Animal models of acute exacerbation of pulmonary fibrosis

Ye, Xu; Zhang, Mingrui; Gu, Huimin; Liu, Mengying; Zhao, Yichao; Shi, Yanchen; Wu, Shufei; Jiang, Cheng; Ye, Xiaoling; Zhu, Huihui; Li, Qi; Huang, Xinmei; Cao, Mengshu

doi:10.1186/s12931-023-02595-z

Cited by 5 publications

(2 citation statements)

References 136 publications

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“…During the development of acute lung injury, the loss of type II alveolar epithelial cells (AEC II) causes a notable reduction in surfactant production. Consequently, the collapse of alveoli occurs, allowing lung proteins to permeate into the alveolar space ( Carignon et al, 2023 ; Ye et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Capsaicin ameliorate pulmonary fibrosis via antioxidant Nrf-2/ PPAR- γ pathway activation and inflammatory TGF-β1/ NF-κB/COX II pathway inhibition

Abdulaal,

Asfour,

Helmi

et al. 2024

Front. Pharmacol.

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Bleomycin is an effective antibiotic with a significant anticancer properties, but its use is limited due to its potential to induce dose-dependent pulmonary fibrosis. Therefore, this study aimed to assess the therapeutic potential of Capsaicin as an additional treatment to enhance patient tolerance to Bleomycin compared to the antifibrotic drug Pirfenidone. Pulmonary fibrosis was induced in rats through by a single intratracheal Bleomycin administration in day zero, followed by either Capsaicin or Pirfenidone treatment for 7 days. After the animals were sacrificed, their lungs were dissected and examined using various stains for macroscopic and histopathological evaluation. Additionally, the study assessed various antioxidant, anti-inflammatory, and antifibrotic parameters were assessed. Rats exposed to Bleomycin exhibited visible signs of fibrosis, histopathological alterations, increased collagen deposition, and elevated mucin content. Bleomycin also led to heightened increased inflammatory cells infiltration in the bronchoalveolar lavage, elevated fibrosis biomarkers such as hydroxyproline, alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β1), increased inflammatory markers including tumor necrosis factor-alpha (TNF-α), interlukine-6 (Il-6), interlukine-1β (Il-1β) nuclear factor-kappa B (NF-κB), and Cyclooxygenase-2 (COX-2), and transforming growth factor-beta (TGF-β1),. Furthermore, it reduced the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ), increased oxidative stress biomarkers like nitric oxide (NO), malondialdehyde (MDA), myeloperoxidase (MPO) and protein carbonyl. Bleomycin also decreased the expression of nuclear factor erythroid 2–related factor 2 (Nrf-2), reduced glutathione (GSH), total antioxidant capacity, and the activities of catalase and superoxide dismutase (SOD). Treating the animals with Capsaicin and Pirfenidone following Bleomycin exposure resulted in improved lung macroscopic and microscopic characteristics, reduced collagen deposition (collagen I and collagen III) and mucin content, decreased inflammatory cell infiltration, lowered levels of hydroxyproline, α-SMA, and TGF-β1, decreased TNF-α, Il-6, Il-1β, NF-κB, and COX-2, increased PPAR-γ and Nrf-2 expression, and improvement improved in all oxidative stress biomarkers. In summary, Capsaicin demonstrates significant antifibrotic activity against Bleomycin-induced lung injury that may be attributed, at least in part, to the antioxidant and anti-inflammatory activities of Capsaicin mediated by upregulation of PPAR-γ and Nrf-2 expression and decreasing. TGF-β1, NF-κB and COX II proteins concentrations.

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Section: Discussionmentioning

confidence: 99%

Capsaicin ameliorate pulmonary fibrosis via antioxidant Nrf-2/ PPAR- γ pathway activation and inflammatory TGF-β1/ NF-κB/COX II pathway inhibition

Abdulaal,

Asfour,

Helmi

et al. 2024

Front. Pharmacol.

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“…Existing animal models have a number of significant limitations. For example, a well-established model of bleomycin-induced pulmonary fibrosis in mice does not lead to the formation of a pathologically self-sustaining process of lung tissue replacement by connective tissue, so researchers observe complete recovery of lung tissue after several months [17]. Moreover, in vivo system is complex, making it challenging to identify the role of individual molecules and cell types.…”

Section: Discussionmentioning

confidence: 99%

Modeling the profibrotic microenvironmentin vitro: model validation

Grigorieva,

Basalova,

Dyachkova

et al. 2023

Preprint

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Establishing the molecular and cellular mechanisms of fibrosis requires the development of validated and reproducible models. The complexity ofin vivomodels challenges the monitoring of an individual cell fate, in some cases making it impossible. However, the set of factors affecting cells inin vitroculture systems differ significantly fromin vivoconditions, insufficiently reproducing living systems. Thus, to model profibrotic conditionsin vitro, usually the key profibrotic factor, transforming growth factor beta (TGFβ-1) is used as a single factor. TGFβ-1 stimulates the differentiation of fibroblasts into myofibroblasts, the main effector cells promoting the development and progression of fibrosis. However, except for soluble factors, the rigidity and composition of the extracellular matrix (ECM) play a critical role in the differentiation process. To develop the model of more complex profibrotic microenvironmentin vitro, we used a combination of factors: decellularized ECM synthesized by human dermal fibroblasts in the presence of ascorbic acid if cultured as cell sheets and recombinant TGFβ-1 as a supplement. When culturing human mesenchymal stromal cells derived from adipose tissue (MSCs) under described conditions, we observed differentiation of MSCs into myofibroblasts due to increased number of cells with stress fibrils with alpha-smooth muscle actin (αSMA), and increased expression of myofibroblast marker genes such as collagen I, EDA-fibronectin and αSMA. Importantly, secretome of MSCs changed in these profibrotic microenvironment: the secretion of the profibrotic proteins SPARC and fibulin-2 increased, while the secretion of the antifibrotic hepatocyte growth factor (HGF) decreased. Analysis of transciptomic pattern of regulatory microRNAs in MSCs revealed 49 miRNAs with increased expression and 3 miRNAs with decreased expression under profibrotic stimuli. Bioinformatics analysis confirmed that at least 184 gene targets of the differently expressed miRNAs genes were associated with fibrosis. To further validate the developed model of profibrotic microenvironment, we cultured human dermal fibroblasts in these conditions and observed increased expression of fibroblast activation protein (FAPa) after 12 hours of cultivation as well as increased level of αSMA and higher number of αSMA+ stress fibrils after 72 hours. The data obtained allow us to conclude that the conditions formed by the combination of profibrotic ECM and TGFβ-1 provide a complex profibrotic microenvironmentin vitro. Thus, this model can be applicable in studying the mechanism of fibrosis development, as well as for the development of antifibrotic therapy.

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