Table 1 Animal models of AE-PF
From: Animal models of acute exacerbation of pulmonary fibrosis
Animal species | Fibrotic Agents | Challenging agents of AE | Lung pathology | Advantages | Disadvantages | References | |||
|---|---|---|---|---|---|---|---|---|---|
Agent | Dose | Route | Time of administration | ||||||
Mouse | FITC | γHV-68①| 5 × 104 PFU | I.N | D14 | Interstitial edema, intraalveolar hemorrhage, alveolar epithelial denudation. | Introduced a novel animal model for herpesvirus-induced AE-PF and offered insights into the underlying mechanisms, including fibrocyte recruitment. | The mortality rate in AE mice did not align consistently with that observed in AE patients. | McMillan et al., 2008 [44] |
Mouse | BLM | γHV-68①| 5 × 104 PFU | I.N | D14 | Focal mononuclear inflammation, diffuse inflammation, stromal collagen deposition. | The model elucidated the underlying mechanism by which increased apoptosis of AEC2 triggers the onset of AE, a key feature of IPF. | The evidence of apoptosis measured by cleaved poly-ADP ribose polymerase was inconclusive. | Ashley et al., 2014 [62] |
Mouse | SPC-DTR | Spn② | 1 × 107 CFU | O.T | D14 | --- | The model mimicked the exaggerated inflammatory mechanisms seen in AE-IPF. | The establishment of the SPC-DTR fibrosis model requires repeated administration, which may lead to drug resistance. | Knippenberg et al., 2015 [61] |
Mouse | BLM | LPSâ‘¢ | 0.5 mg/kg | O.A | D7 | Fibrotic changes, prominent rise in inflammatory cell infiltration. | Assessing the results using chest CT scans and blood gas analysis is more clinically relevant. | Operation-induced AE-IPF occurs rarely in patients, making the practicality of this model poor. | Kimura et al., 2015 [124] |
Mouse | BLM | BLMâ‘¢ | 4 mg/kg | I.T | D21 | Hyaline membrane formation, pulmonary edema, a large amount of collagen deposition | The mouse model of AE-IPF was triggered by a non-infectious mechanism. | The core assumption that fibrosis stems from an external trigger rather than an internal genetic or epigenetic response remains unchanged | Wei et al., 2016127 |
Mouse | BLM | HSV1①| 5 × 105 PFU | I.N | D14 | Diffuse alveolar damage, interstitial edema, intraalveolar hemorrhage, alveolar epithelial denudation, hyaline membranes formation, collagen deposition. | This model simulated some of the clinical manifestations, pathological features, and inflammatory mechanisms in AE-IPF patients. | The causal association between endoplasmic reticulum stress and stimulator of interferon genes deficiency needs further investigation. | Qiu et al., 2017 [65] |
Mouse | PHMG | CdCl2③ | 0.2 µg | I.T | D3, D6, D9, D12 | Granulomatous inflammation, fibrosis alveolar ducts, foamy macrophage infiltration, bronchioloalveolar epithelial hyperplasia, collagen deposition. | Because CdCl2 is a component of tobacco, this model simulates lung fibrosis that may be caused by tobacco. | The reagents are toxic, and PHMG is not the preferred agent; the timing of CdCl2 administration was too early. | Kim et al. 2018 [128] |
Mouse | BLM | Nickel chlorideâ‘¢ | 5 mg/kg | I.T | D0 | Collagen deposition, alveolitis, collapsed alveolar space, inflammatory cells accumulation. | Nickel is heavy metal that can simulate lung fibrosis caused by industrial pollution. | Nickel chloride and BLM were administered simultaneously, which is not consistent with clinical settings. | McElroy et al., 2018 [129] |
Mouse | BLM | HSV1①| 5 × 105 PFU | I.N | D21 | Alveolar septal congestion, edema, inflammation, alveolar epithelial damage, hyaline membrane formation. | This model uses human HSV1, mirroring AE-IPF symptoms including lung function decline, increased mortality, acute lung injury, and abnormal inflammation pathways. | The elevated levels of IL-17 A and endoplasmic reticulum stress may not be the primary drivers of pulmonary fibrosis. | Chen et al., 2019 [64] |
Mouse | Ad TGF-β1 | CNDG② | 1 × 108 CFU | I.T | D5 | Significantly increased macrophage, lymphocyte, and neutrophil infiltration, enhanced collagen deposition, increased epithelial cell apoptosis. | The study included validation experiments in both male and female mice. | Animals may mount an immune response; the expression of transgenes may exceed physiological levels. | D’Alessandro-Gabazza et al., 2020 [59] |
Mouse | BLM | Spn② | 1 × 105 CFU | I.T | D14 | A significant increase in fibrosis and collagen deposition | This study found that AIM2 inflammasome activation plays a crucial role in worsening lung fibrosis during bacterial infections by connecting it to glucose transporter 1-mediated glycolysis. | Did not report the levels of hydroxyproline in the lung tissues | Cho et al., 2020 [63] |
Mouse | Ad TGF-β1 | Spn② | 1 × 107 CFU | O.T | D14 | Increased interstitial inflammation, alveolar epithelial hyperplasia, thickened alveolar septa, elevated collagen deposition | This study enhances our understanding of infection-induced lung fibrosis exacerbation in two preclinical mouse models. | Transgene expression was higher than physiologically possible; Possible immune response to viral vectors. | |
Mouse | BLM | Corisin③ | 300 µg | I.T | D20 | Significantly increased Ashcroft score and collagen-stained (trichrome) area. | The study included validation experiments in both male and female mice. | Future studies should assess corisin’s efficacy in inducing AE in various mouse models of pulmonary fibrosis. | D’Alessandro-Gabazza et al., 2022 [60] |
Mouse | BLM | NT127② | 1 × 107 CFU | I.T | D7 | Increased inflammatory cell infiltration, airway structural damage, collagen deposition. | This is the first report that Gram-negative bacteria have been used to induce AE model of pulmonary fibrosis. | NT127 administrated on day 7 was not in the fibrotic stage; no further evidence of increased interstitial inflammation | Chen et al., 2022 [119] |
Mouse | BLM | LPSâ‘¢ | 1 mg/kg | I.T | D5, D7, D9 | Severe inflammation, thicker interalveolar spaces, collapsed alveoli, increased collagen, and severe lung distortion. | Simulates extreme inflammation in AE-IPF. | LPS-induced AE was applied on days 5, 7, and 9 during the inflammatory phase, rather than the fibrotic phase. | Jia et al., 2022 [123] |
Rat | BLM | LPSâ‘¢ | 0.05 or 0.15 mg/kg | I.T | D7 | Significant fibrosis, prominent inflammatory cells infiltration and alveolar enlargement | Assessing the results using chest CT scans and blood gas analysis is more clinically relevant. Simulates extreme inflammation in AE-IPF. | LPS-induced AE was monitored at 24 h after administration, which differs from clinical settings where changes in related indicators may occur later. | Miyamoto et al., 2022 [67] |