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Organotypic In Vitro Human Airway Models Can Recapitulate Aspects of Pulmonary Fibrosis
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A2206 - Organotypic In Vitro Human Airway Models Can Recapitulate Aspects of Pulmonary Fibrosis
Author Block: A. Maione, G. R. Jackson, O. O'Connell, J. Foisy, M. Klausner, P. Hayden; MatTek Corporation, Ashland, MA, United States.
Introduction: Pulmonary fibrosis (PF) is a debilitating, typically fatal condition that may be caused by a variety of factors, including occupational and environmental exposures, drugs such as amiodarone and bleomycin, radiation exposure, and genetic predisposition. However, in 20-30% of cases the cause is unknown (i.e. idiopathic pulmonary fibrosis, IPF). Currently approved IPF drugs (pirfenidone, nintedanib) have only limited efficacy, and lung transplantation remains the best treatment option for IPF patients. Despite intense research, many of the molecular mechanisms involved in the initiation and progression of IPF remain unknown. Current IPF research relies on animal models and ex vivo lung tissues, which are expensive and are not always predictive of clinical trial results. Currently available in vitro models produced from immortalized cells also do not adequately replicate IPF. The goal of the current work is to develop in vitro organotypic, 3D airway models from primary human cells which can be used to study IPF. Methods: In vitro models composed of differentiated primary human bronchial or alveolar epithelial cells and pulmonary fibroblasts were cultured at the air-liquid interface to replicate the in vivo microenvironment. The tissue models were treated with 10 ng/mL transforming growth factor beta (TGF-β) for at least six days to induce a fibrotic phenotype which was investigated using histological, immunohistochemical and gene expression analyses. Results: Treatment of the models with TGF-β induced changes characteristic of PF, including increased expression of alpha-smooth muscle actin and deposition of Type III collagen and vimentin protein in the stromal compartment. In addition, qRT-PCR revealed increased mRNA expression of other fibrotic markers; matrix metalloproteinase 2, fibronectin and Type III collagen. Conclusions: By recapitulating aspects of PF, these co-culture tissue models provide an experimental system to study the cross-talk between the injured epithelium and fibroblasts, which is believed to be a key factor in PF development. Furthermore, these models can be utilized to investigate the molecular events contributing to pulmonary fibrosis and to evaluate new therapeutic agents.
Author Block: A. Maione, G. R. Jackson, O. O'Connell, J. Foisy, M. Klausner, P. Hayden; MatTek Corporation, Ashland, MA, United States.
Introduction: Pulmonary fibrosis (PF) is a debilitating, typically fatal condition that may be caused by a variety of factors, including occupational and environmental exposures, drugs such as amiodarone and bleomycin, radiation exposure, and genetic predisposition. However, in 20-30% of cases the cause is unknown (i.e. idiopathic pulmonary fibrosis, IPF). Currently approved IPF drugs (pirfenidone, nintedanib) have only limited efficacy, and lung transplantation remains the best treatment option for IPF patients. Despite intense research, many of the molecular mechanisms involved in the initiation and progression of IPF remain unknown. Current IPF research relies on animal models and ex vivo lung tissues, which are expensive and are not always predictive of clinical trial results. Currently available in vitro models produced from immortalized cells also do not adequately replicate IPF. The goal of the current work is to develop in vitro organotypic, 3D airway models from primary human cells which can be used to study IPF. Methods: In vitro models composed of differentiated primary human bronchial or alveolar epithelial cells and pulmonary fibroblasts were cultured at the air-liquid interface to replicate the in vivo microenvironment. The tissue models were treated with 10 ng/mL transforming growth factor beta (TGF-β) for at least six days to induce a fibrotic phenotype which was investigated using histological, immunohistochemical and gene expression analyses. Results: Treatment of the models with TGF-β induced changes characteristic of PF, including increased expression of alpha-smooth muscle actin and deposition of Type III collagen and vimentin protein in the stromal compartment. In addition, qRT-PCR revealed increased mRNA expression of other fibrotic markers; matrix metalloproteinase 2, fibronectin and Type III collagen. Conclusions: By recapitulating aspects of PF, these co-culture tissue models provide an experimental system to study the cross-talk between the injured epithelium and fibroblasts, which is believed to be a key factor in PF development. Furthermore, these models can be utilized to investigate the molecular events contributing to pulmonary fibrosis and to evaluate new therapeutic agents.
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