Tlr9 agonist protects mice from radiation-induced gastrointestinal syndrome

Subhrajit Saha, Payel Bhanja, Laibin Liu, Alan A. Alfieri, Dong Yu, Ekambar R. Kandimalla, Sudhir Agrawal, Chandan Guha

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere29357
JournalPLoS One
Volume7
Issue number1
DOIs
StatePublished - Jan 4 2012

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Whole-Body Irradiation
agonists
irradiation
Irradiation
Radiation
mice
Tumors
Neoplasms
Intestines
neoplasms
Acute Radiation Syndrome
Growth
Toll-Like Receptor 9
Bacterial DNA
Animals
intestines
Xylose
Abdominal Wall
therapeutics
Sepsis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Saha, S., Bhanja, P., Liu, L., Alfieri, A. A., Yu, D., Kandimalla, E. R., ... Guha, C. (2012). Tlr9 agonist protects mice from radiation-induced gastrointestinal syndrome. PLoS One, 7(1), [e29357]. https://doi.org/10.1371/journal.pone.0029357

Tlr9 agonist protects mice from radiation-induced gastrointestinal syndrome. / Saha, Subhrajit; Bhanja, Payel; Liu, Laibin; Alfieri, Alan A.; Yu, Dong; Kandimalla, Ekambar R.; Agrawal, Sudhir; Guha, Chandan.

In: PLoS One, Vol. 7, No. 1, e29357, 04.01.2012.

Research output: Contribution to journalArticle

Saha, S, Bhanja, P, Liu, L, Alfieri, AA, Yu, D, Kandimalla, ER, Agrawal, S & Guha, C 2012, 'Tlr9 agonist protects mice from radiation-induced gastrointestinal syndrome', PLoS One, vol. 7, no. 1, e29357. https://doi.org/10.1371/journal.pone.0029357
Saha S, Bhanja P, Liu L, Alfieri AA, Yu D, Kandimalla ER et al. Tlr9 agonist protects mice from radiation-induced gastrointestinal syndrome. PLoS One. 2012 Jan 4;7(1). e29357. https://doi.org/10.1371/journal.pone.0029357
Saha, Subhrajit ; Bhanja, Payel ; Liu, Laibin ; Alfieri, Alan A. ; Yu, Dong ; Kandimalla, Ekambar R. ; Agrawal, Sudhir ; Guha, Chandan. / Tlr9 agonist protects mice from radiation-induced gastrointestinal syndrome. In: PLoS One. 2012 ; Vol. 7, No. 1.
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AU - Saha, Subhrajit

AU - Bhanja, Payel

AU - Liu, Laibin

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AU - Kandimalla, Ekambar R.

AU - Agrawal, Sudhir

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