TABLE 1.

Overview of nonclinical exploration of nintedanib in animal models of lung fibrosis

	Bleomycin-induced lung fibrosis in mice [43, 53]		Bleomycin-induced lung fibrosis in rats [43]		Silica-induced lung fibrosis in mice [43]		Chronic allergen-induced lung inflammation and remodelling in mice [54]	Rheumatoid arthritis and lung fibrosis in SKG mice [55]		Skin and lung fibrosis in Fra-2 mice [39]
Trigger	Chemical: bleomycin		Chemical: bleomycin		Environmental: silica crystals		Allergic: ovalbumin	Immunological: zymosan		Vascular: Fra-2 transgene
Model characteristics	Epithelial cell injury-induced lung inflammation and fibrosis		Epithelial cell injury-induced lung inflammation and fibrosis		Ongoing epithelial cell injury-induced lung inflammation and progressive fibrosis		AHR, lung inflammation and remodelling with goblet cell hyperplasia, lung fibrosis and ASM hypertrophy	Resembles aspects of arthritic joint inflammation and progressive lung fibrosis		Resembles aspects of skin and progressive lung fibrosis in SSc including microvascular disease and PH
Treatment#	Preventive	Therapeutic	Preventive	Therapeutic	Preventive	Therapeutic	Chronic	Early	Late	Therapeutic
	days 0–14	days 7–21; days 7–19	days 0–21	days 10–21	days 0–30	days 10–30¶	starting at day 35 for 3 months	weeks 5–11	weeks 10–16	weeks 10–16
Effects of nintedanib	Lung fibrosis↓; lung inflammation↓; IL-1β↓; TIMP-1↓; BALF lymphocytes↓	Lung fibrosis↓; Ashcroft score↓; lung tissue density↓; Cstat↑; lung inflammation↓; lung collagen↓; IL-1β↓; TIMP-1↓; BALF lymphocytes↓; vascularisation↓	Ashcroft score↓; TGF-β mRNA↓; pro-collagen 1 mRNA↓	Ashcroft score↓; TGF-β mRNA↓; pro-collagen 1 mRNA↓	Lung fibrosis↓; lung inflammation↓; lung collagen↓; IL-1β↓; KC↓; TIMP-1↓; BALF neutrophils and lymphocytes↓	Lung fibrosis↓; lung inflammation↓; lung collagen↓; IL-1β↓; IL-6↓; KC↓; TIMP-1↓; BALF neutrophils and lymphocytes↓	AHR; total BALF cells↓; OVA-specific IgE↓; IL-4, IL-5, IL-13↓; vascularisation↓; goblet cell hyperplasia↓; ASM area↓; hydroxyproline↓	Arthritis score↓; lung tissue B220+ B-cells↑; CD103+ dendritic cells↑; monocytes↓; neutrophils↑	Hydroxyproline↓; BALF lymphocytes and neutrophils↑; lung tissue inflammatory macrophages↑	Skin and lung myofibroblasts↓; dermal thickness↓; hydroxyproline↓; ECM↓; vessel wall thickness↓; occluded vessels↓; VSMCs↓; MVEC apoptosis↑

↓: significant reduction (independent of dose); ↑: significant increase (independent of dose). Fra-2: fos-related antigen-2; AHR: airway hyperreactivity; ASM: airway smooth muscle; SSc: systemic sclerosis; PH: pulmonary hypertension; IL: interleukin; TIMP: tissue inhibitor of matrix metalloproteinase; BALF: bronchoalveolar lavage fluid; C_stat: static lung compliance; TGF: transforming growth factor; KC: chemokine CXCL1/KC; OVA: ovalbumin; ECM: extracellular matrix; VSMC: vascular smooth muscle cell; MVEC: microvascular endothelial cell. ^#: “preventive” indicates that the administration of nintedanib started simultaneously with the pathogenic trigger and “therapeutic” indicates that the administration of nintedanib began after the onset of substantial fibrosis (the days/weeks listed indicate when nintedanib was administered relative to the pathogenic trigger); ^¶: an effect of nintedanib was shown for treatment from day 10 to 30 (treatment only from day 20 to 30 was less effective).