Recombinant Human MFG-E8 Attenuates Intestinal Injury and Mortality in Severe Whole Body Irradiation in Rats

Michael A. Ajakaiye; Asha Jacob; Rongqian Wu; Weng Lang Yang; Jeffrey Nicastro; Gene F. Coppa; Ping Wang

doi:10.1371/journal.pone.0046540

Recombinant Human MFG-E8 Attenuates Intestinal Injury and Mortality in Severe Whole Body Irradiation in Rats

Michael A. Ajakaiye, Asha Jacob, Rongqian Wu, Weng Lang Yang, Jeffrey Nicastro, Gene F. Coppa, Ping Wang

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

The gastrointestinal (GI) syndrome component of acute radiation syndrome (ARS) results from depletion of immature parenchymal stem cells after high dose irradiation and contributes significantly to early mortality. It is associated with severe, irreparable damage in the GI tract and extremely low survival. There is a need for the development of viable mitigators of whole body irradiation (WBI) due to the possibility of unexpected high level radiation exposure from nuclear accidents or attacks. We therefore examined the effect of recombinant human milk fat globule-EGF factor 8 (rhMFG-E8) in mitigating damage after WBI. Male Sprague-Dawley rats were exposed to 10 Gy WBI using Cesium-137 as the radiation source. The animals in the treatment group received rhMFG-E8 (166 μg/kg BW) subcutaneously once a day with the first dose given 6 h after WBI. Blood and tissue samples from the ileum were collected after 3 days of treatment. A separate cohort of animals was treated for 7 days and the 21 day mortality rate was determined. Treatment with rhMFG-E8 significantly improved the survival from 31% to 75% over 21 days. Furthermore, rhMFG-E8 treatment resulted in a 36% reduction in the radiation injury intestinal mucosal damage score, corresponding to visible histological changes. MFG-E8 gene expression was significantly decreased in WBI-induced animals as compared to sham controls. Treatment with rhMFG-E8 increased p53 and p21 expression by 207% and 84% compared to untreated controls. This was accompanied by an 80% increase in the expression of anti-apoptotic cell regulator Bcl-2. p53 and p21 levels correlate with improved survival after radiation injury. These cell regulators arrest the cell after DNA damage and enable DNA repair as well as optimize cell survival. Taken together, these results indicate that rhMFG-E8 ameliorates the GI syndrome and improves survival after WBI by minimizing intestinal cell damage and optimizing recovery.

Original language	English (US)
Article number	e46540
Journal	PloS one
Volume	7
Issue number	10
DOIs	https://doi.org/10.1371/journal.pone.0046540
State	Published - Oct 8 2012
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences
General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1371/journal.pone.0046540

Cite this

@article{0b7c3c24dde542c79ae1619682e46181,

title = "Recombinant Human MFG-E8 Attenuates Intestinal Injury and Mortality in Severe Whole Body Irradiation in Rats",

abstract = "The gastrointestinal (GI) syndrome component of acute radiation syndrome (ARS) results from depletion of immature parenchymal stem cells after high dose irradiation and contributes significantly to early mortality. It is associated with severe, irreparable damage in the GI tract and extremely low survival. There is a need for the development of viable mitigators of whole body irradiation (WBI) due to the possibility of unexpected high level radiation exposure from nuclear accidents or attacks. We therefore examined the effect of recombinant human milk fat globule-EGF factor 8 (rhMFG-E8) in mitigating damage after WBI. Male Sprague-Dawley rats were exposed to 10 Gy WBI using Cesium-137 as the radiation source. The animals in the treatment group received rhMFG-E8 (166 μg/kg BW) subcutaneously once a day with the first dose given 6 h after WBI. Blood and tissue samples from the ileum were collected after 3 days of treatment. A separate cohort of animals was treated for 7 days and the 21 day mortality rate was determined. Treatment with rhMFG-E8 significantly improved the survival from 31% to 75% over 21 days. Furthermore, rhMFG-E8 treatment resulted in a 36% reduction in the radiation injury intestinal mucosal damage score, corresponding to visible histological changes. MFG-E8 gene expression was significantly decreased in WBI-induced animals as compared to sham controls. Treatment with rhMFG-E8 increased p53 and p21 expression by 207% and 84% compared to untreated controls. This was accompanied by an 80% increase in the expression of anti-apoptotic cell regulator Bcl-2. p53 and p21 levels correlate with improved survival after radiation injury. These cell regulators arrest the cell after DNA damage and enable DNA repair as well as optimize cell survival. Taken together, these results indicate that rhMFG-E8 ameliorates the GI syndrome and improves survival after WBI by minimizing intestinal cell damage and optimizing recovery.",

author = "Ajakaiye, {Michael A.} and Asha Jacob and Rongqian Wu and Yang, {Weng Lang} and Jeffrey Nicastro and Coppa, {Gene F.} and Ping Wang",

year = "2012",

month = oct,

day = "8",

doi = "10.1371/journal.pone.0046540",

language = "English (US)",

volume = "7",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "10",

}

TY - JOUR

T1 - Recombinant Human MFG-E8 Attenuates Intestinal Injury and Mortality in Severe Whole Body Irradiation in Rats

AU - Ajakaiye, Michael A.

