Cross-Talk between Oxidative Stress and Inflammation in Preeclampsia

Abstract

The occurrence of hypertensive syndromes during pregnancy leads to high rates of maternal-fetal morbidity and mortality. Amongst them, preeclampsia (PE) is one of the most common. This review aims to describe the relationship between oxidative stress and inflammation in PE, aiming to reinforce its importance in the context of the disease and to discuss perspectives on clinical and nutritional treatment, in this line of research. Despite the still incomplete understanding of the pathophysiology of PE, it is well accepted that there are placental changes in pregnancy, associated with an imbalance between the production of reactive oxygen species and the antioxidant defence system, characterizing the placental oxidative stress that leads to an increase in the production of proinflammatory cytokines. Hence, a generalized inflammatory process occurs, besides the presence of progressive vascular endothelial damage, leading to the dysfunction of the placenta. There is no consensus in the literature on the best strategies for prevention and treatment of the disease, especially for the control of oxidative stress and inflammation. In view of the above, it is evident the important connection between oxidative stress and inflammatory process in the pathogenesis of PE, being that this disease is capable of causing serious implications on both maternal and fetal health. Reports on the use of anti-inflammatory and antioxidant compounds are analysed and still considered controversial. As such, the field is open for new basic and clinical research, aiming the development of innovative therapeutic approaches to prevent and to treat PE.

Figure 1

Mitochondrial production of some reactive oxygen species. The reduced perfusion due to impaired trophoblastic invasion triggers a condition of oxidative stress in the placenta by some mechanisms: (a) perfusion that can lead to repeated hypoxia/reoxygenation, a potent stimulus for the activation of the xanthine oxidase and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), enzymes that are important precursors in the formation of O₂^•− [–30]; (b) the hypoxia/reperfusion also stimulates the electron transport chain, specifically complexes I and III [31], which increases the O₂^•− production [28]. In the mitochondrial matrix, manganese superoxide dismutase (MnSOD) or copper and zinc superoxide dismutase (CuZnSOD) in the intermembrane space catalyzes the conversion of O₂^•− to hydrogen peroxide (H₂O₂). H₂O₂ can then be completely reduced to water by antioxidant enzymes, such as glutathione peroxidase (GPx) or catalase (CAT) [32, 33]. Adapted from Yiyenoğlu et al. [28], Redman [29], Poston et al. [30], Chamy et al. [32], and Raijmakers et al. [33].

Figure 2

Mechanisms suggested in the pathophysiology of preeclampsia. The process of abnormal trophoblastic invasion, which culminates in repeated episodes of hypoxia/reperfusion, leads to the oxidative stress in PE. In turn, the process of hypoxia/reperfusion culminates with greater production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and lipid peroxides, while the antioxidant defence is reduced, including SOD, GPx, and CAT, leading to an increased systemic oxidative stress condition, besides other factors resulting from oxidative stress, including damaged DNA, low-density lipoprotein (LDL) oxidation, and reduction in melatonin production [37]. Thus, there is a concomitant increase of the inflammatory response, through the cytokine production, such as tumor necrosis factor alpha (TNF-α) and interleukin- (IL-) 6, which led to a reduction in the anti-inflammatory cytokine production, such as IL-10, and, consequently, cell damage [14, 36]. In the inflammatory response, there is the involvement of genes related to oxidative stress, especially the nuclear factor kappa B (NF-κB), located in the cellular cytoplasm. ROS are able to oxidize the IκB kinase (IKK) complex, leading to the release of NF-κB, which is formed by p50 and p65 subunits. Because it is a nuclear factor, the NF-κB molecule enters the cell nucleus and promotes the transcription of several proinflammatory cytokines such as IL-6 and TNF-α. This process occurs naturally during gestation, but in the PE, its action is exacerbated [39, 96]. Advanced glycation end products (AGEs), resulting from the glycation of proteins or other biomolecules, interact with their receptors (RAGEs) located in a wide variety of tissues. Such interaction is responsible for triggering the activation of several signaling pathways, culminating with the activation of NF-κB, leading to an inflammatory process [52, 53]. Beyond the inflammatory process, PE also results in endothelial dysfunction due to reduced bioavailability of nitric oxide (NO^•) and increased production of placental antiangiogenic factors, such as dimethylarginine (ADMA), sEndoglin (soluble endoglin), and Fms-like receptor tyrosine kinase (sFlt-1). The association of these changes leads to health consequences, such as cardiovascular-, endothelial-, renal-, and fetal-related complications [38]. Legend: ADMA: dimethylarginine; AGE: advanced glycation end products; CAT: catalase; GPx: glutathione peroxidase; IL: interleukin; LP: lipid peroxides; NADPH oxidase: nicotinamide adenine dinucleotide phosphate oxidase; NF-κB: nuclear factor kappa B; ONOO⁻: peroxynitrite; PIGF: placental growth factor; RAGE: advanced glycation end product receptors; RNS: reactive nitrogen species; ROS: reactive oxygen species; sFlt-1: soluble Fms-like receptor tyrosine kinase; SOD: superoxide dismutase; TGFB1: transforming growth factor beta; TNF-α: tumor necrosis factor alpha; VEGF: vascular endothelial growth. Adapted from Sanchéz-Araguren et al. [14], Harmon et al. [36], Chiarello et al. [37], Cheng et al. [38], Striz et al. [39], Rayman et al. [96], Sargent et al. [52], and Guedes-Martins et al. [53].

Figure 3

Routes through which the bioavailability of nitric oxide decreases in preeclampsia. Some pathways can contribute to the lower bioavailability of NO^• in the PE. The first one involves ROS, where it is suggested that O₂^•− captures NO^• for the formation of peroxynitrite (ONOO⁻), which has a high redox potential [13]. In addition, ONOO⁻ reacts with lipids, leading to lipid peroxidation (LP) and generation of malondialdehyde (MDA) and its conjugates [97]. The second path involves the increase in the production of the enzyme arginase, responsible for catalyzing the conversion of L-arginine to L-ornithine and urea [98]. Therefore, the bioavailability of arginine for NO^• formation is compromised [99, 100]. The last one involves the presence of ADMA, an endogenous inhibitor of the enzyme nitric oxide synthase (eNOS), which is increased in PE and is able to decrease the synthesis of NO^• [14]. Legend: ADMA: dimethylarginine; NOS: nitric oxide synthase. Adapted from Sanchéz-Araguren et al. [14], Sankaralingam et al. [13], Takacs et al. [97], Rabelo et al. [98], Coman et al. [99], and Morris Jr. [100].