Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin
Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin
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DOI：
10.1007/s00408-019-00257-w
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发表时间：
2019-10-01
期刊：
影响因子：
5
通讯作者：
Jackson, Robert M.
中科院分区：
文献类型：
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作者：
Zhang, Chongxu;Cai, Renzhi;Jackson, Robert M.
目的 生长激素释放激素 (GHRH) 是一种 44 个氨基酸的肽，可调节生长激素 (GH) 的分泌。我们假设 GHRH 受体 (GHRH-R) 拮抗剂 MIA-602 会抑制 C57Bl/6J 小鼠中博来霉素诱导的肺部炎症和/或纤维化。方法 我们测试了腹膜内 (IP) 博来霉素（第 1、3、7、10、14 和 21 天 0.8 单位）治疗的小鼠中，MIA-602（第 1-21 天皮下注射 [SC] 5 μg 或载体）是否会减少肺部炎症（第 14 天）和/或纤维化（第 28 天）。博来霉素导致气道和血管周围的炎症和纤维化，在第 14 天和第 28 天时在组织学上很明显。结果 在用 MIA-602 治疗 14 天的小鼠中，炎症（盲目评估的组织病理学评分）明显不那么明显。 28天后，用载体治疗的小鼠肺羟脯氨酸（HP）含量显着增加；相比之下，用 GHRH-R 拮抗剂治疗的小鼠中，与初始对照组相比，肺 HP 没有显着增加。 GHRH-R 拮抗剂增加培养的肺成纤维细胞的基础耗氧量和最大耗氧量。在用博莱霉素和 MIA-602 治疗的小鼠肺中，与趋化性、IL-1、趋化因子、炎症调节和细胞外信号调节激酶 (ERK) 相关的多个基因上调。 MIA-602 还显着抑制与细胞免疫反应相关的多个基因，包括 T 细胞分化、受体信号传导、激活和细胞因子产生的基因。结论 MIA-602 减少了博莱霉素引起的肺部炎症和纤维化。与免疫反应和 T 细胞功能相关的多个基因被下调，支持 MIA-602 可以调节对博莱霉素肺损伤的细胞免疫反应的观点。
Purpose Growth hormone-releasing hormone (GHRH) is a 44-amino acid peptide that regulates growth hormone (GH) secretion. We hypothesized that a GHRH receptor (GHRH-R) antagonist, MIA-602, would inhibit bleomycin-induced lung inflammation and/or fibrosis in C57Bl/6J mice. Methods We tested whether MIA-602 (5 mu g or vehicle given subcutaneously [SC] on days 1-21) would decrease lung inflammation (at day 14) and/or fibrosis (at day 28) in mice treated with intraperitoneal (IP) bleomycin (0.8 units on days 1, 3, 7, 10, 14, and 21). Bleomycin resulted in inflammation and fibrosis around airways and vessels evident histologically at days 14 and 28. Results Inflammation (histopathologic scores assessed blindly) was visibly less evident in mice treated with MIA-602 for 14 days. After 28 days, lung hydroxyproline (HP) content increased significantly in mice treated with vehicle; in contrast, lung HP did not increase significantly compared to naive controls in mice treated with GHRH-R antagonist. GHRH-R antagonist increased basal and maximal oxygen consumption of cultured lung fibroblasts. Multiple genes related to chemotaxis, IL-1, chemokines, regulation of inflammation, and extracellular signal-regulated kinases (ERK) were upregulated in lungs of mice treated with bleomycin and MIA-602. MIA-602 also prominently suppressed multiple genes related to the cellular immune response including those for T-cell differentiation, receptor signaling, activation, and cytokine production. Conclusions MIA-602 reduced lung inflammation and fibrosis due to bleomycin. Multiple genes related to immune response and T-cell functions were downregulated, supporting the view that MIA-602 can modulate the cellular immune response to bleomycin lung injury.