AU - Jacob, Asha

AU - Wu, Rongqian

AU - Yang, Weng Lang

AU - Nicastro, Jeffrey

AU - Coppa, Gene F.

AU - Wang, Ping

PY - 2012/10/8

Y1 - 2012/10/8

N2 - The gastrointestinal (GI) syndrome component of acute radiation syndrome (ARS) results from depletion of immature parenchymal stem cells after high dose irradiation and contributes significantly to early mortality. It is associated with severe, irreparable damage in the GI tract and extremely low survival. There is a need for the development of viable mitigators of whole body irradiation (WBI) due to the possibility of unexpected high level radiation exposure from nuclear accidents or attacks. We therefore examined the effect of recombinant human milk fat globule-EGF factor 8 (rhMFG-E8) in mitigating damage after WBI. Male Sprague-Dawley rats were exposed to 10 Gy WBI using Cesium-137 as the radiation source. The animals in the treatment group received rhMFG-E8 (166 μg/kg BW) subcutaneously once a day with the first dose given 6 h after WBI. Blood and tissue samples from the ileum were collected after 3 days of treatment. A separate cohort of animals was treated for 7 days and the 21 day mortality rate was determined. Treatment with rhMFG-E8 significantly improved the survival from 31% to 75% over 21 days. Furthermore, rhMFG-E8 treatment resulted in a 36% reduction in the radiation injury intestinal mucosal damage score, corresponding to visible histological changes. MFG-E8 gene expression was significantly decreased in WBI-induced animals as compared to sham controls. Treatment with rhMFG-E8 increased p53 and p21 expression by 207% and 84% compared to untreated controls. This was accompanied by an 80% increase in the expression of anti-apoptotic cell regulator Bcl-2. p53 and p21 levels correlate with improved survival after radiation injury. These cell regulators arrest the cell after DNA damage and enable DNA repair as well as optimize cell survival. Taken together, these results indicate that rhMFG-E8 ameliorates the GI syndrome and improves survival after WBI by minimizing intestinal cell damage and optimizing recovery.

AB - The gastrointestinal (GI) syndrome component of acute radiation syndrome (ARS) results from depletion of immature parenchymal stem cells after high dose irradiation and contributes significantly to early mortality. It is associated with severe, irreparable damage in the GI tract and extremely low survival. There is a need for the development of viable mitigators of whole body irradiation (WBI) due to the possibility of unexpected high level radiation exposure from nuclear accidents or attacks. We therefore examined the effect of recombinant human milk fat globule-EGF factor 8 (rhMFG-E8) in mitigating damage after WBI. Male Sprague-Dawley rats were exposed to 10 Gy WBI using Cesium-137 as the radiation source. The animals in the treatment group received rhMFG-E8 (166 μg/kg BW) subcutaneously once a day with the first dose given 6 h after WBI. Blood and tissue samples from the ileum were collected after 3 days of treatment. A separate cohort of animals was treated for 7 days and the 21 day mortality rate was determined. Treatment with rhMFG-E8 significantly improved the survival from 31% to 75% over 21 days. Furthermore, rhMFG-E8 treatment resulted in a 36% reduction in the radiation injury intestinal mucosal damage score, corresponding to visible histological changes. MFG-E8 gene expression was significantly decreased in WBI-induced animals as compared to sham controls. Treatment with rhMFG-E8 increased p53 and p21 expression by 207% and 84% compared to untreated controls. This was accompanied by an 80% increase in the expression of anti-apoptotic cell regulator Bcl-2. p53 and p21 levels correlate with improved survival after radiation injury. These cell regulators arrest the cell after DNA damage and enable DNA repair as well as optimize cell survival. Taken together, these results indicate that rhMFG-E8 ameliorates the GI syndrome and improves survival after WBI by minimizing intestinal cell damage and optimizing recovery.

UR - http://www.scopus.com/inward/record.url?scp=84867290303&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867290303&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0046540

DO - 10.1371/journal.pone.0046540

M3 - Article

C2 - 23056336

AN - SCOPUS:84867290303

SN - 1932-6203

VL - 7

JO - PloS one

JF - PloS one

IS - 10

M1 - e46540

ER -

Recombinant Human MFG-E8 Attenuates Intestinal Injury and Mortality in Severe Whole Body Irradiation in Rats

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this