Hyaluronic acid is radioprotective in the intestine through a TLR4 and COX-2-mediated mechanism.

Abstract

The intestinal epithelium is sensitive to radiation injury. Damage to the intestinal epithelium is dose limiting in radiation therapy of abdominal cancers. There is a need for agents that can be given before radiation therapy to protect the intestinal epithelium. C57BL6 mice were subjected to 12 Gy of total body radiation. Some mice received intraperitoneal hyaluronic acid (HA) before radiation. Mice were killed 6 h after radiation to assess radiation-induced apoptosis in the intestine; other mice were killed at 84 h to assess crypt survival. Total body radiation (12 Gy) resulted in increased expression of HA synthases and HA in the intestine and increased plasma HA (5-fold). Intraperitoneal injection of HA (30 mg/kg) before radiation resulted in a 1.8-fold increase in intestinal crypt survival and a decrease in radiation-induced apoptosis. The radioprotective effects of HA were not seen in Toll-like receptor 4 (TLR4)- or cyclooxygenase-2 (COX-2)-deficient mice. Intraperitoneal injection of HA induced a 1.5-fold increase in intestinal COX-2 expression, a 1.5-fold increase in intestinal PGE₂, and the migration of COX-2-expressing mesenchymal stem cells from the lamina propria in the villi to the lamina propria near the crypt. We conclude that 1) radiation induces increased HA expression through inducing HA synthases, 2) intraperitoneal HA given before radiation reduces radiation-induced apoptosis and increases crypt survival, and 3) these radioprotective effects are mediated through TLR4, COX-2, and the migration of COX-2-expressing mesenchymal stem cells.

• Authors: Terrence E Riehl, Lynne Foster, William F Stenson
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 302 Issue 3 Pg. G309-16 (Feb 01 2012) ISSN: 1522-1547 [Electronic] United States
• PMID: 22038822 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, CD
• Cd44 protein, mouse
• Hyaluronan Receptors
• Radiation-Protective Agents
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Hyaluronic Acid
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Glucuronosyltransferase
• Hyaluronan Synthases
• Dinoprostone

Topics

• Animals
• Antigens, CD (metabolism)
• Apoptosis (drug effects, radiation effects)
• Cell Movement (drug effects)
• Cyclooxygenase 2 (genetics, metabolism)
• Dinoprostone (metabolism)
• Gene Expression (genetics, radiation effects)
• Glucuronosyltransferase (genetics)
• Hyaluronan Receptors (genetics)
• Hyaluronan Synthases
• Hyaluronic Acid (antagonists & inhibitors, blood, metabolism, pharmacology)
• Intestinal Mucosa (drug effects, metabolism, pathology, radiation effects)
• Intestines (drug effects, pathology, radiation effects)
• Jejunum (drug effects, metabolism, pathology, radiation effects)
• Mesenchymal Stem Cells (cytology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Radiation-Protective Agents (metabolism, pharmacology)
• Toll-Like Receptor 4 (agonists, genetics, metabolism)