Table 2.
Preclinical Inducible Models in Studies of Systemic Sclerosis
| Target preclinical feature | Animal Models | Observed Characteristics | The Underlying Mechanisms of Model Designing | Advantages | Disadvantages | References |
|---|---|---|---|---|---|---|
| Systemic phenotype of the disease | HOCl-injected mice |
-skin, lung and kidney implication -vascular abnormalities -autoantibodies production -↑CD4 + T-cell and B-cell in the spleen |
HOCl injection→↑ROS: -↑collagen and α-SMA production in skin - anti-DNA topoisomerase-1 autoantibodies production→ systemic symptoms HOCl injection→↑AOPP→ systemic fibrosis |
-presenting the key features of the human disease (in three main aspects of fibrosis, inflammation and vasculopathy) - Presenting the role of ROS and AOPPs in the pathogenesis of SSc |
ND | (Rozier et al. 2018; Asano and Sato 2013; Morin et al. 2015) |
| Skin fibrosis | Vinyl Chloride Injected mice |
-skin and spleen fibrosis and cell infiltration -↑IL-4 and IL-13 during a Th2 immune response |
vinyl chloride injection→ activation of micro chimeric fetal cells→ cell division→ symptoms presentation |
-showing the role of micro chimeric fetal circulating cells and chemical exposure in the pathogenesis of SSc -an easily reproducible model |
ND | (Morin et al. 2015; Storkanova and Tomcik 2017; Christner et al. 2000) |
| Lung fibrosis | Silica-induced lung fibrosis mice | - pulmonary tissue fibrosis | instillation of silica→ macrophage activation→ phagocytosis of silica particles→ pro-fibrotic cytokines(PDGF, TGFβ) production→ lung fibrosis | -mimicking the pulmonary phenotype of long-term exposure to silica dust(as a permanent fibrotic stimuli) |
-an expensive animal model -a time consuming process -specialized equipment requirement -lacking the characteristics of UIP |
(Storkanova and Tomcik 2017) |
| FITC induced lung fibrosis mice | -pulmonary edema, inflammation and fibrosis |
FITC usage: - binding to the protein in the lungs→ formation of a new antigen→ antibody formation -↑mononuclear cells and neutrophils infiltration→ acute lung injury -↑CCL12 and CCL2 → ↑CCR2 expressing fibroblasts→ pulmonary fibrosis |
-fibrosis detection using green fluorescence. -the phenotype occurs rather fast (during 14–28 days) and continues for at least 6 months. |
-lacking the characteristics of UIP | (Storkanova and Tomcik 2017; Chung et al. 2003) | |
| Radiation-induced lung fibrosis mice | -pulmonary tissue fibrosis | Radiation→ pneumocystis I and II death→ the production of pro-inflammatory and pro-fibrotic cytokines (TGFβ, TNF-α) by macrophages→ fibrosis | -presenting the characteristics of UIP. |
-an expensive animal model -a time consuming process |
(Storkanova and Tomcik 2017) | |
| Lung fibrosis / Immunogenic/inflammatory features | Bleomycin-Injected mice |
-lung and skin fibrosis -↑hydroxyproline -↑type-I collagen -Antinuclear autoantibodies production (anti-Scl-70, anti-U1-RNP, and anti-histone) |
Bleomycin injection→↑ROS → endothelial cell damage and ↑adhesion molecules→ leukocytes attraction and fibroblast activation→ fibrosis |
-presenting some of the early inflammatory symptoms of the disease. -useful to test the efficacy of anti-fibrotic therapeutics -useful to assess the potential of the pro-inflammatory genes of the patient |
-not presenting the typical clinical features and autoantibody patterns of the disease | (Rozier et al. 2018; Morin et al. 2015; Yamamoto 2010) |
| Immunogenic/inflammatory features | Scl-GVHD mice |
-fibrosis formation and chronic inflammation of the skin, lung, and gastrointestinal tract -↑CCL2, CCL5, CCL17, IFN-γ-inducible chemokines, PDGF, CTGF, FGF, EGF, NGF, VEGF and adhesion molecules in the skin |
BM and spleen cells transplantation into BALB/cJ (H-2d) mice→ the donor immune cells infiltration+ auto-reactive host T cells escape from thymic negative selection | -demonstrating many clinical and histological similarities to scleroderma | -ND on symptoms of vasculopathy presentation in mice while vasculopathy is one the signs of patients with Scl-GVHD | (Morin et al. 2015; Yamamoto 2010) |
