Abstract
Large multicenter clinical trials have led to two recently approved drugs for patients with idiopathic pulmonary fibrosis (IPF); yet, both of these therapies only slow disease progression and do not provide a definitive cure. Traditionally, preclinical trials have utilized mouse models of bleomycin (BLM)-induced pulmonary fibrosis—though several limitations prevent direct translation to human IPF. Spontaneous pulmonary fibrosis occurs in other animal species, including dogs, horses, donkeys, and cats. While the fibrotic lungs of these animals share many characteristics with lungs of patients with IPF, current veterinary classifications of fibrotic lung disease are not entirely equivalent. Additional studies that profile these examples of spontaneous fibroses in animals for similarities to human IPF should prove useful for both human and animal investigators. In the meantime, studies of BLM-induced fibrosis in aged male mice remain the most clinically relevant model for preclinical study for human IPF. Addressing issues such as time course of treatment, animal size and characteristics, clinically irrelevant treatment endpoints, and reproducibility of therapeutic outcomes will improve the current status of preclinical studies. Elucidating the mechanisms responsible for the development of fibrosis and disrepair associated with aging through a collaborative approach between researchers will promote the development of models that more accurately represent the realm of interstitial lung diseases in humans.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease, primarily affecting middle aged and older adults [1, 2]
This review aims to summarize current state of knowledge on animal modeling of lung fibrosis, mainly focusing on rodents, including environmental and genetic models, highlight limitations, and suggest future potentials
In view of the pathologic hallmarks of idiopathic pulmonary fibrosis (IPF), appropriate read-out assays include assessment of collagen deposition, alveolar epithelial cell apoptosis, and BALF complemented by survival analysis and respiratory mechanics. These are achieved with the following modalities: [1] histological analysis with Masson trichrome and H&E staining coupled with Aschroft score that quantifies extent of fibrotic changes, [2] hydroxyproline or total collagen content for quantification of lung collagen deposition, [3] TUNEL assay for the identification of apoptotic cells, [4] BALF analysis to assess changes in differential cell count and levels of inflammatory and fibrotic markers, [5] survival analysis with Kaplan–Meier plots, [6] in vivo lung function measurements using the Flexi-vent ventilator, and [7] micro-CT imaging which provides state-of-the art multidimensional imaging of the injured lung that is reminiscent of HRCT applied for IPF diagnosis [19]
Summary
Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease, primarily affecting middle aged and older adults [1, 2]. The model presents with major caveats including problematic and highly expensive equipment for aerosolized delivery, prolonged waiting periods until development of fibrosis (4–16 weeks), lack of reproducibility of fibrotic pattern, and absence of characteristic UIP-like lesions such as fibroblastic foci, regional heterogeneity, and hyperplastic epithelium These have severely limited its widespread applicability in the preclinical setting [20]. Similar kinetics are observed with adenoviral delivery of TGF-β through the intranasal route leading to epithelial cell apoptosis (day 1), mononuclear cell infiltration (days 3–7), and fibrotic scarring that tends to be more persistent than those produced by BLM exposure and tend to mimic better human disease features [71] Both models quite often produce highly variable and heterogeneous kinetics of injury with regards to severity and extent of lesions and lack of major reproducibility. These are achieved with the following modalities: [1] histological analysis with Masson trichrome and H&E staining coupled with Aschroft score that quantifies extent of fibrotic changes, [2] hydroxyproline or total collagen content for quantification of lung collagen deposition, [3] TUNEL assay for the identification of apoptotic cells, [4] BALF analysis to assess changes in differential cell count and levels of inflammatory and fibrotic markers, [5] survival analysis with Kaplan–Meier plots, [6] in vivo lung function measurements (elastance and compliance) using the Flexi-vent ventilator, and [7] micro-CT imaging which provides state-of-the art multidimensional imaging of the injured lung that is reminiscent of HRCT applied for IPF diagnosis [19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
