A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide

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A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. / Williams, Jonathan M; Duckworth, Carrie A; Watson, Alastair J M; Frey, Mark R; Miguel, Jennifer C; Burkitt, Michael D; Sutton, Robert; Hughes, Kevin R; Hall, Lindsay J; Caamaño, Jorge H; Campbell, Barry J; Pritchard, D Mark.

In: Disease Models & Mechanisms, Vol. 6, No. 6, 11.2013, p. 1388-99.

Research output: Contribution to journalArticle

Harvard

Williams, JM, Duckworth, CA, Watson, AJM, Frey, MR, Miguel, JC, Burkitt, MD, Sutton, R, Hughes, KR, Hall, LJ, Caamaño, JH, Campbell, BJ & Pritchard, DM 2013, 'A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide', Disease Models & Mechanisms, vol. 6, no. 6, pp. 1388-99. https://doi.org/10.1242/dmm.013284

APA

Williams, J. M., Duckworth, C. A., Watson, A. J. M., Frey, M. R., Miguel, J. C., Burkitt, M. D., Sutton, R., Hughes, K. R., Hall, L. J., Caamaño, J. H., Campbell, B. J., & Pritchard, D. M. (2013). A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. Disease Models & Mechanisms, 6(6), 1388-99. https://doi.org/10.1242/dmm.013284

Vancouver

Author

Williams, Jonathan M ; Duckworth, Carrie A ; Watson, Alastair J M ; Frey, Mark R ; Miguel, Jennifer C ; Burkitt, Michael D ; Sutton, Robert ; Hughes, Kevin R ; Hall, Lindsay J ; Caamaño, Jorge H ; Campbell, Barry J ; Pritchard, D Mark. / A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. In: Disease Models & Mechanisms. 2013 ; Vol. 6, No. 6. pp. 1388-99.

Bibtex

@article{590e291451ee4340b4054343de2c3500,
title = "A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide",
abstract = "The gut barrier, composed of a single layer of intestinal epithelial cells (IECs) held together by tight junctions, prevents the entrance of harmful microorganisms, antigens and toxins from the gut lumen into the blood. Small intestinal homeostasis is normally maintained by the rate of shedding of senescent enterocytes from the villus tip exactly matching the rate of generation of new cells in the crypt. However, in various localized and systemic inflammatory conditions, intestinal homeostasis can be disturbed as a result of increased IEC shedding. Such pathological IEC shedding can cause transient gaps to develop in the epithelial barrier and result in increased intestinal permeability. Although pathological IEC shedding has been implicated in the pathogenesis of conditions such as inflammatory bowel disease, our understanding of the underlying mechanisms remains limited. We have therefore developed a murine model to study this phenomenon, because IEC shedding in this species is morphologically analogous to humans. IEC shedding was induced by systemic lipopolysaccharide (LPS) administration in wild-type C57BL/6 mice, and in mice deficient in TNF-receptor 1 (Tnfr1(-/-)), Tnfr2 (Tnfr2(-/-)), nuclear factor kappa B1 (Nfκb1(-/-)) or Nfĸb2 (Nfĸb2(-/-)). Apoptosis and cell shedding was quantified using immunohistochemistry for active caspase-3, and gut-to-circulation permeability was assessed by measuring plasma fluorescence following fluorescein-isothiocyanate-dextran gavage. LPS, at doses ≥0.125 mg/kg body weight, induced rapid villus IEC apoptosis, with peak cell shedding occurring at 1.5 hours after treatment. This coincided with significant villus shortening, fluid exudation into the gut lumen and diarrhea. A significant increase in gut-to-circulation permeability was observed at 5 hours. TNFR1 was essential for LPS-induced IEC apoptosis and shedding, and the fate of the IECs was also dependent on NFκB, with signaling via NFκB1 favoring cell survival and via NFκB2 favoring apoptosis. This model will enable investigation of the importance and regulation of pathological IEC apoptosis and cell shedding in various diseases. ",
keywords = "Animals, Apoptosis/drug effects, Caspase 3/metabolism, Enzyme Activation, Intestinal Mucosa/drug effects, Intestine, Small/drug effects, Lipopolysaccharides/administration & dosage, Mice, Models, Animal, NF-kappa B/genetics, Tumor Necrosis Factor-alpha/genetics",
author = "Williams, {Jonathan M} and Duckworth, {Carrie A} and Watson, {Alastair J M} and Frey, {Mark R} and Miguel, {Jennifer C} and Burkitt, {Michael D} and Robert Sutton and Hughes, {Kevin R} and Hall, {Lindsay J} and Caama{\~n}o, {Jorge H} and Campbell, {Barry J} and Pritchard, {D Mark}",
year = "2013",
month = nov,
doi = "10.1242/dmm.013284",
language = "English",
volume = "6",
pages = "1388--99",
journal = "Disease Models & Mechanisms",
issn = "1754-8403",
publisher = "The Company of Biologists Ltd.",
number = "6",

