Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2017; 23(26): 4701-4711
Published online Jul 14, 2017. doi: 10.3748/wjg.v23.i26.4701
Fibrinogen deficiency suppresses the development of early and delayed radiation enteropathy
Junru Wang, Rupak Pathak, Sarita Garg, Martin Hauer-Jensen
Junru Wang, Rupak Pathak, Sarita Garg, Martin Hauer-Jensen, Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
Author contributions: Wang J and Pathak R planned and performed experiments, analyzed and interpreted data, and wrote the manuscript; Garg S performed experiments and collected data; Hauer-Jensen M conceived and directed the study, interpreted data, and edited the manuscript.
Supported by Arkansas Space Grant Consortium and National Space Biomedical Research Institute through National Aeronautics and Space Administration, No. NNX15AK32A (RP) and No. RE03701 (MH-J), and National Institutes of Health, No. P20 GM109005 (MH-J).
Institutional animal care and use committee statement: All the experimental protocols involving animals were reviewed and approved by the University of Arkansas for Medical Sciences Institutional Animal Care and Use Committee.
Conflict-of-interest statement: It is hereby confirmed that no actual or potential conflict of interest in relation to this article exists.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at mhjensen@uams.edu. Participants gave informed consent for data sharing. No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Martin Hauer-Jensen, MD, PhD, Professor, Director, Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, United States. mhjensen@uams.edu
Telephone: +1-501-6867912 Fax: +1-501-4210022
Received: November 17, 2016
Peer-review started: November 18, 2016
First decision: April 17, 2017
Revised: June 5, 2017
Accepted: June 18, 2017
Article in press: June 19, 2017
Published online: July 14, 2017
Processing time: 237 Days and 4.2 Hours
Abstract
AIM

To determine the mechanistic role of fibrinogen, a key regulator of inflammation and fibrosis, in early and delayed radiation enteropathy.

METHODS

Fibrinogen wild-type (Fib+/+), fibrinogen heterozygous (Fib+/-), and fibrinogen knockout (Fib-/-) mice were exposed to localized intestinal irradiation and assessed for early and delayed structural changes in the intestinal tissue. A 5-cm segment of ileum of mice was exteriorized and exposed to 18.5 Gy of x-irradiation. Intestinal tissue injury was assessed by quantitative histology, morphometry, and immunohistochemistry at 2 wk and 26 wk after radiation. Plasma fibrinogen level was measured by enzyme-linked immunosorbent assay.

RESULTS

There was no difference between sham-irradiated Fib+/+ and Fib+/- mice in terms of fibrinogen concentration in plasma and intestinal tissue, intestinal histology, morphometry, intestinal smooth muscle cell proliferation, and neutrophil infiltration. Therefore, Fib+/- mice were used as littermate controls. Unlike sham-irradiated Fib+/+ and Fib+/- mice, no fibrinogen was detected in the plasma and intestinal tissue of sham-irradiated Fib-/- mice. Moreover, fibrinogen level was not elevated after irradiation in the intestinal tissue of Fib-/- mice, while significant increase in intestinal fibrinogen level was noticed in irradiated Fib+/+ and Fib+/- mice. Importantly, irradiated Fib-/- mice exhibited substantially less overall intestinal structural injury (RIS, P = 0.000002), intestinal wall thickness (P = 0.003), intestinal serosal thickness (P = 0.009), collagen deposition (P = 0.01), TGF-β immunoreactivity (P = 0.03), intestinal smooth muscle proliferation (P = 0.046), neutrophil infiltration (P = 0.01), and intestinal mucosal injury (P = 0.0003), compared to irradiated Fib+/+ and Fib+/- mice at both 2 wk and 26 wk.

CONCLUSION

These data demonstrate that fibrinogen deficiency directly attenuates development of early and delayed radiation enteropathy. Fibrinogen could be a novel target in treating intestinal damage.

Keywords: Radiation enteropathy; Knockout mouse model; Fibrinogen; Inflammation; Fibrosis; Ionizing radiation

Core tip: Fibrinogen, a plasma protein, and fibrin (breakdown product of fibrinogen) induce inflammation, and fibrosis. Suppression of coagulation, inflammation, and fibrosis attenuate intestinal radiation injury. While fibrinogen has been presumed to be involved in intestinal fibrosis development, a direct role has only been supported by indirect evidence. We investigated the direct role of fibrinogen deficiency in early and delayed intestinal radiation injury. Radiation caused less intestinal injury in mice deficient in the fibrinogen gene, than in mice bearing two or one wild type fibrinogen alleles. We conclude that fibrinogen is essential for full-blown intestinal radiation fibrosis to occur.