RESUMEN
Inflammation is associated with the release of soluble mediators that drive cellular activation and migration of inflammatory leukocytes to the site of injury, together with endothelial expression of adhesion molecules, and increased vascular permeability. It is a stepwise tightly regulated process that has been evolved to cope with a wide range of different inflammatory stimuli. However, under certain physiopathological conditions, the inflammatory response overwhelms local regulatory mechanisms and leads to systemic inflammation that, in turn, might affect metabolism in distant tissues and organs. In this sense, as mitochondria are able to perceive signals of inflammation is one of the first organelles to be affected by a dysregulation in the systemic inflammatory response, it has been associated with the progression of the physiopathological mechanisms. Mitochondria are also an important source of ROS (reactive oxygen species) within most mammalian cells and are therefore highly involved in oxidative stress. ROS production might contribute to mitochondrial damage in a range of pathologies and is also important in a complex redox signaling network from the organelle to the rest of the cell. Therefore, a role for ROS generated by mitochondria in regulating inflammatory signaling was postulated and mitochondria have been implicated in multiple aspects of the inflammatory response. An inflammatory condition that affects mitochondrial function in different organs is the exposure to air particulate matter (PM). Both after acute and chronic pollutants exposure, PM uptake by alveolar macrophages have been described to induce local cell activation and recruitment, cytokine release, and pulmonary inflammation. Afterwards, inflammatory mediators have been shown to be able to reach the bloodstream and induce a systemic response that affects metabolism in distant organs different from the lung. In this proinflammatory environment, impaired mitochondrial function that leads to bioenergetic dysfunction and enhanced production of oxidants have been shown to affect tissue homeostasis and organ function. In the present review, we aim to discuss the latest insights into the cellular and molecular mechanisms that link systemic inflammation and mitochondrial dysfunction in different organs, taking the exposure to air pollutants as a case model.
Asunto(s)
Contaminantes Atmosféricos/metabolismo , Mediadores de Inflamación/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiología , Contaminantes Atmosféricos/efectos adversos , Animales , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Mitocondrias/efectos de los fármacos , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Exposure to ambient air particulate matter (PM) is associated with increased cardiorespiratory morbidity and mortality. In this context, alveolar macrophages exhibit proinflammatory and oxidative responses as a result of the clearance of particles, thus contributing to lung injury. However, the mechanisms linking these pathways are not completely clarified. Therefore, the oxinflammation phenomenon was studied in RAW 264.7 macrophages exposed to Residual Oil Fly Ash (ROFA), a PM surrogate rich in transition metals. While cell viability was not compromised under the experimental conditions, a proinflammatory phenotype was observed in cells incubated with ROFA 100 µg/mL, characterized by increased levels of TNF-α and NO production, together with PM uptake. This inflammatory response seems to precede alterations in redox metabolism, characterized by augmented levels of H2O2, diminished GSH/GSSG ratio, and increased SOD activity. This scenario resulted in increased oxidative damage to phospholipids. Moreover, alterations in mitochondrial respiration were observed following ROFA incubation, such as diminished coupling efficiency and spare respiratory capacity, together with augmented proton leak. These findings were accompanied by a decrease in mitochondrial membrane potential. Finally, NADPH oxidase (NOX) and mitochondria were identified as the main sources of superoxide anion () in our model. These results indicate that PM exposure induces direct activation of macrophages, leading to inflammation and increased reactive oxygen species production through NOX and mitochondria, which impairs antioxidant defense and may cause mitochondrial dysfunction.
