Doxorubicin increases permeability of murine small intestinal epithelium and cultured T84 monolayers

Abstract Enteric bacteria and/or their products are necessary for doxorubicin (DXR)-induced small intestine mucosal damage. While DXR does not induce gross loss of epithelium, others have shown elevated serum endotoxin after DXR administration. However, the mechanism of movement is unknown. We hypot...

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Autores principales:	Paul Cray, Breanna J. Sheahan, Jocsa E. Cortes, Christopher M. Dekaney
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/78603ac7a081400ca719e9c2c2854856
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spelling	oai:doaj.org-article:78603ac7a081400ca719e9c2c28548562021-12-02T16:18:05ZDoxorubicin increases permeability of murine small intestinal epithelium and cultured T84 monolayers10.1038/s41598-020-78473-12045-2322https://doaj.org/article/78603ac7a081400ca719e9c2c28548562020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78473-1https://doaj.org/toc/2045-2322Abstract Enteric bacteria and/or their products are necessary for doxorubicin (DXR)-induced small intestine mucosal damage. While DXR does not induce gross loss of epithelium, others have shown elevated serum endotoxin after DXR administration. However, the mechanism of movement is unknown. We hypothesized that DXR treatment resulted in increased paracellular translocation of bacteria or bacterial products through the small intestinal epithelium. We measured permeability after DXR administration using transepithelial resistance and macromolecular flux and assessed tight junctional gene expression and protein localization both in vitro using T84 cells and ex vivo using murine jejunum. DXR treatment increased flux of 4 kDa dextrans in mouse jejenum, but increased flux of 4, 10 and 20 kDa dextrans in T84 cells. Following DXR, we observed increased permeability, both in vitro and ex vivo, independent of bacteria. DXR induced increased expression of Cldn2 and Cldn4 in murine small intestine but increased only CLDN2 expression in T84 cells. DXR treatment induced disorganization of tight junctional proteins. We conclude that DXR increases paracellular transit of small macromolecules, including bacterial products, through the epithelium, by altering expression of tight junctional components and dynamic loosening of cellular tight junctions.Paul CrayBreanna J. SheahanJocsa E. CortesChristopher M. DekaneyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paul Cray Breanna J. Sheahan Jocsa E. Cortes Christopher M. Dekaney Doxorubicin increases permeability of murine small intestinal epithelium and cultured T84 monolayers
description	Abstract Enteric bacteria and/or their products are necessary for doxorubicin (DXR)-induced small intestine mucosal damage. While DXR does not induce gross loss of epithelium, others have shown elevated serum endotoxin after DXR administration. However, the mechanism of movement is unknown. We hypothesized that DXR treatment resulted in increased paracellular translocation of bacteria or bacterial products through the small intestinal epithelium. We measured permeability after DXR administration using transepithelial resistance and macromolecular flux and assessed tight junctional gene expression and protein localization both in vitro using T84 cells and ex vivo using murine jejunum. DXR treatment increased flux of 4 kDa dextrans in mouse jejenum, but increased flux of 4, 10 and 20 kDa dextrans in T84 cells. Following DXR, we observed increased permeability, both in vitro and ex vivo, independent of bacteria. DXR induced increased expression of Cldn2 and Cldn4 in murine small intestine but increased only CLDN2 expression in T84 cells. DXR treatment induced disorganization of tight junctional proteins. We conclude that DXR increases paracellular transit of small macromolecules, including bacterial products, through the epithelium, by altering expression of tight junctional components and dynamic loosening of cellular tight junctions.
format	article
author	Paul Cray Breanna J. Sheahan Jocsa E. Cortes Christopher M. Dekaney
author_facet	Paul Cray Breanna J. Sheahan Jocsa E. Cortes Christopher M. Dekaney
author_sort	Paul Cray
title	Doxorubicin increases permeability of murine small intestinal epithelium and cultured T84 monolayers
title_short	Doxorubicin increases permeability of murine small intestinal epithelium and cultured T84 monolayers
title_full	Doxorubicin increases permeability of murine small intestinal epithelium and cultured T84 monolayers
title_fullStr	Doxorubicin increases permeability of murine small intestinal epithelium and cultured T84 monolayers
title_full_unstemmed	Doxorubicin increases permeability of murine small intestinal epithelium and cultured T84 monolayers
title_sort	doxorubicin increases permeability of murine small intestinal epithelium and cultured t84 monolayers
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/78603ac7a081400ca719e9c2c2854856
work_keys_str_mv	AT paulcray doxorubicinincreasespermeabilityofmurinesmallintestinalepitheliumandculturedt84monolayers AT breannajsheahan doxorubicinincreasespermeabilityofmurinesmallintestinalepitheliumandculturedt84monolayers AT jocsaecortes doxorubicinincreasespermeabilityofmurinesmallintestinalepitheliumandculturedt84monolayers AT christophermdekaney doxorubicinincreasespermeabilityofmurinesmallintestinalepitheliumandculturedt84monolayers
_version_	1718384176722345984

Doxorubicin increases permeability of murine small intestinal epithelium and cultured T84 monolayers

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