RESUMEN
PROBLEM: Antiphospholipid syndrome (APS) is characterized by the clinical manifestation of vascular thrombosis (VT) or pregnancy morbidity (PM) and antiphospholipid antibodies (aPL) that can modify the nitric oxide production. Low-dose aspirin is used in the prevention and treatment of diverse alterations of pregnancy. One of the mechanisms of action of aspirin is to induce the production of aspirin-triggered-lipoxins (ATL). The aim of this study was to evaluate the modulatory effect of ATL over the activation of endothelial nitric oxide synthase (eNOS) and nitrosative stress biomarkers induced by aPL. METHODS: We used polyclonal IgG and sera from women with aPL and PM/VT or VT only, and from women with PM only and positive for non-criteria aPL (SN-OAPS). In these sera, biomarkers of nitrosative stress (nitrites and nitrotyrosine) were measured. The protein expression of nitrotyrosine and the phosphorylation of eNOS (at Ser1177) were estimated in human umbilical vein endothelial cells (HUVECs) stimulated with polyclonal IgG with or without ATL. RESULTS: Women with SN-OAPS showed increased circulating levels of nitrites and nitrotyrosine. Likewise, polyclonal IgG from either SN-OAPS or VT patients stimulated nitrotyrosine expression in HUVECs. ATL decreased the nitrotyrosine expression induced by polyclonal IgG from the SN-OAPS group. ATL also recovered the reduced eNOS phosphorylation at Ser1177 in HUVECs stimulated with polyclonal IgG from women with PM/VT or SN-OAPS. CONCLUSIONS: Increased nitrosative stress present in serum of women with SN-OAPS is associated with IgG-mediated impaired endothelial NO synthesis in endothelial cells. ATL prevent these cellular changes.
Asunto(s)
Síndrome Antifosfolípido , Lipoxinas , Embarazo , Humanos , Femenino , Aspirina/farmacología , Aspirina/uso terapéutico , Lipoxinas/farmacología , Óxido Nítrico Sintasa de Tipo III , Estrés Nitrosativo , Nitritos , Células Endoteliales de la Vena Umbilical Humana , Inmunoglobulina GRESUMEN
PROBLEM: Oxidative stress and inflammation are key events leading to pre-eclampsia, involved in several maternal deaths. Low doses of acetylsalicylic acid (ASA) are used in the prevention and treatment of pre-eclampsia. The synthesis of aspirin-triggered lipoxin (ATL) by cyclooxygenase-2 acetylation is an alternative mechanism of ASA, which could explain the effectiveness of ASA treatments. The aim of this study was to evaluate the role of ASA, salicylates, and ATL in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia. METHOD OF STUDY: Plasma from 14 women with pre-eclampsia and 17 normotensive pregnant women was probed for inducing oxidative and inflammatory responses on endothelial cells and U937 promonocytes. The role of ATL, ASA, and salicylic acid (SA) on these events was evaluated. RESULTS: Plasma from women with pre-eclampsia induced TBARS and nitrotyrosine production on endothelial and U937 cells. Pre-treatment with both ATL and ASA decreased the TBARS production, while ATL decreased the nitrotyrosine. Pre-eclamptic plasma augmented the translocation of NF-kB on U937 cells, which decreased by a high dose of ASA and SA. Finally, the pre-eclamptic plasma increased the adhesion of leukocytes-PMN and monocytes-to endothelium, and we were able to determine a state of resolution of inflammation, since ATL decreased the PMN adhesion, and conversely, it increased the monocytes adhesion to endothelium. CONCLUSION: Together, these results suggest that ATL could explain the beneficial actions of ASA and support further research on mechanisms, real efficacy, and rational use of ASA in pre-eclampsia.
