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      Invited review: human air-liquid-interface organotypic airway tissue models derived from primary tracheobronchial epithelial cells—overview and perspectives


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          The lung is an organ that is directly exposed to the external environment. Given the large surface area and extensive ventilation of the lung, it is prone to exposure to airborne substances, such as pathogens, allergens, chemicals, and particulate matter. Highly elaborate and effective mechanisms have evolved to protect and maintain homeostasis in the lung. Despite these sophisticated defense mechanisms, the respiratory system remains highly susceptible to environmental challenges. Because of the impact of respiratory exposure on human health and disease, there has been considerable interest in developing reliable and predictive in vitro model systems for respiratory toxicology and basic research. Human air-liquid-interface (ALI) organotypic airway tissue models derived from primary tracheobronchial epithelial cells have in vivo–like structure and functions when they are fully differentiated. The presence of the air-facing surface allows conducting in vitro exposures that mimic human respiratory exposures. Exposures can be conducted using particulates, aerosols, gases, vapors generated from volatile and semi-volatile substances, and respiratory pathogens. Toxicity data have been generated using nanomaterials, cigarette smoke, e-cigarette vapors, environmental airborne chemicals, drugs given by inhalation, and respiratory viruses and bacteria. Although toxicity evaluations using human airway ALI models require further standardization and validation, this approach shows promise in supplementing or replacing in vivo animal models for conducting research on respiratory toxicants and pathogens.

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          Most cited references273

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          Airway mucus function and dysfunction.

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            TEER measurement techniques for in vitro barrier model systems.

            Transepithelial/transendothelial electrical resistance (TEER) is a widely accepted quantitative technique to measure the integrity of tight junction dynamics in cell culture models of endothelial and epithelial monolayers. TEER values are strong indicators of the integrity of the cellular barriers before they are evaluated for transport of drugs or chemicals. TEER measurements can be performed in real time without cell damage and generally are based on measuring ohmic resistance or measuring impedance across a wide spectrum of frequencies. The measurements for various cell types have been reported with commercially available measurement systems and also with custom-built microfluidic implementations. Some of the barrier models that have been widely characterized using TEER include the blood-brain barrier (BBB), gastrointestinal (GI) tract, and pulmonary models. Variations in these values can arise due to factors such as temperature, medium formulation, and passage number of cells. The aim of this article is to review the different TEER measurement techniques and analyze their strengths and weaknesses, determine the significance of TEER in drug toxicity studies, examine the various in vitro models and microfluidic organs-on-chips implementations using TEER measurements in some widely studied barrier models (BBB, GI tract, and pulmonary), and discuss the various factors that can affect TEER measurements.
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              Is Open Access

              Long‐term expanding human airway organoids for disease modeling

              Abstract Organoids are self‐organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long‐term‐expanding human airway organoids from broncho‐alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi‐ciliated cells, mucus‐producing secretory cells, and CC10‐secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non‐structural viral NS2 protein, and preferentially recruits neutrophils upon co‐culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

                Author and article information

                In Vitro Cell Dev Biol Anim
                In Vitro Cell Dev Biol Anim
                In Vitro Cellular & Developmental Biology. Animal
                Springer US (New York )
                11 November 2020
                : 1-29
                [1 ]GRID grid.483504.e, ISNI 0000 0001 2158 7187, Division of Genetic and Molecular Toxicology, , National Center for Toxicological Research, US Food and Drug Administration, ; 3900 NCTR Rd., AR Jefferson, USA
                [2 ]GRID grid.416809.2, ISNI 0000 0004 0423 0663, Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, , National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, ; Morgantown, WV USA
                [3 ]GRID grid.280664.e, ISNI 0000 0001 2110 5790, Division of the National Toxicology Program, , National Institute of Environmental Health Sciences, ; Durham, NC USA
                [4 ]GRID grid.423031.7, BioSurfaces Inc., ; Ashland, MA USA
                Author notes

                Editor: Tetsuji Okamoto

                Author information
                © The Society for In Vitro Biology 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                : 26 June 2020
                : 29 September 2020
                Invited Review

                Developmental biology
                air-liquid-interface (ali) airway cultures,exposure system,inhalation toxicology,pulmonary drug testing,pathogen-host interaction


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