Cyclosporin A significantly improves preeclampsia signs and suppresses inflammation in a rat model
Introduction
Preeclampsia (PE) is a pregnancy-specific disorder characterized by the new onset of hypertension and proteinuria following 20 weeks of gestation in a previously normotensive woman. It is one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity worldwide, affecting 2–8% of pregnancies [6], [22]. The only effective treatment for preeclampsia is delivery of the fetus and placenta.
Although many advances have been achieved during the past decades, the precise pathogenesis of this disorder remains elusive. Recently, accumulating evidence indicates that immune system activation and excessive inflammation play a crucial role in the development of preeclampsia [11]. Changes in maternal peripheral blood indicate that pregnancy is associated with a mild yet sustained systemic inflammatory response [17]. Monocytes display increased activation, and this activation seems to be further exaggerated in preeclampsia [13], [16]. Studies have reported increased serum levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines in women with PE compared to normal pregnancy [15]. Several studies have demonstrated that successful pregnancy is a Th1-Th2 co-operation phenomenon with a predominantly Th2-type lymphocyte response [19]. The imbalance of Th1 and Th2 cells and the alterations of the prevalence of Th17 and regulatory T cells have been related to pregnancy disorders, including preeclampsia [3], [18], [26]. Despite preeclampsia being identified as an exaggerated inflammatory state resulting from an altered immune response, currently, there is no novel and effective treatment for preeclampsia targeting the immune system.
Cyclosporine A (CsA) is an immunosuppressant agent that is widely used in clinical practice, predominantly for the prevention of rejection in various types of post-allogenic organ transplantation [10]. In addition to solid organ transplant prophylaxis, CsA has also been used for the treatment of immune-related disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and a wide variety of other autoimmune diseases [5], [7]. In addition, some studies have focused on immune therapy in reproductive system disorders, such as spontaneous miscarriage [23], [27].
Although CsA is administered routinely for the prevention of rejection in various types of post-allogenic organ transplantation and even used in recurrent miscarriage patients, the addition of CsA for the management of preeclampsia has not been reported. In our previous study, we used LPS to successfully induce preeclampsia in a rat model, we found significantly increased serum levels of the inflammatory cytokines TNF-α and IL-1β [8]. Since preeclampsia is associated with increased circulating inflammatory cytokines, it is possible that CsA may down regulate the immune system to decrease inflammatory cytokines and attenuate preeclampsia signs. Therefore, in the present study, we hypothesized that administration of CsA could reduce systolic blood pressure, urinary albumin and proinflammatory cytokines to restore the Th1/Th2 imbalance in the LPS induced rat model of preeclampsia.
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Animals
The Guangzhou Medical University Animal Ethics Committee approved all of the experimental protocols. Sprague-Dawley (SD) rats were purchased from the Medical Experimental Animal Center of Guangdong. Rats were housed in a standard laboratory condition (temperature 23–26 °C, relative humidity 50–60%, illumination between 06:00 am and 06:00 pm) with free access to pellet food and water.
Reagents
LPS (strain Escherichia coli 055:B5, Sigma-Aldrich, St. Louis, MO) and CsA (SandimmunNeoral, Novartis, Switzerland)
Systolic blood pressure
The SBP values in NPC and PC did not change significantly during the study period. There were no significant differences in the SBP values among the 5 groups on GD14 before infusion of LPS or saline solution, but it increased significantly on day 16 after infusion with 1 μg/kg LPS. The higher SBP values in the PE group persisted during the pregnancy. The SBP on GD16 and GD19 in PE group were 124.1 ± 1.2 mmHg and 125 ± 1.4 mmHg. The SBP in PE + CsA5 and PE + CsA10 group were 128.3 ± 1.6 mmHg and 125.4 ± 1.1 mmHg
Discussion
Preeclampsia is a condition characterized by increased inflammatory cytokines. In the present study, we investigated the effects of CsA in a LPS-induced PE model and found that CsA attenuated the LPS-mediated hypertension and urinary proteinuria excretion. In addition, we demonstrated that CsA significantly decreased levels of IL-6, IL-17, IFN-γ and TNF-α that were increased in PE model. In contrast, IL-4 was reduced in the PE model but was increased after CsA treatment.
Recent studies support
Acknowledgments
The authors thank Lijun Dai, Chengjie Liang in Guangzhou Medical University for the help with the animal experiments. This study was supported by Grants from the National Natural Sciences Foundation of China (81170594, 30471828, and 30973206).
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