دورية أكاديمية
An in vitro alveolar epithelial cell model recapitulates LRRK2 inhibitor-induced increases in lamellar body size observed in preclinical models.
| العنوان: | An in vitro alveolar epithelial cell model recapitulates LRRK2 inhibitor-induced increases in lamellar body size observed in preclinical models. |
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| المؤلفون: | Harney J; Drug Safety Research and Development, Pfizer, Groton, CT, USA. Electronic address: Julie.Harney@pfizer.com., Bajaj P; Drug Safety Research and Development, Pfizer, Groton, CT, USA., Finley JE; Drug Safety Research and Development, Pfizer, Groton, CT, USA., Kopec AK; Drug Safety Research and Development, Pfizer, Groton, CT, USA., Koza-Taylor PH; Drug Safety Research and Development, Pfizer, Groton, CT, USA., Boucher GG; Drug Safety Research and Development, Pfizer, Groton, CT, USA., Lanz TA; Drug Safety Research and Development, Pfizer, Groton, CT, USA., Doshna CM; Drug Safety Research and Development, Pfizer, Groton, CT, USA., Somps CJ; Drug Safety Research and Development, Pfizer, Groton, CT, USA., Adkins K; Drug Safety Research and Development, Pfizer, Groton, CT, USA., Houle C; Drug Safety Research and Development, Pfizer, Groton, CT, USA. |
| المصدر: | Toxicology in vitro : an international journal published in association with BIBRA [Toxicol In Vitro] 2021 Feb; Vol. 70, pp. 105012. Date of Electronic Publication: 2020 Oct 10. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Pergamon Press Country of Publication: England NLM ID: 8712158 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-3177 (Electronic) Linking ISSN: 08872333 NLM ISO Abbreviation: Toxicol In Vitro Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Oxford ; New York : Pergamon Press, c1987- |
| مواضيع طبية MeSH: | Models, Biological*, Alveolar Epithelial Cells/*pathology , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/*antagonists & inhibitors, ATP-Binding Cassette Transporters/metabolism ; Adenocarcinoma of Lung/metabolism ; Alveolar Epithelial Cells/metabolism ; Alveolar Epithelial Cells/ultrastructure ; Cells, Cultured ; Drug Evaluation, Preclinical ; Gene Expression ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Lung Neoplasms/metabolism ; Pulmonary Surfactant-Associated Protein C/metabolism |
| مستخلص: | Alveolar type II (ATII) epithelial cells contain lamellar bodies (LBs) which synthesize and store lung surfactants. In animals, the inhibition or knockout of leucine-rich repeat kinase 2 (LRRK2) causes abnormal enlargement of LBs in ATII cells. This effect of LRRK2 inhibition in lung is largely accepted as being mediated directly through blocking of the kinase function; however, downstream consequences in the lung remain unknown. In this work we established an in vitro alveolar epithelial cell (AEC) model that recapitulates the in vivo phenotype of ATII cells and developed an assay to quantify changes in LB size in response to LRRK2 inhibitors. Culture of primary human AECs at the air-liquid interface on matrigel and collagen-coated transwell inserts in the presence of growth factors promoted the LB formation and apical microvilli and induced expression of LRRK2 and ATII cell markers. Treatment with a selective LRRK2 inhibitor resulted in pharmacological reduction of phospho-LRRK2 and a significant increase in LB size; effects previously reported in lungs of non-human primates treated with LRRK2 inhibitor. In summary, our human in vitro AEC model recapitulates the abnormal lung findings observed in LRRK2-perturbed animals and holds the potential for expanding current understanding of LRRK2 function in the lung. (Copyright © 2020 Elsevier Ltd. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Alveolar epithelial cell; LRRK2; Lung; Surfactant; Transwell |
| المشرفين على المادة: | 0 (ABCA3 protein, human) 0 (ATP-Binding Cassette Transporters) 0 (Pulmonary Surfactant-Associated Protein C) 0 (SFTPC protein, human) EC 2.7.11.1 (LRRK2 protein, human) EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2) |
| تواريخ الأحداث: | Date Created: 20201013 Date Completed: 20210916 Latest Revision: 20210916 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.tiv.2020.105012 |
| PMID: | 33049313 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1879-3177 |
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| DOI: | 10.1016/j.tiv.2020.105012 |