Ghrelin accelerates wound healing through GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways in combined radiation and burn injury in rats.

Cong Liu,Yuhui Hao,Hong Li,Zhangyou Yang,Jing Liu,Rong Li,Yiping Zeng,Jiawei Huang

doi:10.1038/srep27499

Cong Liu, Yuhui Hao + Show 6 more

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https://doi.org/10.1038/srep27499

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Journal: Scientific Reports	Publication Date: Jun 7, 2016
Citations: 30	License type: CC BY 4.0

Affiliation: Army Medical University

Abstract

The therapeutic effect of ghrelin on wound healing was assessed using a rat model of combined radiation and burn injury (CRBI). Rat ghrelin, anti-rat tumor necrosis factor (TNF) α polyclonal antibody (PcAb), or selective antagonists of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and growth hormone secretagogue receptor (GHS-R) 1a (SB203580, SP600125, and [D-Lys3]-GHRP-6, respectively), were administered for seven consecutive days. Levels of various signaling molecules were assessed in isolated rat peritoneal macrophages. The results showed that serum ghrelin levels and levels of macrophage glucocorticoid receptor (GR) decreased, while phosphorylation of p38MAPK, JNK, and p65 nuclear factor (NF) κB increased. Ghrelin inhibited the serum induction of proinflammatory mediators, especially TNF-α, and promoted wound healing in a dose-dependent manner. Ghrelin treatment decreased phosphorylation of p38MAPK, JNK, and p65NF-κB, and increased GR levels in the presence of GHS-R1a. SB203580 or co-administration of SB203580 and SP600125 decreased TNF-α level, which may have contributed to the inactivation of p65NF-κB and increase in GR expression, as confirmed by western blotting. In conclusion, ghrelin enhances wound recovery in CRBI rats, possibly by decreasing the induction of TNF-α or other proinflammatory mediators that are involved in the regulation of GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways.

Highlights

Combined radiation and burn injury (CRBI) is a classical type of combined radiation injury (CRI), where a major radiation injury is accompanied by burn, simultaneously or consecutively[1]
The serum ghrelin levels gradually decreased after combined radiation and burn injury (CRBI), reaching the lowest value at day 7 (Fig. 1A), and slowly increased until they reached the initial concentration at day 28
Ghrelin is an endogenous “brain-gut” peptide that participates in various biological processes through interacting with its specified receptor GHS-R1a located in cell membranes[33]

Summary

Introduction

Combined radiation and burn injury (CRBI) is a classical type of combined radiation injury (CRI), where a major radiation injury is accompanied by burn, simultaneously or consecutively[1]. Acute severe inflammatory response (ASIR) induced by endogenous gastrointestinal or/and respiratory tract infection, and exogenous infection caused by impaired wound healing, is an important cause of death of CRBI animals[1,9,10]. Usually phosphorylated, GC-GR protein dimers translocate into the nucleus and bind specific DNA sequences called glucocorticoid response elements (GREs). This results in diverse events, such as the widely known anti-inflammatory effect[24,25]. In severely burned subjects, both humans and animals, GC levels markedly increase whereas GR expression decreases, which leads to glucocorticoid resistance (GCR)[26,27].

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