| Pulmonary atrial hypertension (PAH) | chronic hypoxia+ semaxanib (SU5416)-induced PAH mice | -PAH |
hypoxia→ pro-inflammatory cytokines secretion SU5416: -↑growth factors (FGF, PDGF) → endothelial cells proliferation→ PAH -↑shear stress in the artery wall→ angioobliterative PAH |
-exhibiting the pathophysiological role of endothelial proliferation of pulmonary artery in PAH | -the hypoxia-induced PAH is slight and reversible | (Storkanova and Tomcik 2017; Nicolls et al. 2012) |
| MCTP- induced PAH rats | -PAH |
MCTP→ endothelium and smooth muscle cell proliferation and mononuclear inflammatory cells infiltration→ PAH |
-presenting the acute process of PAH | -the induced phenotype is easily treatable that is different from PAH in human SSc | (Storkanova and Tomcik 2017; Stenmark et al. 2009) | |
| SU5416-induced PAH athymic rats | -severe PAH | macrophage, B cell and anti-endothelial antibodies→ pulmonary artery inflammation→ lack of regulatory T cell→ severe PAH | -studying the function of T reg anti-inflammatory cells in counteracting PAH in SSc patients. | ND | (Storkanova and Tomcik 2017; Nicolls et al. 2012) | |
| ETAR and AT1R antibodies injected mice |
- obliterative vasculopathy of pulmonary vessels -PAH |
anti-ETAR and anti-AT1R injection→↑α-SMA expression and lymphocyte infiltration in perivascular areas→ obliterative vasculopathy, ↑vascular reactivity and vascular remodeling | -useful to assess the roles of ETAR and AT1R antibodies in the disease pathogenesis | ND | (Morin et al. 2015; Becker et al. 2014) | |
| Phenotypes caused by a particular factor | topoisomerase-1+ CFA injected mice |
-skin and lung fibrosis -↑IL-6, TGF-β1, IL-17 and IL-10 -Th2 and Th17 in BAL |
topoisomerase-1 + CFA injection→↑Th2/Th17 immune pathway→ skin sclerosis, ILD, and ↑inflammatory cytokines |
-mimicking diffuse SSc symptoms -proposing the relationship between responses to topo I and the pathogenesis of the disease. -advantageous for studying the effects of immunosuppressive and anti-inflammatory drugs on SSc. |
ND | (Asano and Sato 2013; Morin et al. 2015) |
| Angiotensin II-Induced mice |
-↑collagen, CTGF, TGFβ and pSmad2 expression -↑hydroxyproline content in skin -↑immune cell infiltration into the skin -↑vascular injury markers(vWF, TSP-1 and MMP-12) |
-exogenous angiotensin II: -collagen I receptor stimulation→ skin fibrosis -the dysregulation of endothelial-to-mesenchymal transition→ activated fibroblasts production |
-showing the role of the renin-angiotensin pathway in the process of fibrosis formation -advantageous for studying the effects of anti-inflammatory drugs on SSc. |
-not mimicking the auto-immune process of the human disease. -blockage of related signaling pathway has little effect on the pathophysiology of the disease |
(Asano and Sato 2013; Morin et al. 2015) | |
| Exogenous TGFβ+ CTGF injected mice |
-ECM-rich skin fibrosis -↑macrophages |
TGFβ→granulation and fibrotic tissue formation CTGF and bFGF→ sustained ↑collagen I gene expression→ fibrosis maintenance |
-presenting sustained fibrosis due to the use of CTGF in combination with TGFβ | ND | (Yamamoto 2017) |
HOCl Hypochlorous Acid, CCR CC chemokine receptor, FITC Fuorescein Isothiocyanate, TNF-α Tumour Necrosis Factor Alpha, UIP Usual Interstitial Pneumonia, RNP Ribonucleoprotein, ROS Reactive Oxygen Species, CCL C-C Chemokine Ligand, IFN-γ Interferon-Gamma, NGF Nerve Growth Factor, EGF Epidermal growth factor, GVHD Graft versus host disease, VEGF Vascular Endothelial Growth Factor, FGF Fibroblast Growth Factor, PDGF Platelet-Derived Growth Factor, SU5416 Semaxanib, MCTP Monocrotaline, PAH Pulmonary Atrial Hypertension, ETAR Anti-endothelin receptor Type-A, AT1R Anti-angiotensin Receptor Type − 1, ILD Interstitial Lung Disease, IL Interleukin, CFA Complete Freund’s Adjuvant, Th T helper, pSmad2 phospho-Smad2, α-SMA Alpha-Smooth Muscle Actin, vWF von Willebrand Factor, TSP-1 Thrombospondin-1, MMP Matrix Metalloproteinases, SSc Systemic Sclerosis, ECM Extracellular Matrix, bFGF Basic Fibroblast Growth Factor, CTGF Connective Tissue Growth Factor, TGFβ Transforming Growth Factor beta, ND No Data