Animal models of acute exacerbation of pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive scarring interstitial lung disease with an unknown cause. Some patients may experience acute exacerbations (AE), which result in severe lung damage visible on imaging or through examination of tissue samples, often leading to high mortality rates. However, the etiology and pathogenesis of AE-IPF remain unclear. AE-IPF patients exhibit diffuse lung damage, apoptosis of type II alveolar epithelial cells, and an excessive inflammatory response. Establishing a reliable animal model of AE is critical for investigating the pathogenesis. Recent studies have reported a variety of animal models for AE-IPF, each with its own advantages and disadvantages. These models are usually established in mice with bleomycin-induced pulmonary fibrosis, using viruses, bacteria, small peptides, or specific drugs. In this review, we present an overview of different AE models, hoping to provide a useful resource for exploring the mechanisms and targeted therapies for AE-IPF.

Keywords: Acute exacerbation; Animal model; Pulmonary fibrosis.

Fig. 1

Potential mechanism of AE-PF in animal models The mechanism of AE-PF possibly driven by the stress of viruses, bacteria and other agents, such as LPS and small molecule compounds is focused on the enhanced apoptosis of AEC2, excessive inflammation and extracellular matrix deposition. Firstly, the stresses of infection and other challenging agents may promote the secretion of chemokines CCL2 and CCL12 of AEC2 and AMs, leading to increased recruitment of circulating fibrocytes and deposition of extracellular matrix. Additionally, it upregulates the expressions of pro-inflammatory cytokines TNF-α, IL-6, and IL-17 A of AEC2 and CD4⁺ T cells, while inhibits the production of IFN. Furthermore, the challenging agents can increase the expressions of IL-1, IL-18, NO, and Mincle of AMs, and lead to the excessive inflammation. Secondly, the stress may augment the expressions of TGF-β receptor 1 on AEC2, activate SMAD3 phosphorylation. Some pathogens may also produce small molecule substances which result in pore-like damage on the surface of AEC2, provoke caspase 3 activation, Bcl2 upregulation and Bax downregulation, ultimately causes the enhanced apoptosis of AEC2 Abbreviations: AE: acute exacerbation; AE-PF: acute exacerbations of pulmonary fibrosis; AEC2: type II alveolar epithelial cells; AMs: alveolar macrophages; BLM: bleomycin; ERS: endoplasmic reticulum stress; ECM: Extracellular matrix; HSV1: Herpes simplex virus 1; γHV-68: γ-Herpesvirus -68; LPS: lipopolysaccharide; NO: nitric oxide; Spn: Streptococcus pneumoniae; IFN: interferon

Fig. 2

Schematic diagram depicting the mouse model of AE-PF On Day 0, mice were administered with a single dose of BLM via the transtracheal route. On Day 14 after BLM treatment, mice in the AE group were challenged with bacteria, viruses, or other challenging reagents such as BLM or lipopolysaccharide. Chest CT scans were performed on Day 20 before animal sacrificed. The mice were killed on Day 21, and the samples of blood, bronchoalveolar lavage fluids, and lung tissues were collected Abbreviations: AE: acute exacerbation; AE-PF: acute exacerbation of pulmonary fibrosis; BLM: bleomycin; CT: computed tomography