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Animal models of drug-induced pulmonary fibrosis: an overview of molecular mechanisms and characteristics

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by progressive loss of pulmonary function. Drug-induced interstitial lung disease has been reported as a severe adverse effect of some drugs, such as bleomycin, amiodarone, and methotrexate. Based on good characteristics, drug-induced pulmonary fibrosis (PF) animal model has played a key role in our understanding of the molecular mechanisms of PF pathogenesis and recapitulates the specific pathology in patients and helps develop therapeutic strategies. Here, we summarize the mechanisms and characteristics of given fibrotic drug-induced animal models for PFs. Together with the key publications describing these models, this brief but detailed overview would be helpful for the pharmacological research with animal models of PFs.

Graphical abstract

Potential mechanisms underlying drug induced lung toxicity.

Highlights

  • Bleomycin mainly causes lung injuries via inducing DNA damage and bleomycin-ANXA2-YWHA-TFEB complex induces dysfunction of autophagy in AECs.

  • Amiodarone mainly induces intracellular phospholipid accumulation (phospholipidosis) in AEC2s and alveolar macrophages.

  • Methotrexate significantly promotes the epithelial-mesenchymal transition (EMT) process of AEC2s.

  • Nitrogen mustard facilitates the activation and recruitment of macrophages.

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Abbreviations

AEC:

Alveolar epithelial cell

AD:

Amiodarone

ALP:

Alkaline phosphatase

ANXA2:

Annexin A2

ATF:

Activating transcription factor

ATS:

American Thoracic Society

BALF:

Bronchoalveolar lavage fluid

bFGF:

Basic fibroblast growth factor

BLM:

Bleomycin

CAT:

Catalase

CHOP:

C/EBP homologous protein

CP:

Cyclophosphamide

CTD:

Comparative Toxicogenomics Database

DHFR:

Dihydrofolate reductase

DNA:

Deoxyribonucleic acid

DPPC:

Dipalmitoyl phosphatidylcholine

ECM:

Extracellular matrix

EMT:

Epithelial-mesenchymal transition

ER:

Endoplasmic reticulum

FA:

Folic acid

FN:

Fibronectin

FVC:

Forced vital capacity

GAG:

Glycosaminoglycan

GGO:

Ground glass opacity

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSH:

Glutathione

GSSG:

Glutathione disulfide

GST:

Glutathione S-transferase

HMGB:

High mobility group box protein

HRCT:

High-resolution computed tomography

HSP:

Heat shock protein

IL:

Interleukin

IPF:

Idiopathic pulmonary fibrosis

I.T.:

Intratracheal instillation

LAMP1:

Lysosomal-associated membrane protein 1

LBPA:

Lysobisphosphatidic acid

LC3:

Microtubule-associated protein1 light chain 3

LDH:

Lactate dehydrogenase

LPO:

Lipid peroxidase

MAPK:

Mitogen-activated protein kinase

MCP:

Monocyte chemoattractant protein

MIP:

Macrophage inflammatory protein

MPR300:

Mannose 6-phosphate/IGF-II receptor

mTOR:

Mammalian target of rapamycin

MTX:

Methotrexate

NF-кB:

Nuclear factor kappa-light-chain-enhancer of activated B-cells

O.A.:

Oropharyngeal administration

PAI:

Plasminogen activator inhibitor

PDGF:

Platelet-derived growth factor

PF:

Pulmonary fibrosis

PL:

Phospholipase

PLDsis:

Phospholipidosis

Rab7:

RAS-related GTP binding protein 7

RFC:

Reduced folate carrier

ROS:

Reactive oxygen species

α-SMA:

Alpha-smooth muscle actin

SOD:

Superoxide dismutase

SP:

Surfactant protein

TAK:

TGF-beta activated kinase

TFEB:

Transcription factor EB

TGF-β:

Transforming growth factor beta

THF:

Tetrahydrofolic acid

TNF-α:

Tumor necrosis factor alpha

V-ATPase:

Vacuolar ATPase

YWHA:

Tyrosine 3/tryptophan 5 monooxygenase activation protein

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Funding

The study was supported by the National Natural Science Foundation of China (Grant No. 81402989 and 81570056) and the Natural Science Foundation of Zhejiang province, China (Grant No. LY18H310002 and LGD20H010002).

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  1. Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, China

    Shuchan Li & Huifang Tang

  2. Department of Clinical Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China

    Jianrong Shi

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LSC performed the literature search and drafted the article; SJR gave critical suggestion for the article; THF had the idea for the article and critically revised the work.

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Li, S., Shi, J. & Tang, H. Animal models of drug-induced pulmonary fibrosis: an overview of molecular mechanisms and characteristics. Cell Biol Toxicol 38, 699–723 (2022). https://doi.org/10.1007/s10565-021-09676-z

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