Postoperative pain and delayed healing in surgical wounds, which require complex management strategies have understudied complicated mechanisms. Here we investigated temporal changes in behavior, tissue structure, and transcriptomic profiles in a rat model of a surgical incision, using hyperalgesic behavioral tests, histological analyses, and next-generation RNA sequencing, respectively. The most rapidly (1 hour) expressed genes were the chemokines, Cxcl1 and Cxcl2. Consequently, infiltrating leukocytes were abundantly observed starting at 6 and peaking at 24 hours after incising which was supported by histological analysis and appearance of the neutrophil markers, S100a8 and S100a9. At this time, hyperalgesia was at a peak and overall transcriptional activity was most highly activated. At the 1-day timepoint, Nppb, coding for natriuretic peptide precursor B, was the most strongly upregulated gene and was localized by in situ hybridization to the epidermal keratinocytes at the margins of the incision. Nppb was basically unaffected in a peripheral inflammation model transcriptomic dataset. At the late phase of wound healing, five secreted, incision-specific peptidases, Mmp2, Aebp1, Mmp23, Adamts7, and Adamtsl1, showed increased expression, supporting the idea of a sustained tissue remodeling process. Transcripts that are specifically upregulated at each timepoint in the incision model may be potential candidates for either biomarkers or therapeutic targets for wound pain and wound healing. This study incorporates the examination of longitudinal temporal molecular responses, corresponding anatomical localization, and hyperalgesic behavioral alterations in the surgical incision model that together provide important and novel foundational knowledge to understand mechanisms of wound pain and wound healing.

中文翻译：

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大鼠足底手术切口模型中的纵向外周组织 RNA-Seq 转录组学分析、痛觉过敏和伤口愈合

手术伤口的术后疼痛和延迟愈合需要复杂的管理策略，但其复杂的机制尚未得到充分研究。在这里，我们分别使用痛觉过敏行为测试、组织学分析和下一代 RNA 测序，研究了手术切口大鼠模型中行为、组织结构和转录组谱的时间变化。表达最快（1 小时）的基因是趋化因子Cxcl1和Cxcl2。因此，从 6 岁开始大量观察到浸润性白细胞，并在切开后 24 小时达到峰值，这得到了组织学分析和中性粒细胞标志物S100a8和S100a9出现的支持。. 此时，痛觉过敏达到顶峰，整体转录活性最高。在 1 天的时间点，编码利钠肽前体 B 的Nppb是最强烈上调的基因，并且通过原位杂交定位到切口边缘的表皮角质形成细胞。Nppb在外周炎症模型转录组数据集中基本不受影响。在伤口愈合的后期，五种分泌的切口特异性肽酶Mmp2、Aebp1、Mmp23、Adamts7和Adamtsl1，表现出增加的表达，支持持续组织重塑过程的想法。在切口模型中的每个时间点特异性上调的转录本可能是用于伤口疼痛和伤口愈合的生物标志物或治疗靶点的潜在候选者。本研究结合了对手术切口模型中纵向时间分子反应、相应解剖定位和痛觉过敏行为改变的检查，这些共同提供了重要且新颖的基础知识，以了解伤口疼痛和伤口愈合的机制。