Compared to radiation injury alone (RI), radiation injury combined wound (CI) further enhances acute radiation syndrome and subsequently mortality. We previously reported that therapy with Ghrelin, the 28-amino-acid-peptide secreted from the stomach, significantly increased 30-day survival and mitigated hematopoietic death by enhancing and sustaining granulocyte-colony stimulating factor (G-CSF) and keratinocyte chemoattractant (KC) in the blood and bone marrow; increasing circulating white blood cell depletion; inhibiting splenocytopenia; and accelerating skin-wound healing on day 30 after CI. Herein, we aimed to study the efficacy of Ghrelin on intestinal injury at early time points after CI. B6D2F1/J female mice were exposed to 60Co-γ-photon radiation (9.5 Gy, 0.4 Gy/min, bilateral), followed by 15% total-body-surface-area skin wounds. Several endpoints were measured: at 4–5 h and on days 1, 3, 7, and 15. Ghrelin therapy mitigated CI-induced increases in IL-1β, IL-6, IL-17A, IL-18, KC, and TNF-α in serum but sustained G-CSF, KC and MIP-1α increases in ileum. Histological analysis of ileum on day 15 showed that Ghrelin treatment mitigated ileum injury by increasing villus height, crypt depth and counts, as well as decreasing villus width and mucosal injury score. Ghrelin therapy increased AKT activation and ERK activation; suppressed JNK activation and caspase-3 activation in ileum; and reduced NF-κB, iNOS, BAX and Bcl-2 in ileum. This therapy recovered the tight junction protein and mitigated bacterial translocation and lipopolysaccharides levels. The results suggest that the capacity of Ghrelin therapy to reduce CI-induced ileum injury is mediated by a balanced NF-κB-AKT-MAPK network that leads to homeostasis of pro-inflammatory and anti-inflammatory cytokines. Our novel results are the first to suggest that Ghrelin therapy effectively decreases intestinal injury after CI.

中文翻译：

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Ghrelin 是一种新型疗法，可纠正细胞因子和 NF-κB-AKT-MAPK 网络，并减轻放射线和皮肤创伤联合引起的肠道损伤。

与单独放射损伤（RI）相比，放射损伤合并伤口（CI）进一步增加急性放射综合征和随后的死亡率。我们之前报道过，Ghrelin（一种从胃中分泌的 28 个氨基酸肽）治疗可通过增强和维持粒细胞集落刺激因子 (G-CSF) 和角质形成细胞趋化因子 (KC) 显着提高 30 天生存率并减轻造血细胞死亡）在血液和骨髓中；增加循环白细胞的消耗；抑制脾细胞减少症；CI 后第 30 天加速皮肤伤口愈合。在此，我们的目的是研究 Ghrelin 在 CI 后早期时间点对肠道损伤的功效。B6D2F1/J 雌性小鼠暴露于 60Co-γ-光子辐射（9.5 Gy，0.4 Gy/min，双侧），随后造成 15% 全身表面积的皮肤伤口。测量了几个终点：第 4-5 小时以及第 1、3、7 和 15 天。Ghrelin 治疗减轻了 CI 诱导的 IL-1β、IL-6、IL-17A、IL-18、KC 和 TNF 的增加血清中-α，但回肠中 G-CSF、KC 和 MIP-1α 持续增加。第15天的回肠组织学分析表明，Ghrelin治疗通过增加绒毛高度、隐窝深度和计数以及减少绒毛宽度和粘膜损伤评分来减轻回肠损伤。Ghrelin 治疗增加 AKT 激活和 ERK 激活；抑制回肠中 JNK 激活和 caspase-3 激活；并减少回肠中的 NF-κB、iNOS、BAX 和 Bcl-2。这种疗法恢复了紧密连接蛋白并减轻了细菌易位和脂多糖水平。结果表明，Ghrelin 疗法减少 CI 诱导的回肠损伤的能力是由平衡的 NF-κB-AKT-MAPK 网络介导的，该网络导致促炎和抗炎细胞因子的稳态。我们的新结果首次表明 Ghrelin 疗法可有效减少 CI 后的肠道损伤。