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TPN‐associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways
dc.contributor.authorFreeman, Jennifer J.
dc.contributor.authorFeng, Yongjia
dc.contributor.authorDemehri, Farokh R.
dc.contributor.authorDempsey, Peter J.
dc.contributor.authorTeitelbaum, Daniel H.
dc.date.accessioned2020-03-17T18:29:03Z
dc.date.available2020-03-17T18:29:03Z
dc.date.issued2015-07
dc.identifier.citationFreeman, Jennifer J.; Feng, Yongjia; Demehri, Farokh R.; Dempsey, Peter J.; Teitelbaum, Daniel H. (2015). "TPN‐associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways." The FASEB Journal 29(7): 2943-2958.
dc.identifier.issn0892-6638
dc.identifier.issn1530-6860
dc.identifier.urihttps://hdl.handle.net/2027.42/154328
dc.description.abstractRecent studies suggest a close interaction between epidermal growth factor (EGF) and TLR signaling in the modulation of intestinal epithelial cell (IEC) proliferation; however, how these signaling pathways adjust IEC proliferation is poorly understood. We utilized a model of total parenteral nutrition (TPN), or enteral nutrient deprivation, to study this interaction as TPN results in mucosal atrophy due to decreased IEC proliferation and increased apoptosis. We identified the novel finding of decreased mucosal atrophy in TLR4 knockout (TLR4KO) mice receiving TPN. We hypothesized that EGF signaling is preserved in TLR4KO‐TPN mice and prevents mucosal atrophy. C57B1/6 and strain‐matched TLR4KO mice were provided either enteral feeding or TPN. IEC proliferation and apoptosis were measured. Cytokine and growth factor abundances were detected in both groups. To examine interdependence of these pathways, ErbB1 pharmacologic blockade was used. The marked decline in IEC proliferation with TPN was nearly prevented in TLR4KO mice, and intestinal length was partially preserved. EGF was significantly increased, and TNF‐α decreased in TLR4KO‐TPN versus wild‐type (WT)‐TPN mice. Apoptotic positive crypt cells were 15‐fold higher in WT‐TPN versus TLR4KO‐TPN mice. Bcl‐2 was significantly increased in TLR4KOTPN mice, while Bax decreased 10‐fold. ErbB1 blockade prevented this otherwise protective effect in TLR4KO‐sTPN mice. TLR4 blockade significantly prevented TPN‐associated atrophy by preserving proliferation and preventing apoptosis. This is driven by a reduction in TNF‐α abundance and increased EGF. Potential manipulation of this regulatory pathway may have significant clinical potential to prevent TPN‐associated atrophy.—Freeman, J. J., Feng, Y., Demehri, F. R., Dempsey, P. J., Teitelbaum, D. H. TPN‐associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways. FASEB J. 29, 2943‐2958 (2015). www.fasebj.org
dc.publisherFederation of American Societies for Experimental Biology
dc.publisherWiley Periodicals, Inc.
dc.subject.otherapoptosis
dc.subject.otherepidermal growth factor
dc.subject.otherepithelial cell proliferation
dc.subject.othermucosal atrophy
dc.subject.othertotal parenteral nutrition
dc.titleTPN‐associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelBiology
dc.subject.hlbtoplevelScience
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/154328/1/fsb2fj14269480.pdf
dc.identifier.doi10.1096/fj.14-269480
dc.identifier.sourceThe FASEB Journal
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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