Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis

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.

Animal Models Reflecting Chronic Obstructive Pulmonary Disease and Related Respiratory Disorders: Translating Pre-Clinical Data into Clinical Relevance

“…The most common method of bleomycin administration consists of a single intranasal or intratracheal dose of bleomycin, with analysis 3-4 weeks later. Bleomycin causes acute tissue damage in lung regions where the solution permeates, followed by localized inflammation which peaks after 7 days, and subsequent fibrosis [220]. Intratracheal/intranasal bleomycin-induced fibrosis is reproducible, only affects the lungs, and is utilized by many research groups globally, allowing the generation of comparative results [221,222].…”

“…Unfortunately, several bleomycin administrations are required over a longer time period to achieve this fibrotic effect [222]. The systemic administration of bleomycin results in less inflammation compared to direct intratracheal administration and is less predictive of localized fibrotic conditions such as idiopathic pulmonary fibrosis [220].…”

“…Fluorescein isothiocyanate (FITC) induces a similarly localized pattern of inflammation in mice compared to bleomycin, which persists for up to 5 months after administration, comparably longer than most other administered substances [220]. FITC is also fluorescent, allowing FITC-exposed lung regions to be easily imaged [222].…”

“…FITC is also fluorescent, allowing FITC-exposed lung regions to be easily imaged [222]. However, the FITC model does not produce robust results due to difficulties in FITC preparation, causing groups to utilize other models [220].…”

Multiomic and quantitative label-free microscopy-based analysis of ex vivo culture and TGFbeta1 stimulation of human precision-cut lung slices

“…Murine experimental models of fibrosis are frequently used to study lung, liver and kidney fibrosis. Typically, pulmonary fibrosis is induced either using genetic manipulation (MUC5b overexpression, a genetic risk factor identified in large cohorts of IPF patients) 12 or chemical induction (bleomycin sulphate, amiodarone, carbon tetrachloride) 13 . While these model systems help to understand acute signalling pathways preceding tissue damage and, in some instances, chemicals such as bleomycin sulphate can be used as causative agents 14 .…”