The Study Of Oxidative Stress And Inflammatory Reaction In Preeclampsia

Background Preeclampsia (PE ) is a complication unique to human pregnancy which cause largely remains to be understood. Although the mechanisms underlying the pathogenesis are not fully understood, oxidative stress and a generalized inflammatory state are features of the maternal syndrome.Up to date, many theories regarding its etiology and pathogenesis have been proposed. Of these theories, endothelial dysfunction, existed before the onset of PE, has been widely considered as playing an important role in the progression of PE. Several lines of evidence support oxidative stress and systemic inflammation are involved in the pathogenesis of PE. Some authorities believe that a systemic maternal inflammatory response to pregnancy is responsible for the endothelial dysfunction. Previous studies have provided evidence that PE results from exaggeration of a maternal systemic inflammatory response common to all pregnancies. Factors in the maternal circulation might induce oxidative stress and/or elicit an inflammatory response in the maternal endothelium, resulting in the altered expression of several genes involved in the regulation of vascular tone.The theory is consistent with many of the clinical observations and associations of PE. However, little is known about the association between oxidative stress and levels of inflammatory markers for PE. On the assumption that the effects of inflammatory reaction and oxidative stress and their interactions on vascular endothelial cells in PE patients and consequently contribute to the development of PE, changes in the production of oxidative stress (MDA,ox-LDL and 8-isoprostane)and inflammatory reaction markers (hs-CRP,IL-6,TNF-α) were measured in the plasma to investigate whether these changes would contribute to the occurrence or the development of PE.In addition, PE has many of the same pathophysiologic features as atherosclerosis. Endothelial dysfunction, insulin resistance and inflammation have been recognized features in PE. Many of adipocytes hormones such as tumor necrosis factor (TNF)- , leptin, adiponectin , and interleukin (IL)-6, collectively called adipokines, play important roles in the inflammatory and atherosclerotic processes. Adiponectin, one of the most abundant adipose tissue-specific proteins, is exclusively expressed and secreted from adipose tissue, which has been considered to improve insulin sensitivity and inhibit vascular inflammation and have anti-atherogenic effects. Hypoadiponectinemia has been found and considered as an independent risk factor in hypertension, especially in PE.Like adiponectin, leptin is yet another adipocytokine that is thought to have some role in regulating insulin sensitivity. Previous studies have suggested that leptin is increased in PE. The present study therefore hypothesized that there would be an inverse correlation between adiponectin and leptin in PE.Cyclooxygenase is the key enzyme in the biosynthesis of prostaglandins and thromboxane from arachidonic acid. Two isoenzymes,COX-1 and COX-2, have been identified,the former as a regulator of physiologic functions and the latter as a mediator in pathophysiologic reactions such as inflammation. COX-1 and COX-2 are expressed in the placental tissue samples and several studies have reported that placental levels of COX-2 were increased in the placentas of healthy pregnant women in labor at term. But there are controversial data regarding COX-2 levels or activities in the placentas of women with PE, which have been found increased,unchanged or decreased.The present study is divided into three parts as follows. Part I The Study of Oxidative Stress and Inflammatory Reaction in PreeclampsiaObjective The purpose of the present study was to investigate the changes in plasma markers of oxidative stress and inflammatory reaction in preeclampsia(PE) and to evaluate their clinical significance and interactions in the pathogenesis of preeclampsia. Methods A prospective study was conducted involving 53 women with PE(study group:including 32 cases of mild PE and 21 severe PE) and 20 normotensive pregnant women(control group) in the third trimester. The plasma concentrations of high-sensitive C-reactive protein (hs-CRP),interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha),malondialdehyde(MDA),and 8-isoprostane were determined. Results①The plasma comcentrations of hs-CRP,IL-6,TNF-alpha, 8-isoprostane and ox-LDL were significantly higher in the study group [(2.17±1.29)mg/L, (26.49±12.73)pg/ml, (18.47±4.17)pg/ml,(153.07±44.84)pg/ml, (772.04±151.00)μg/L, respectively] than those of the control(P<0.01,or P<0.05),while no significant differences were noted between the plasma levels of MDA in these two groups [(5.25±0.11)μmol/L vs (4.67±0.38)μmol/L, P>0.05].