models Therapeutic applications not yet demonstrated
Sftpc mouse models	Develop spontaneous fibrosis Model early disease Elaborate cytokines and biomarkers detected in pulmonary fibrosis patients Can be used to benchmark drug efficacy	Sftpc locus unavailable for lineage tracing Does not model bronchiolization
Precision-cut lung slices	Natural composition of cells and ECM Live imaging of cell–cell and cell–ECM interaction ex vivo Early stages of fibrosis can be induced Can be used for drug discovery and validation	Limited culture time No ventilation/perfusion No homing of nonresident cells Limited value for translation in relation to route of administration of therapeutic agents (e.g., inhaled or systemic administration)
Hydrogel biomaterials	Enable manipulation of mechanical properties Biochemical changes can be decoupled from biophysical changes Can probe cell–matrix interactions Can create sex-specific models Many cell types can be included Can be used for drug discovery and validation	No air–liquid interface No cyclic stretch Current models may not capture the complexity of the in vivo ECM or in vivo inflammatory milieu
Lung organoids	Enable epithelial–mesenchymal cellular interactions to be studied High-throughput analysis possible for drug screening and biological readouts Many cell types can be included Mechanotransduction forces can be modeled	No vasculature or airflow Does not model bronchiolization Takes a reductionist approach; not all cellular and matrix components are present No homing of nonresident cells
Pluripotent stem cells	Inexhaustible source of cells for generating lung lineages of interest for disease modeling, drug screening, or cell-based therapies Patient-specific, editable, and scalable Allows production of initially normal patient-derived cells to replay or recapitulate disease onset/emergence in vitro	Lack of standardized differentiation procedures for all lung cell types Differentiation protocols for some relevant cell types (e.g., AT2 cells and lung mesenchymal lineages) are currently a work in progress Cocultures of multiple cell types needed to fully recapitulate in vivo environment
Single cell profiling	Allows discovery of novel cellular phenotypes and states associated with fibrosis Provides a detailed atlas of molecular changes and cellular interactions that occur in lung fibrosis Information obtained can be used to orient therapy development focused on specific cell populations in the fibrotic lung	Dependent on tissue availability Only captures transcriptional regulation, not post-transcriptional effects (e.g., mRNA stability or post-translational modifications) Most results to date have been from end-stage lung tissue and are limited in ethnic, racial, and geographical representation

Definition of abbreviation: ECM = extracellular matrix.