Asunto(s)
Macrófagos Alveolares/efectos de los fármacos , Mitocondrias/efectos de los fármacos , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Material Particulado/toxicidad , Superóxidos/metabolismo , Contaminantes Atmosféricos/toxicidad , Animales , Antioxidantes/metabolismo , Ceniza del Carbón/toxicidad , Peróxido de Hidrógeno/metabolismo , Inflamación , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Ratones , Mitocondrias/inmunología , Mitocondrias/metabolismo , Oxidación-Reducción , Estrés Oxidativo/inmunología , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Several epidemiological studies have shown a positive correlation between daily increases in airborne particulate matter (PM) concentration and the occurrence of respiratory and cardiovascular diseases. Transition metals present in air PM were associated with adverse health effects after PM exposure. The aim of this work was to study lung O2 metabolism after an acute exposure to transition metal-coated nanoparticles (NPs). Female Swiss mice (25g) were intranasally instilled with a suspension of silica NP containing Ni (II), Cd (II), Fe (III), or Cr (VI) at 0, 0.01, 0.05, 0.1, and 1.0mg metal/kg body weight. Lung O2 consumption was found to be significantly increased after the exposure to most doses of Ni-NP and Fe-NP, and the 0.05mg metal/kg body weight dose of Cr-NP, while no changes were observed for Cd-NP. Lucigenin chemiluminescence (as an indicator of NADPH oxidase (NOX) activity) was evaluated in lung homogenates. Only Ni-NP and Fe-NP have shown the ability to induce a significant increase in lucigenin chemiluminescence. In order to establish the possible occurrence of pulmonary oxidative stress, TBARS levels and the GSH/GSSG ratio were determined. The higher doses of Ni-NP and Fe-NP were able to induce an oxidative stress condition, as shown by changes in both TBARS levels and the GSH/GSSG ratio. Taken together, the present results show differential effects for all the metals tested. These findings emphasize the importance of transition metals present air PM in PM adverse health effects, and contribute to the understanding of the pathological mechanisms triggered by the exposure to environmental PM.
Asunto(s)
Pulmón/efectos de los fármacos , Oxígeno/metabolismo , Material Particulado , Elementos de Transición/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Exposición a Riesgos Ambientales , Femenino , Pulmón/química , Ratones , Modelos Animales , Oxígeno/química , Material Particulado/química , Material Particulado/toxicidad , Elementos de Transición/químicaRESUMEN
PURPOSE: During the postnatal stage, cardiovascular nitric oxide (NO) system and caveolins (cav) may be regulated differentially in response to hypovolemic state induced by water restriction. Our aim was to examine the effects of water restriction on NO synthases (NOS) and cav in the atria, ventricle and aorta of growing rats. METHODS: Male Sprague-Dawley rats aged 25 and 50 days were divided into (n = 15): WR: water restriction 3 days; WAL: water ad libitum 3 days. Systolic blood pressure, NOS activity and NOS/cav protein levels were measured. RESULTS: Dehydration induced a larger increase in SBP in WR25 group. Ventricular NOS activity, endothelial NOS (eNOS) and neuronal isoform (nNOS) of WR25 pups were increased, and both cav were decreased. In the WR50 group, NOS activity remained unchanged. In the atria, NOS activity, eNOS and nNOS decreased in WR25 associated with increased cav-1; in the WR50 group, NOS activity was increased without changes in NOS isoforms. In the aorta of WR25, NOS activity and inducible NOS (iNOS) were decreased; NOS activity was unchanged in WR50, despite the decreased levels of eNOS and increased iNOS, cav-1 and cav-3. CONCLUSIONS: NO system adjustments in cardiovascular system under osmotic stress in vivo depend on postnatal age, being eNOS and nNOS, the isoforms that determine NOS activity in cardiac tissue in 25-day-old pups. Changes in cav abundance during hypovolemic state may contribute to age-related NO production.