Asunto(s)
Aspirina/uso terapéutico , Lipoxinas/sangre , Estrés Oxidativo/efectos de los fármacos , Preeclampsia/sangre , Ácido Salicílico/sangre , Acetilación , Adolescente , Adulto , Aspirina/sangre , Aspirina/farmacología , Adhesión Celular/efectos de los fármacos , Ciclooxigenasa 2/sangre , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inflamación/sangre , Lipoxinas/biosíntesis , Lipoxinas/farmacología , FN-kappa B/metabolismo , Neutrófilos/efectos de los fármacos , Preeclampsia/tratamiento farmacológico , Preeclampsia/prevención & control , Embarazo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Ácido Salicílico/farmacología , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Tirosina/análogos & derivados , Tirosina/biosíntesis , Células U937 , Adulto JovenRESUMEN
Problem Oxidative stress and inflammation are key events leading to pre-eclampsia, involved in several maternal deaths. Low doses of acetylsalicylic acid (ASA) are used in the prevention and treatment of pre-eclampsia. The synthesis of aspirin-triggered lipoxin (ATL) by cyclooxygenase-2 acetylation is an alternative mechanism of ASA, which could explain the effectiveness of ASA treatments. The aim of this study was to evaluate the role of ASA, salicylates, and ATL in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre-eclampsia. Method of study Plasma from 14 women with pre-eclampsia and 17 normotensive pregnant women was probed for inducing oxidative and inflammatory responses on endothelial cells and U937 promonocytes. The role of ATL, ASA, and salicylic acid (SA) on these events was evaluated. Results Plasma from women with pre-eclampsia induced TBARS and nitrotyrosine production on endothelial and U937 cells. Pre-treatment with both ATL and ASA decreased the TBARS production, while ATL decreased the nitrotyrosine. Pre-eclamptic plasma augmented the translocation of NF-kB on U937 cells, which decreased by a high dose of ASA and SA. Finally, the pre-eclamptic plasma increased the adhesion of leukocytes—PMN and monocytes—to endothelium, and we were able to determine a state of resolution of inflammation, since ATL decreased the PMN adhesion, and conversely, it increased the monocytes adhesion to endothelium. Conclusion Together, these results suggest that ATL could explain the beneficial actions of ASA and support further research on mechanisms, real efficacy, and rational use of ASA in pre-eclampsia.
RESUMEN
Aspirin is one of the most frequently used and cheapest drugs in medicine. It belongs to the non-steroidal anti-inflammatory drugs with a wide range of pharmacological activities, including analgesic, antipyretic, and antiplatelet properties. Currently, it is accepted to prescribe a low dose of aspirin to pregnant women who are at high risk of preeclampsia (PE) because it reduces the onset of this complication. Another pregnancy alteration in which a low dose of aspirin is recommended is the obstetric antiphospholipid syndrome (APS). The most recognized mechanism of action of aspirin is to inhibit the synthesis of prostaglandins but this by itself does not explain the repertoire of anti-inflammatory effects of aspirin. Later, another mechanism was described: the induction of the production of aspirin-triggered lipoxins (ATLs) from arachidonic acid by acetylation of the enzyme cyclooxygenase-2. The availability of a stable analog of ATL has stimulated investigations on the use of this analog and it has been found that, similar to endogenously produced lipoxins, ATL resolves inflammation and acts as antioxidant and immunomodulator. If we consider that in PE and in the obstetric APS, there is an underlying inflammatory process, aspirin might be used based on the induction of ATL. The objective of this review is to revisit the old and new mechanisms of action of aspirin. In particular, it intends to show other potential uses of this drug to prevent certain pregnancy complications in the light of its ability to induce anti-inflammatory and pro-resolving lipid-derived mediators.
RESUMEN
La preeclampsia es un síndrome hipertensivo que se presenta a partir de la semana 20 de gestación. El objetivo de este trabajo es describir la producción y los mecanismos de acción de las lipoxinas inducidas por la aspirina y proponerlas como una alternativa adecuada para modular los procesos oxidativos característicos de la preeclampsia y los ciclos proinflamatorios que inician con la cascada de activación del factor nuclear-kappa B, y en consecuencia de sus productos. La preeclampsia se caracteriza por la producción de sustancias proinflamatorias, que inducen la activación de células endoteliales, directa o indirectamente, a través de la activación previa de los monocitos, los cuales pueden generar especies reactivas de oxígeno y expresar moléculas de adhesión que median la interacción con el endotelio, contribuyendo a su estado de disfunción, activación e inducción de la cascada de señalización del factor nuclear-kappa B. La aspirina por su parte, induce la producción de lipoxinas que inhiben la activación del factor nuclear-kappa B mediante el bloqueo de la proteína quinasa IkB, necesaria para desencadenar la activación de la vía canónica y no canónica de este factor nuclear.
Preeclampsia is a hypertensive syndrome that occurs after the 20th weeks of gestation. The objective of this review was to describe the mechanisms of production and action of aspirin- triggered lipoxins in order to consider them as a suitable alternative to modulate oxidative processes, which are characteristic of preeclampsia and proinflammatory cycles starting with cascade activation of nuclear factor-kappa B, consequently of their products. Preeclampsia is characterized by the production of proinflammatory substances that induce directly or indirectly endothelial cell activation,, through prior activation of monocytes, which can generate reactive oxygen species and expression of adhesion molecules that mediate interacting with the endothelium, contributing to its dysfunction, activation and induction of signaling cascade nuclear factor-kappa B. Aspirin induces lipoxin, which inhibits the activation of nuclear factor-kappa B by blocking IkB protein kinase, necessary to trigger the activation of canonical and non-canonical pathway of this nuclear factor.