大鼠經誘導胃穿孔後，其神經生長因子在心血管系統的表現以及其生理意義

神經系統的功能以及分佈受到末端器官分泌的生長因子所調控。分布於心血管系統的自律神經系統對於心跳速率、血壓、波傳導速率、收縮及舒張功能均扮演相當重要的調控角色。在嚴重敗血症等末期病患，自律神經系統常常出現失調的情形。儘管這樣的情形已經在許多內毒素血症或敗血症的動物模式中被驗證，關於導致心血管自律神經系統失調的詳細機轉卻仍然有待研究。消化性潰瘍是很普遍的疾病，包括十二指腸潰瘍及胃潰瘍，嚴重的潰瘍甚至可能導致胃穿孔。胃潰瘍穿孔所引發的腹膜炎會使血液中發炎性的細胞激素大量增加，可能導致自律神經病變，包含了支配心臟與血管之自律神經纖維的傷害，這將導致心跳與血管力學調控的異常。有甚多的方法與分析技術己被發展來探討心臟自律神經活性的改變，例如心跳變異(heart rate variability, HRV)之頻譜分析，其分析資訊可當作交感神經與副交感神經對心血管系統之調控的指標，心跳變異之低頻分量對高頻分量的比值可用來評估自律神經系統之交感與迷走對心臟調控的平衡度。在本研究中的第一部分，我們發現大鼠經過誘導胃穿孔後，血液中的內皮素會大量上升，同時心臟中的神經生長因子和神經生長指標蛋白表現也會增加，伴隨HRV分析中低頻分量的雙相（biphasic）變化。如果利用類固醇抑制胃穿孔後的發炎反應，則內皮素及神經生長因子的表現將會被抑制，HRV低頻分量的雙相變化也隨之延遲。在實驗的第二部分，我們進一步研究系統性發炎對於動物體主動脈中內皮素/神經生長因子路徑的影響，更進一步的去研究這路徑的活化是否與神經新生有關聯。我們以手術方式誘發大鼠的胃穿孔以及系統性發炎，之後以免疫染色方式測定主動脈中神經生長因子及神經新生指標(growth-associated protein 43)的分布量，發現胃穿孔的確誘發大鼠主動脈中神經生長因子及神經新生指標的表現。利用大鼠胃穿孔的實驗模型，我們的實驗結果顯示，心血管系統中的神經生長因子會在遠端發炎的情形下被誘發表現，同時伴隨神經新生及自律神經活性的改變。本研究結果將可提供吾人對系統性發炎反應與心血管自律神經系統之間的交互作用，以及其調控機制的了解，並提供臨床上對於治療時機的基礎。

關鍵字

系統性發炎；神經生長因子；自律神經失調；自動回歸演算方法；胃穿孔；心跳變異；發炎性細胞激素

並列摘要

Neuronal function and innervation density is regulated by target organ-derived neurotrophic factors. The cardiovascular autonomic nerve plays an important role in modulating heart rate, blood pressure, wave conducting velocity, myocardial contraction, and relaxation. Autonomic modulation can frequently be altered in septic and critically ill patients. Although several studies have shown the change of autonomic system controlling the cardiovascualr in endotoxemic and/or septic models, little is known about the mechanism that regulates the change of autonomic dysfunction during endoxemia and sepsis. Peptic ulcer disease represents a common disease entity and results in symptoms of a variable severity in about 10% of the patients who suffer it. Peritonitis due to gastric ulcer perforation will significantly increase the pro-inflammatory cytokines in blood and therefore encompass damage to the autonomic nerve fibers that innervate the heart and blood vessels, resulting in abnormalities in heart control and vascular dynamics. There are many techniques developed to study changes in autonomic cardiac activity in diabetic neuropathy. Heart rate (HR) variability is viewed as an index of sympathetic and parasympathetic modulation of the cardiovascular system. It has been shown that cardiovascular variability in the low-frequency (LF) band but not the high-frequency (HF) band largely reflex the integrity of the baroreflex control of both peripheral resisatnce and of heart rate in humans, in rats, and in mice. Meanwhile, the ratio of the normalized spectral powers of the LF and HF components of HR variability provides a measure of the autonomic sympatho-vagal balance in the heart control. In the first part of our study, gastric perforation (GP) resulted in upregulation of plasma endothelin (ET) -1, cardiac nerve growth factor (NGF), growth associtated protein (GAP) 43 and tyrosine hydroxylase (Th) expression that coincided with recovery of cardiac autonomic sympatho-vagal balance. GP-induced NGF upregulation and the restoration of autonomic balance can be effectively blocked by methyprednisolone. In the second part of this study, we investigated whether systemic inflammation can activate ET-1/NGF pathway in aorta, as it did in the heart. We further examined whether this activation is associated with aortic nerve sprouting.GP and inflammation was induced by surgery in Wistar rats. The aortic NGF expression and the GAP43 was examined by immunohistochemical staining. We found that GP resulted in upregulation of aortic NGF that coincided with aortic nerve sprouting. Methylprednisolone effectively blocked GP-induced NGF upregulation. By using the GP animal model, we concluded that remote inflammation leads to enhanced cardiovascular expression of NGF, which coincides nerve sprouting and the change of autonomic activity. Results from this study provide an insight view of how systemic inflammation influences the cardiovascular autonomic system and the possible underlying mechanisms, which may be helpful for the clinical therapy of inflammation in the future.

並列關鍵字

systemic inflammation ； nerve growth factor ； autonomic dysregulation ； autoregressive method ； gastric perforation ； heart rate variability ； pro-inflammatory cytokines

參考文獻

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國際替代計量

大鼠經誘導胃穿孔後，其神經生長因子在心血管系統的表現以及其生理意義

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