P2.05-001 α7-nAchR Agonist GTS-21 Reduces Radiation-Induced Lung Injury by Inhibiting HMGB1/TLR-4/NF-κB Pathway: Topic: Biology

Abstract

The cholinergic anti-inflammatory signaling pathway allows the autonomic nervous system to modulate immunologic stimuli and inflammatory processes α7 nicotinic acetylcholine receptor (α7-nAChR) is a major component in this pathway. GTS-21, a selective α7 nicotinic acetylcholine receptor agonist, has been demonstrated as a promising treatment for inflammation. So, the aim of this study is to determine whether treatment GTS-21 can mitigate the radiation induced lung injury. C57BL/6 mice were randomly divided into three groups: a control group, a 12 Gy thoracic irradiation group, a 12 Gy thoracic irradiation group treated with 4mg/kg GTS-21 immediately after irradiation. Each of group were sacrificed at 1, 3, 7, 14, 21d and 3m, 6m post-irradiation, and the sections were respectively stained with hematoxylin and eosin (HE) and Masson’s trichrome to assess the degree of inflammation and fibrosis. Serum concentrations of TNF-α, IL-1β and IL-6 were quantitatively measured by Cytometric Bead Array (CBA) kit. Real-time PCR and Western blot were used to detect the mRNA and protein levels of HMGB1, TLR-4, NF-κB, MyD88 and TGF-β in lung tissue from GTS-21 group and irradiation control group at different time after radiation. The result from HE and Masson staining showed that GTS-21 could dramatically reduce radiation-induced lung inflammation and following mitigate lung fibrosis. Then, we found that radiation-induced TNF-α, IL-1β and IL-6 in serum were also inhibited by GTS-21. Comparing to the control group, the mRNA levels of HMGB1,TLR-4 and NF-κB were decreased at the early time of radiation pneumonitis, and the most significant difference was observed at 21d post-irradiation(P<0.05). the mRNA levels of TGF-β was decrease in GTS-21group at 3m and 6m post -irradiation when compared to control (P<0.05). However, there did not have any different on MyD88 between GTS-21and control groups. The result from western blot showed that the protein levels of HMGB1, TLR-4 and NF-κB in GTS-21 group were also significantly decreased at 21d after radiation. After 3m and 6m from radiation, the protein level of TGF-β was decreased dramatically at GTS-21 group. GTS-21 can reduce radiation pneumonitis and fibrosis by inhibiting HMGB1/TLR-4/NF-κB pathway which subsequently decrease TGF-β expression.