TLR9 agonist protects mice from radiation-induced gastrointestinal syndrome.

Abstract

PURPOSE:

Radiation-induced gastrointestinal syndrome (RIGS) is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9.

METHODS AND MATERIALS:

Male C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI) (8.4-10.4 Gy), TLR9 agonist (1 mg/kg s.c.), 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88). Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR) for tumor growth study.

RESULTS:

Mice receiving pre-WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03), 9.4 Gy (p<0.008) and 8.4 Gy (p<0.002) of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01). Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008) with significant reduction of tumor growth (p<0.0001).

CONCLUSIONS:

TLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies.

• Authors: Subhrajit Saha, Payel Bhanja, Laibin Liu, Alan A Alfieri, Dong Yu, Ekambar R Kandimalla, Sudhir Agrawal, Chandan Guha
• Journal: PloS one (PLoS One) Vol. 7 Issue 1 Pg. e29357 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22238604 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Gastrointestinal Agents
• Radiation-Protective Agents
• Tlr9 protein, mouse
• Toll-Like Receptor 9

Topics

• Animals
• Cell Line, Tumor
• Cytoprotection (drug effects)
• Drug Evaluation, Preclinical
• Gastrointestinal Agents (pharmacology, therapeutic use)
• Gastrointestinal Diseases (etiology, prevention & control)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Radiation Injuries, Experimental (prevention & control)
• Radiation Tolerance (drug effects)
• Radiation-Protective Agents (pharmacology, therapeutic use)
• Rats
• Syndrome
• Toll-Like Receptor 9 (agonists, metabolism)