Current models of pulmonary fibrosis for future drug discovery efforts

Yanagihara, Toyoshi; Chong, Sy Giin; Vierhout, Megan; Hirota, Jeremy A.; Ask, Kjetil; Kolb, Martin

doi:10.1080/17460441.2020.1755252

Cited by 36 publications

(20 citation statements)

References 99 publications

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“…Animal models play a crucial role either in understanding the pathobiology of fibrosis or in drug discovery. Animals of different species, gender and age, as well as different BLM dose regimens have been used to induce lung fibrosis [ 6 , 8 , 15 , 20 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

Pivotal role of micro-CT technology in setting up an optimized lung fibrosis mouse model for drug screening

Khalajzeyqami

Grandi²,

Ferrini³

et al. 2022

PLoS ONE

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Idiopathic pulmonary fibrosis (IPF) is a progressive disease with no curative pharmacological treatment. The most used animal model of IPF for anti-fibrotic drug screening is bleomycin (BLM)-induced lung fibrosis. However, several issues have been reported: the balance among disease resolution, an appropriate time window for therapeutic intervention and animal welfare remain critical aspects yet to be fully elucidated. In this study, C57Bl/6 male mice were treated with BLM via oropharyngeal aspiration (OA) following either double or triple administration. The fibrosis progression was longitudinally assessed by micro-CT every 7 days for 4 weeks after BLM administration. Quantitative micro-CT measurements highlighted that triple BLM administration was the ideal dose regimen to provoke sustained lung fibrosis up to 28 days. These results were corroborated with lung histology and Bronchoalveolar Lavage Fluid cells. We have developed a mouse model with prolonged lung fibrosis enabling three weeks of a curative therapeutic window for the screening of putative anti-fibrotic drugs. Moreover, we have demonstrated the pivotal role of longitudinal micro-CT imaging in reducing the number of animals required per experiment in which each animal can be its own control. This approach permits a valuable decrease in costs and time to develop disease animal models.

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Section: Discussionmentioning

confidence: 99%

Pivotal role of micro-CT technology in setting up an optimized lung fibrosis mouse model for drug screening

Khalajzeyqami

Grandi²,

Ferrini³

et al. 2022

PLoS ONE

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“…However, most of these models still lack the use of primary cells and tissue-specific ECM components required for cell differentiation, as well as 3D geometries that are important for lung cell differentiation [ 9 , 15 ]. Notably, pulmonary diseases including IPF and COPD frequently cause significant changes and remodeling in the ECM, which is rarely an integrated feature in in vitro models [ 16 , 17 , 18 ]. Ex vivo models have not been employed extensively and are also limited by access to fresh human lung tissue and face complications to be scaled up to a high-throughput system [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

A Robust Protocol for Decellularized Human Lung Bioink Generation Amenable to 2D and 3D Lung Cell Culture

Dabaghi

Saraei

Carpio

et al. 2021

Cells

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Decellularization efforts must balance the preservation of the extracellular matrix (ECM) components while eliminating the nucleic acid and cellular components. Following effective removal of nucleic acid and cell components, decellularized ECM (dECM) can be solubilized in an acidic environment with the assistance of various enzymes to develop biological scaffolds in different forms, such as sheets, tubular constructs, or three-dimensional (3D) hydrogels. Each organ or tissue that undergoes decellularization requires a distinct and optimized protocol to ensure that nucleic acids are removed, and the ECM components are preserved. The objective of this study was to optimize the decellularization process for dECM isolation from human lung tissues for downstream 2D and 3D cell culture systems. Following protocol optimization and dECM isolation, we performed experiments with a wide range of dECM concentrations to form human lung dECM hydrogels that were physically stable and biologically responsive. The dECM based-hydrogels supported the growth and proliferation of primary human lung fibroblast cells in 3D cultures. The dECM is also amenable to the coating of polyester membranes in Transwell™ Inserts to improve the cell adhesion, proliferation, and barrier function of primary human bronchial epithelial cells in 2D. In conclusion, we present a robust protocol for human lung decellularization, generation of dECM substrate material, and creation of hydrogels that support primary lung cell viability in 2D and 3D culture systems

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“…It has been reported that the elastic modulus (stiffness) of a healthy human lung is ∼2.0 ± 0.1 kPa, and that the lung tissue stiffness can be changed by various diseases ( Booth et al, 2012 ). For instance, the stiffness of the lung tissue increases up to 17 ± 2 kPa in idiopathic pulmonary fibrosis (IPF), an interstitial lung disease that is characterized by the excessive deposition of ECM proteins in the lung ( Yanagihara et al, 2020 ). Fibroblasts are a major cell responsible for pathology in IPF, and are able to transition to myofibroblasts that continuously produce and secrete fibrillar collagen-rich ECM, thereby increasing the stiffness of the lung tissue ( Pakshir and Hinz 2018 ).…”

Section: Introductionmentioning

confidence: 99%

3D Bioprinting Strategies, Challenges, and Opportunities to Model the Lung Tissue Microenvironment and Its Function

Carpio

Dabaghi

Ungureanu

et al. 2021

Front. Bioeng. Biotechnol.

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Human lungs are organs with an intricate hierarchical structure and complex composition; lungs also present heterogeneous mechanical properties that impose dynamic stress on different tissue components during the process of breathing. These physiological characteristics combined create a system that is challenging to model in vitro. Many efforts have been dedicated to develop reliable models that afford a better understanding of the structure of the lung and to study cell dynamics, disease evolution, and drug pharmacodynamics and pharmacokinetics in the lung. This review presents methodologies used to develop lung tissue models, highlighting their advantages and current limitations, focusing on 3D bioprinting as a promising set of technologies that can address current challenges. 3D bioprinting can be used to create 3D structures that are key to bridging the gap between current cell culture methods and living tissues. Thus, 3D bioprinting can produce lung tissue biomimetics that can be used to develop in vitro models and could eventually produce functional tissue for transplantation. Yet, printing functional synthetic tissues that recreate lung structure and function is still beyond the current capabilities of 3D bioprinting technology. Here, the current state of 3D bioprinting is described with a focus on key strategies that can be used to exploit the potential that this technology has to offer. Despite today’s limitations, results show that 3D bioprinting has unexplored potential that may be accessible by optimizing bioink composition and looking at the printing process through a holistic and creative lens.

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Current models of pulmonary fibrosis for future drug discovery efforts

Cited by 36 publications

References 99 publications

Pivotal role of micro-CT technology in setting up an optimized lung fibrosis mouse model for drug screening

Pivotal role of micro-CT technology in setting up an optimized lung fibrosis mouse model for drug screening

A Robust Protocol for Decellularized Human Lung Bioink Generation Amenable to 2D and 3D Lung Cell Culture

3D Bioprinting Strategies, Challenges, and Opportunities to Model the Lung Tissue Microenvironment and Its Function

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