②The plasma levels of hs-CRP,IL-6,TNF-alpha, and 8-isoprostane were markedly elevated in the severe PE group[(2.84±1.76)mg/L, (27.27±18.38)pg/ml, (22.13±12.35)pg/ml, (163.99±51.01) pg/ml, respectively] than those mild PE group (P<0.01,or P<0.05),while there were no significant differences between the plasma levels of MDA as well as ox-LDL between the MPE and SPE group[(5.49±0.15)μmol/L vs (5.08±0.19)umol/L,P>0.05; (809.29±211.83)μg/L vs (741.66±190.73)μg/L,P>0.05].③Plasma levels of 8-isoprostane were significantly correlated with the plasma levels of hs-CRP,IL-6,and TNF-alpha in PE women (r=0.618,P<0.01; r=0.689,P<0.01;r=0.712,P<0.01;respectively). But plasma levels of MDA were uncorrelated with the plasma levels of hs-CRP,IL-6,and TNF-alpha (r=0.168,P>0.05;r=0.113,P>0.05;and =0.110,P>0.05,respectively). In addition, no significant relationship was observed between plasma levels of ox-LDL and hs-CRP, IL-6 and TNF-alpha in PE women (r=0.140, P>0.05;r=0.134,P>0.05;and r=0.144, P>0.05, respectively). Conclusion Oxidative stress and inflammatory reaction are closely associated with PE, and the interactions play an important role in the pathogenesis of PE. Antioxidant treatment and anti-inflammatory treatment may prevent the onset and progression of PE.Part II The Study of Relationship between Adipocytokine and PreeclampsiaObjective To explore the role of adipocytokine, adiponectin and leptin,in the pathogenesis of preeclampsia(PE). Methods The serum levels of adiponectin and leptin were measured using the enzyme-linked immunosorbent assay in 53 PE patients and 20 normal pregnant women. Seventy-three women were divided into three groups: group A consisted of 20 normotensive pregnant women (NPW); group B consisted of 32 women with mild preeclampsia (MPE); and group C consisted of 21 women with severe preeclampsia (SPE). Results The serum levels of adiponectin in women with MPE or SPE were significantly lower (8.88±4.67 ng/ml,5.14±2.79 ng/ml,respectively)than those in NPW(11.61±2.90ng/ml; bothP<0.01) .While the serum levels of leptin in women with MPE or SPE were significantly higher than those in NPW(MPE: 21.79±15.19 ng/ml versus 12.35±6.51 ng/ml,P<0.05; SPE: 27.27±18.38 ng/ml versus 12.35±6.51 ng/ml,P<0.01). In the pre-eclamptic women serum levels of triglycerides(TG),total cholesterol(TC) and low-density lipoprotein -cholesterol(LDL-C) were significantly increased (P<0.01),while high-density lipoprotein -cholesterol(HDL-C) were significantly decreased compared to levels in NPW (P<0.01). Serum levels of adiponectin were correlated significantly with TG, TC, LDL-C, and HDL-C in pre-eclamptic women (r=-0.658,P<0.01;r=-0.624,P<0.01; r=-0.419,P<0.05; r= 0.461, P<0.05, respectively). In addition,serum levels of leptin were significantly correlated with the serum levels of TG, TC,LDL-C,and HDL-C in pre-eclamptic women (r=0.534,P<0.05;r=0.707,P<0.01;r=0.418, P<0.05;and r=-0.513, P<0.01, respectively). There was a negative correlation between the serum levels of adiponectin and leptin in preeclamptic women (r=-0.760,P<0.01). Conclusion These findings suggest that adiponectin and leptin may be involved in the pathogenesis of PE. Moreover,reduced serum concentrations of adiponectin and elevated leptin are associated with development of severe disease.Part III The Study of COX-2 in PreeclampsiaObjective The purpose of the present study was to investigate the expression of cyclooxyygenase-2(COX-2)in placentas with preeclapsia(PE) and to evaluate its clinical significance. Methods Placentas of 32 PE pregnancies(PE group) and 20 normotensive pregnancies(control group) were investigated for COX-2 protein and mRNA expression using immunohistochemistry and RT-PCR. Results There was no statistical difference in the expression positive rate of COX-2 protein between PE group and control group(65.5% vs 50%, P>0.05). Similarly,no significant difference was noted between the mRNA levels in the PE group and those in control group[(0.50±0.22) vs (0.44±0.17), P>0.05]. Conclusion Our findings suggest that the role of COX-2 in the pathogenesis of PE is uncertain and complicated.