Relationship between bleomycin and radiation-induced interstitial pneumonia and activation of serotonin degradation system and exploration of its treatment
10.16438/j.0513-4870.2022-0212
- VernacularTitle:博来霉素和放射线诱导的间质性肺炎与5-羟色胺降解系统激活的关系及其治疗探讨
- Author:
Jing GUAN
1
;
Meng WANG
2
;
Jia-qi JIN
1
;
Yu-xin ZHANG
1
;
Pan NI
2
;
Yi ZHANG
1
;
Fan XU
1
;
Xiu-rui LIANG
1
;
Yi-zhou LUO
2
;
Ji-hua FU
1
Author Information
1. School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
2. Department of Radiotherapy, Air Force Hospital of Eastern Theater Command of PLA, Nanjing 210002, China
- Publication Type:Research Article
- Keywords:
pulmonary inflammation;
lung fibrosis;
5-hydroxytryptamine degradation system;
macrophage;
reactive oxygen species
- From:
Acta Pharmaceutica Sinica
2022;57(8):2342-2351
- CountryChina
- Language:Chinese
-
Abstract:
Previously, we discovered that cells contain a 5-hydroxytryptamine (5-HT) degradation system (5DS), which includes 5-HT2A receptor (5-HT2AR), 5-HT synthase, and monoamine oxidase A (MAO-A). Among these, 5-HT2AR has the ability to regulate the expression of 5-HT synthase and MAO-A, and activation of 5DS causes upregulation of these proteins at the same time, resulting in the production of reactive oxygen species (ROS) in the mitochondria. In this study, we investigated the relationship between interstitial pneumonia (IP) and 5DS activation, as well as the therapeutic effect of inhibiting 5DS on IP. Animal models of bleomycin (BLM)-induced IP in mice and radiation (Rad)-induced IP in rats were established, and the models were treated with the 5-HT2AR antagonist sarpogrelate hydrochloride (SH), 5-HT synthesis inhibitor carbidopa (CDP), and their combination (SH∶CDP = 2∶1). The animal experiments were carried out in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University. In the two IP models, immunohistochemistry staining and Western blot analysis showed that the expression of 5-HT synthase was significantly upregulated in all cells of lung tissue, while the expression of 5-HT2AR and MAO-A was most significantly upregulated in the macrophages. Treatment with SH or CDP significantly reduced pulmonary interstitial thickening, alveolar atrophy with collapse, massive macrophage infiltration and interstitial fibrosis in the two IP models, as measured by HE and Masson staining, and a combination of both almost eliminated the lung tissue lesions. Moreover, treatment with the combination of SH and CDP almost completely eliminated increased ROS and malondialdehyde levels, decreased superoxide dismutase activity, increased tumor necrosis factor-α and interleukin-1β levels, and upregulated nuclear factor-κB phosphorylation and α-smooth muscle actin, matrix metalloproteinase-2, and collagen expression. SH and CDP worked together to create a synergistic effect. The findings suggested that the activation of 5DS, as evidenced by increased 5-HT synthesis in all cells of lung tissue and increased 5-HT synthesis and degradation in macrophages, is probably related to the occurrence of IP and that inhibition of 5DS can effectively treat IP.