Asunto(s)
Sistema Cardiovascular/metabolismo , Caveolina 1/metabolismo , Caveolina 3/metabolismo , Deshidratación , Óxido Nítrico Sintasa de Tipo I/metabolismo , Animales , Presión Sanguínea , Caveolina 1/genética , Caveolina 3/genética , Endotelio/metabolismo , Atrios Cardíacos/metabolismo , Ventrículos Cardíacos/metabolismo , Hemodinámica , Hipovolemia/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Presión Osmótica , Ratas , Ratas Sprague-Dawley , Sustancias Reactivas al Ácido TiobarbitúricoRESUMEN
An adequate redox status is important for maintaining mitochondrial function in inflammatory conditions. The aim of this work was to evaluate the effects of α-lipoic acid (LA) in kidney oxidative metabolism and mitochondrial function in lipopolysaccharide (LPS) treated rats. Sprague-Dawley rats (female, 45 ± 5 days old) were treated with LPS (10 mg kg(-1)) and/or LA (100 mg kg(-1)). It was observed in LPS-treated animals that the LA prevented the increase in 1.2 fold of NO production, decreased (30-40%) mitochondrial complex I-III and IV activities, and decreased (26%) membrane potential and cardiolipin oxidation (76%). No differences were observed in mitochondrial O2 consumption, mitochondrial complex II-III activity, and ATP production when LPS group was compared to LA + LPS group. Based on the improvement of mitochondrial function, the decreased production of mitochondrial NO and restoration of cardiolipin levels, this work provides a new evidence that α-lipoic acid protects kidney from oxidative stress and mitochondrial dysfunction.
Asunto(s)
Inflamación/tratamiento farmacológico , Riñón/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/administración & dosificación , Ácido Tióctico/administración & dosificación , Animales , Femenino , Inflamación/metabolismo , Riñón/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Mitochondrial biogenesis emerges as a compensatory mechanism involved in the recovery process in endotoxemia and sepsis. The aim of this work was to analyze the time course of the cardiac mitochondrial biogenesis process occurring during endotoxemia, with emphasis on the quantitative analysis of mitochondrial function. Female Sprague-Dawley rats (45 days old) were ip injected with LPS (10 mg/kg). Measurements were performed at 0-24 h after LPS administration. PGC-1α and mtTFA expression for biogenesis and p62 and LC3 expression for autophagy were analyzed by Western blot; mitochondrial DNA levels by qPCR, and mitochondrial morphology by transmission electron microscopy. Mitochondrial function was evaluated as oxygen consumption and respiratory chain complex activity. PGC-1α and mtTFA expression significantly increased in every time point analyzed, and mitochondrial mass was increased by 20% (P<0.05) at 24 h. p62 expression was significantly decreased in a time-dependent manner. LC3-II expression was significantly increased at all time points analyzed. Ultrastructurally, mitochondria displayed several abnormalities (internal vesicles, cristae disruption, and swelling) at 6 and 18 h. Structures compatible with fusion/fission processes were observed at 24 h. A significant decrease in state 3 respiration was observed in every time point analyzed (LPS 6h: 20%, P<0.05). Mitochondrial complex I activity was found decreased by 30% in LPS-treated animals at 6 and 24h. Complex II and complex IV showed decreased activity only at 24 h. The present results show that partial restoration of cardiac mitochondrial architecture is not accompanied by improvement of mitochondrial function in acute endotoxemia. The key implication of our study is that cardiac failure due to bioenergetic dysfunction will be overcome by therapeutic interventions aimed to restore cardiac mitochondrial function.
