An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis

Abstract

Numerous compounds have shown efficacy in limiting development of pulmonary fibrosis using animal models, yet few of these compounds have replicated these beneficial effects in clinical trials. Given the challenges associated with performing clinical trials in patients with idiopathic pulmonary fibrosis (IPF), it is imperative that preclinical data packages be robust in their analyses and interpretations to have the best chance of selecting promising drug candidates to advance to clinical trials. The American Thoracic Society has convened a group of experts in lung fibrosis to discuss and formalize recommendations for preclinical assessment of antifibrotic compounds. The panel considered three major themes (choice of animal, practical considerations of fibrosis modeling, and fibrotic endpoints for evaluation). Recognizing the need for practical considerations, we have taken a pragmatic approach. The consensus view is that use of the murine intratracheal bleomycin model in animals of both genders, using hydroxyproline measurements for collagen accumulation along with histologic assessments, is the best-characterized animal model available for preclinical testing. Testing of antifibrotic compounds in this model is recommended to occur after the acute inflammatory phase has subsided (generally after Day 7). Robust analyses may also include confirmatory studies in human IPF specimens and validation of results in a second system using in vivo or in vitro approaches. The panel also strongly encourages the publication of negative results to inform the lung fibrosis community. These recommendations are for preclinical therapeutic evaluation only and are not intended to dissuade development of emerging technologies to better understand IPF pathogenesis.

Anlotinib attenuated bleomycin-induced pulmonary fibrosis via the TGF-β1 signalling pathway

“…Idiopathic pulmonary fibrosis is a chronic progressive interstitial lung disease of unknown origin which leads rapidly to death. Currently, BLM‐induced pulmonary fibrosis is the most classic model for exploring the pathogenesis of IPF and testing the effectiveness of new antifibrotic drugs . Recent studies have shown the mechanism of bleomycin‐induced pulmonary fibrosis: ANXA2(membrane‐associated protein A2) is a specific bleomycin target, and bleomycin binding with ANXA2 blocks TFEB (transcription factor EB)induced autophagic flux and further promotes apoptosis of epithelial cells, leading to pulmonary fibrosis .…”

Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin

“…RNA-seq data, importantly, show suppression of the adaptive immune response, T-cell differentiation and activation, and cytokine production by MIA-602 in bleomycin-treated mouse lungs. The effects of the GHRH-R antagonist we observe have implications for fibrosing lung diseases in humans, and they could, importantly, reveal novel pathways amenable to clinical drug development [29]. …”

The role of periostin in lung fibrosis and airway remodeling

“…There has been significant debate about the usefulness of animal models for IPF research, but they do represent well-characterized models of the evolution of fibrosis from injury to acute inflammation to chronic inflammation and ECM deposition [94]. Furthermore, an American Thoracic Society working group recommended that the bleomycin model be used as an important tool for the preclinical testing of anti-fibrotic agents [95]. With that context, two previous studies have noted that periostin accumulates in the lungs of both Balb/c and C57Bl/6 mice treated with bleomycin [20,96].…”