Transplantation/Immunology
Cordyceps sinensis Extracts Attenuate Aortic Transplant Arteriosclerosis in Rats

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Background

Transplant arteriosclerosis is a hallmark of chronic rejection and is still the major limiting factor affecting the success of long-term organ transplants. Development of transplant arteriosclerosis is refractory to conventional immunosuppressive drugs, and adequate therapy is not yet available. The aim of this study was to determine the role of Cordyceps sinensis extracts in reducing the formation of transplant arteriosclerosis in a rat aortic transplant model.

Methods

Lewis rat aortic allografts were transplanted into Brown-Norway recipient rats. Recipients received 0.5, 1, 2, and 5 mg/kg of Cordyceps sinensis extracts (or control saline) daily via intragastric injection for 60 d. Grafts were harvested 60 d post-transplantation and intimal thickness determined microscopically following hematoxylin and eosin (H and E) staining and abdominal aorta protein profiles determined by Western blot analysis. Cellular localization was assessed by histology and immunohistochemistry and the serum analyzed for tumor necrosis factor alpha (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) by enzyme-linked immunosorbent assay (ELISA).

Results

C. sinensis administration resulted in a significant reduction in neointimal formation (neointimal thickness 8.27 ± 1.95 μm [0.5 mg/kg], 3.69 ± 1.43 μm [1 mg/kg], 3.69 ± 1.43 μm [1 mg/kg], 3.69 ± 1.43 μm [1 mg/kg] versus 11.42 ± 2.67 μm [control]) and in the proliferative activity of vascular smooth muscle cells. In addition, localized expression of TNF-α and ICAM-1 in transplant aortas was characterized by immunohistochemistry and immunoblot analyses demonstrating that C. sinensis treatment significantly reduced TNF-α and ICAM-1 levels compared with levels observed in controls (P < 0.05). Serum TNF-α and ICAM-1 levels were significantly reduced in C. sinensis-treated animals compared with controls (P < 0.05).

Conclusion

C. sinensis treatment effectively reduced the formation of transplant arteriosclerosis in a rat aortic transplant model.

Introduction

Although advances in immunosuppressive therapies have dramatically increased clinical organ transplantation success rates, transplant arteriosclerosis presentation has become a major obstacle in long-term allograft survival, a major cause of late allograft dysfunction and late death in some patients [1]. Therefore, developing new therapies aimed at attenuating transplant arteriosclerosis is critical. Cordyceps sinensis (the Chinese caterpillar fungus) is a highly valued medicinal fungus used in Chinese herbal medicine that has been used in tonics to increase longevity, endurance, and vitality, and its medicinal value has gained worldwide attention in recent years 2, 3. C. sinensis has been shown to have multiple pharmacologic activities, including antiproliferative activities on a variety of tumor cells [4]. Recently, it has also been shown that C. sinensis inhibited the migration and proliferation of VSMC (vascular smooth muscle) and neointima formation [5]. Although these data suggest that C. sinensis possess properties that may affect vascular diseases 5, 6, a defined mechanism for C. sinensis in mediating transplant arteriosclerosis success has not been established. The present study was designed to determine the effects of C. sinensis on the success of transplant arteriosclerosis in a rat model, as well to define potential molecular mechanisms.

Section snippets

Animals

Inbred male BN (Brown-Norway) and Lewis rats weighing between 250 and 300 g were purchased from Beijing Vital River Laboratory. Rats had access to standard rat chow and water ad libitum and were maintained following conditions established by the Guide for the Care and Use of Laboratory Animals.

Cordyceps sinensis Extracts Preparation

C. sinensis was obtained from the Zhongmei Huadong Company (Hangzhou, China). C. sinensis and asexual phase Histutella sinensis isolates were cultured in hydrolysable nutrient media at 15°C for 45 d to

Effect of C. sinensis on Neointimal Thickness

When recipient rats were treated daily with 0.5 mg/kg C. sinensis, neointimal thickness was significantly decreased compared to untreated controls (8.27 ± 1.95 μm versus 11.42 ± 2.67 μm, P < 0.05; Fig. 1). Daily treatment with 1 mg/kg, 2 mg/kg or 5 mg/kg C. sinensis also significantly reduced neointimal thickness compared thickness observed in untreated controls (neointimal thickness of 3.69 ± 1.43 μm [1 mg/kg], 3.78 ± 1.65μm [2 mg/kg], 3.66 ± 1.58 μm [5 mg/kg] versus 11.42 ± 2.67 μm [control];

Discussion

Although currently used immunosuppressive regimens are highly effective in preventing acute rejection, there are no adequate therapies available to prevent or treat chronic transplant disease. The most common histopathologic hallmark of chronic transplant disease is transplant arteriosclerosis 8, 9. Immunosuppressive treatments based on calcineurin inhibition (cyclosporine, tacrolimus), as well as newer second messenger inhibitors such as the mammalian target of rapamycin (mTOR) inhibitors

Acknowledgments

This work was supported by the Zhejiang Provincial Top Key Discipline in Surgery.

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