Asunto(s)
Mitocondrias Cardíacas/fisiología , Recambio Mitocondrial , Animales , Autofagia , Temperatura Corporal , Endotoxemia/inmunología , Endotoxemia/metabolismo , Femenino , Lipopolisacáridos/farmacología , Proteínas Asociadas a Microtúbulos/metabolismo , Miocardio/inmunología , Miocardio/metabolismo , Miocardio/patología , Consumo de Oxígeno , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Ratas Sprague-Dawley , Factores de Transcripción/metabolismoRESUMEN
Reactive O2 species production triggered by particulate matter (PM) exposure is able to initiate oxidative damage mechanisms, which are postulated as responsible for increased morbidity along with the aggravation of respiratory diseases. The aim of this work was to quantitatively analyse the major sources of reactive O2 species involved in lung O2 metabolism after an acute exposure to Residual Oil Fly Ashes (ROFAs). Mice were intranasally instilled with a ROFA suspension (1.0mg/kg body weight), and lung samples were analysed 1h after instillation. Tissue O2 consumption and NADPH oxidase (Nox) activity were evaluated in tissue homogenates. Mitochondrial respiration, respiratory chain complexes activity, H2O2 and ATP production rates, mitochondrial membrane potential and oxidative damage markers were assessed in isolated mitochondria. ROFA exposure was found to be associated with 61% increased tissue O2 consumption, a 30% increase in Nox activity, a 33% increased state 3 mitochondrial O2 consumption and a mitochondrial complex II activity increased by 25%. During mitochondrial active respiration, mitochondrial depolarization and a 53% decreased ATP production rate were observed. Neither changes in H2O2 production rate, nor oxidative damage in isolated mitochondria were observed after the instillation. After an acute ROFA exposure, increased tissue O2 consumption may account for an augmented Nox activity, causing an increased O2(-) production. The mitochondrial function modifications found may prevent oxidative damage within the organelle. These findings provide new insights to the understanding of the mechanisms involving reactive O2 species production in the lung triggered by ROFA exposure.
Asunto(s)
Ceniza del Carbón/toxicidad , Contaminantes Ambientales/toxicidad , Pulmón/metabolismo , Mitocondrias/metabolismo , NADPH Oxidasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Administración Intranasal , Animales , Ceniza del Carbón/administración & dosificación , Contaminantes Ambientales/administración & dosificación , Femenino , Pulmón/efectos de los fármacos , Pulmón/enzimología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimologíaRESUMEN
Acute endotoxemia (LPS, 10 mg/kg ip, Sprague Dawley rats, 45 days old, 180 g) decreased the O2 consumption of rat heart (1 mm³ tissue cubes) by 33% (from 4.69 to 3.11 µmol O2/min. g tissue). Mitochondrial O2 consumption and complex I activity were also decreased by 27% and 29%, respectively. Impaired respiration was associated to decreased ATP synthesis (from 417 to 168 nmol/min. mg protein) and ATP content (from 5.40 to 4.18 nmol ATP/mg protein), without affecting mitochondrial membrane potential. This scenario is accompanied by an increased production of O2·â» and H2O2 due to complex I inhibition. The increased NO production, as shown by 38% increased mtNOS biochemical activity and 31% increased mtNOS functional activity, is expected to fuel an increased ONOOâ» generation that is considered relevant in terms of the biochemical mechanism. Heart mitochondrial bioenergetic dysfunction with decreased O2 uptake, ATP production and contents may indicate that preservation of mitochondrial function will prevent heart failure in endotoxemia.
Asunto(s)
Adenosina Trifosfato/biosíntesis , Complejo I de Transporte de Electrón/metabolismo , Endotoxemia/metabolismo , Potencial de la Membrana Mitocondrial , Mitocondrias Cardíacas/metabolismo , Consumo de Oxígeno , Animales , Transporte de Electrón , Endotoxemia/complicaciones , Endotoxemia/patología , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Peróxido de Hidrógeno/metabolismo , Mitocondrias Cardíacas/patología , Óxido Nítrico/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
The aim of this work was to study the time course of the oxidative metabolism in mice lung after exposure to ambient particles (ROFA). Swiss mice were intranasally instilled with a ROFA suspension (0.20 mg/kg). Animals were sacrificed 1 or 3 h after the exposure. Eighty percentage of increased oxygen consumption was observed in tissue cubes after 1 h of exposure. This observation was accompanied by an increased NADPH oxidase activity (40%) and mitochondrial oxygen consumption in state 3 (19%). NO production by lung homogenates was found to be increased by 43% after 3 h of exposure. Phospholipid oxidation in lung homogenates showed a 29% increase after 1 h of exposure, while a 30% increase in the carbonyl content was found only after 3 h of exposure. Our data show the relative importance of different sources of reactive oxygen species (NADPH oxidase activity and mitochondrial respiration) to the increased tissue oxygen consumption, oxidative damage and antioxidant status observed in an acute model of ROFA particles exposure.