Shock/Sepsis/Trauma/Critical care
The role of neuropeptide Y and aquaporin 4 in the pathogenesis of intestinal dysfunction caused by traumatic brain injury

https://doi.org/10.1016/j.jss.2013.03.096Get rights and content

Abstract

Background

Although the exact incidence is unknown, traumatic brain injury (TBI) can lead to intestinal dysfunction. It has important influence on the early nutrition and prognosis of TBI patients. Experiments were designed to study the roles of neuropeptide Y (NPY) and aquaporin 4 (AQP4) in the pathogenesis of intestinal dysfunction caused by TBI and to find some new solutions for the treatment of intestinal dysfunction after TBI.

Methods

Forty adult male Wistar rats were randomly divided into control, mild trauma, moderate trauma, and severe trauma groups. TBI was induced by Feeney's impact method. Control animals were sham operated but not subjected to the impact test. All rats were killed 24 h after surgery. Blood samples were obtained from the abdominal aorta for enzyme-linked immunosorbent assay measurement of NPY concentrations. Jejunum segments 15 cm distal to the Treitz ligament were taken for analysis of NPY and AQP4 expression by polymerase chain reaction, Western blot, and immunohistochemistry. Pathologic changes in intestinal cell structure and ultrastructure were studied by light microscopy and transmission electron microscopy.

Results

The specimens from different groups showed different degrees of structural changes, ranging from swelling and degeneration of villous epithelial cells to extensive denudation and collapse of the villi. The more severe the trauma, the more serious the degree of intestinal mucosal injury. Intestinal smooth muscle also showed varying degrees of edema and structural disorder. Electron microscopy showed that intestinal mitochondria had varying degrees of swelling and the structure of mitochondrial crista was disordered and even fractured. Plasma concentrations of NPY and jejunal gene and protein expressions of NPY and AQP4 increased significantly following TBI (P < 0.05), with greater increases at higher levels of injury. Moreover, there were positive correlations between NPY and AQP4 (P < 0.05).

Conclusions

Increasing grades of TBI caused increasing degrees of intestinal ischemia and edema, and thus caused increasingly severe intestinal dysfunction. AQP4 and NPY may be involved in the pathogenesis of intestinal dysfunction after TBI. Increased NPY levels may be responsible for intestinal ischemia and hypoxia, and AQP4 may play an important role in intestinal edema. Increased NPY levels may be one of the main causes for the increase in AQP4 after TBI.

Introduction

Although the exact incidence is unknown, traumatic brain injury (TBI) can lead to intestinal dysfunction [1]. Its symptoms include anorexia, dyspepsia, abdominal distension, and constipation. Some studies suggest that TBI causes gastrointestinal ischemia and edema [2]. Neuropeptide Y (NPY) is a strong vasoconstrictor [3], and aquaporin 4 (AQP4) plays an important role in the regulation of the intracellular and interstitial water content [4]. Little is known about the interaction between NPY and AQP4 and their roles in intestinal dysfunction after TBI. This study was designed to test the hypothesis that TBI increases the excitability of the sympathetic nervous system, causing an increase in NPY production by sympathetic nerve endings. The subsequent increase in plasma NPY concentrations acts on the intestinal vessels, leading to vascular spasms and contraction, intestinal ischemia, intestinal epithelial cell and intestinal smooth muscle cell hypoxia, and intracellular aerobic metabolic disorders. Increased intracellular concentrations of acidic metabolites such as lactic acid then increase the intracellular osmotic pressure and stimulate AQP4 gene and protein expression, which then increases the membrane permeability for water molecules to reduce the concentrations of intracellular acidic metabolites, protect the organelles, and maintain normal organelle functions. However, the increased influx of water into the cells may lead to cell edema, organelle swelling, increased tension of cell and organelle membranes, and even rupture of the cell membrane and organelle disintegration. This then seriously affects intestinal functions such as the secretion of digestive juices, absorption of nutrients, and intestinal peristalsis.

Section snippets

Experimental animals and grouping

The study was performed according to the guidelines of the Institutional Animal Care Committee of Shanxi Medical University (Taiyuan, China). Forty adult healthy male Wistar rats weighing 280 ± 10 g were obtained from the Animal Center of Shanxi Medical University. The animals were randomly divided into a control group (C, n = 10), a mild trauma group (M1, n = 10), a moderate trauma group (M2, n = 10), and a severe trauma group (S, n = 10).

Animal model and sample preparation

TBI was induced as previously described [5]. Briefly,

Jejunum histology

The specimens of the control group showed normal and typical leaf-like villi crypts. In contrast, the specimens from the mild, moderate, and severe groups showed different degrees of structural changes, ranging from swelling and degeneration of villous epithelial cells to extensive denudation and collapse of the villi. The more severe the grade of trauma, the more serious the degree of intestinal mucosal injury. Similarly, intestinal smooth muscle also showed varying degrees of edema and

Discussion

Although the exact incidence is unknown, TBI can lead to intestinal dysfunction. At present the pathologic mechanism is not yet clear. Some studies speculated that TBI affects gastrointestinal function through the hypothalamus-pituitary-adrenal axis, brain-gut peptides, the vagus nerve in the medulla oblongata, and cytokine pathways [1]. Hang et al. found that some brain-gut peptides in the plasma and small intestine changed significantly after TBI [6]. For example, the concentration of

Acknowledgment

This study was supported by the National Natural Science Foundation Youth Fund (Fund No. 30600637), the Shanxi Province Basic Research Program Youth Science and Technology Research Fund (Fund No. 2010021034-4), the Shanxi Scholarship Council of China (No. 2011-096), and the Technology Innovation Fund of Shanxi Medical University (No. 01201010).

References (19)

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