}

RIS

TY - JOUR

T1 - A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide

AU - Williams, Jonathan M

AU - Duckworth, Carrie A

AU - Watson, Alastair J M

AU - Frey, Mark R

AU - Miguel, Jennifer C

AU - Burkitt, Michael D

AU - Sutton, Robert

AU - Hughes, Kevin R

AU - Hall, Lindsay J

AU - Caamaño, Jorge H

AU - Campbell, Barry J

AU - Pritchard, D Mark

PY - 2013/11

Y1 - 2013/11

N2 - The gut barrier, composed of a single layer of intestinal epithelial cells (IECs) held together by tight junctions, prevents the entrance of harmful microorganisms, antigens and toxins from the gut lumen into the blood. Small intestinal homeostasis is normally maintained by the rate of shedding of senescent enterocytes from the villus tip exactly matching the rate of generation of new cells in the crypt. However, in various localized and systemic inflammatory conditions, intestinal homeostasis can be disturbed as a result of increased IEC shedding. Such pathological IEC shedding can cause transient gaps to develop in the epithelial barrier and result in increased intestinal permeability. Although pathological IEC shedding has been implicated in the pathogenesis of conditions such as inflammatory bowel disease, our understanding of the underlying mechanisms remains limited. We have therefore developed a murine model to study this phenomenon, because IEC shedding in this species is morphologically analogous to humans. IEC shedding was induced by systemic lipopolysaccharide (LPS) administration in wild-type C57BL/6 mice, and in mice deficient in TNF-receptor 1 (Tnfr1(-/-)), Tnfr2 (Tnfr2(-/-)), nuclear factor kappa B1 (Nfκb1(-/-)) or Nfĸb2 (Nfĸb2(-/-)). Apoptosis and cell shedding was quantified using immunohistochemistry for active caspase-3, and gut-to-circulation permeability was assessed by measuring plasma fluorescence following fluorescein-isothiocyanate-dextran gavage. LPS, at doses ≥0.125 mg/kg body weight, induced rapid villus IEC apoptosis, with peak cell shedding occurring at 1.5 hours after treatment. This coincided with significant villus shortening, fluid exudation into the gut lumen and diarrhea. A significant increase in gut-to-circulation permeability was observed at 5 hours. TNFR1 was essential for LPS-induced IEC apoptosis and shedding, and the fate of the IECs was also dependent on NFκB, with signaling via NFκB1 favoring cell survival and via NFκB2 favoring apoptosis. This model will enable investigation of the importance and regulation of pathological IEC apoptosis and cell shedding in various diseases.

AB - The gut barrier, composed of a single layer of intestinal epithelial cells (IECs) held together by tight junctions, prevents the entrance of harmful microorganisms, antigens and toxins from the gut lumen into the blood. Small intestinal homeostasis is normally maintained by the rate of shedding of senescent enterocytes from the villus tip exactly matching the rate of generation of new cells in the crypt. However, in various localized and systemic inflammatory conditions, intestinal homeostasis can be disturbed as a result of increased IEC shedding. Such pathological IEC shedding can cause transient gaps to develop in the epithelial barrier and result in increased intestinal permeability. Although pathological IEC shedding has been implicated in the pathogenesis of conditions such as inflammatory bowel disease, our understanding of the underlying mechanisms remains limited. We have therefore developed a murine model to study this phenomenon, because IEC shedding in this species is morphologically analogous to humans. IEC shedding was induced by systemic lipopolysaccharide (LPS) administration in wild-type C57BL/6 mice, and in mice deficient in TNF-receptor 1 (Tnfr1(-/-)), Tnfr2 (Tnfr2(-/-)), nuclear factor kappa B1 (Nfκb1(-/-)) or Nfĸb2 (Nfĸb2(-/-)). Apoptosis and cell shedding was quantified using immunohistochemistry for active caspase-3, and gut-to-circulation permeability was assessed by measuring plasma fluorescence following fluorescein-isothiocyanate-dextran gavage. LPS, at doses ≥0.125 mg/kg body weight, induced rapid villus IEC apoptosis, with peak cell shedding occurring at 1.5 hours after treatment. This coincided with significant villus shortening, fluid exudation into the gut lumen and diarrhea. A significant increase in gut-to-circulation permeability was observed at 5 hours. TNFR1 was essential for LPS-induced IEC apoptosis and shedding, and the fate of the IECs was also dependent on NFκB, with signaling via NFκB1 favoring cell survival and via NFκB2 favoring apoptosis. This model will enable investigation of the importance and regulation of pathological IEC apoptosis and cell shedding in various diseases.

KW - Animals

KW - Apoptosis/drug effects

KW - Caspase 3/metabolism

KW - Enzyme Activation

KW - Intestinal Mucosa/drug effects

KW - Intestine, Small/drug effects

KW - Lipopolysaccharides/administration & dosage

KW - Mice

KW - Models, Animal

KW - NF-kappa B/genetics

KW - Tumor Necrosis Factor-alpha/genetics

U2 - 10.1242/dmm.013284

DO - 10.1242/dmm.013284

M3 - Article

C2 - 24046352

VL - 6

SP - 1388

EP - 1399

JO - Disease Models & Mechanisms

JF - Disease Models & Mechanisms

SN - 1754-8403

IS - 6

ER -