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The involvement of innate immune mediators to the Zika virus (ZIKV)-induced neuroinflammation is not yet well known. Here, we investigated whether neutrophil extracellular traps (NETs), which are scaffolds of DNA associated with proteins, have the potential to injure peripheral nervous. The tissue lesions were evaluated after adding NETs to dorsal root ganglia (DRG) explants and to DRG constituent cells or injecting them into mouse sciatic nerves. Identification of NET harmful components was achieved by pharmacological inhibition of NET constituents. We found that ZIKV inoculation into sciatic nerves recruited neutrophils and elicited the production of the cytokines CXCL1 and IL-1ß, classical NET inducers, but did not trigger NET formation. ZIKV blocked PMA- and CXCL8-induced NET release, but, in contrast, the ZIKV nonstructural protein (NS)-1 induced NET formation. NET-enriched supernatants were toxic to DRG explants, decreasing neurite area, length, and arborization. NETs were toxic to DRG constituent cells and affected myelinating cells. Myeloperoxidase (MPO) and histones were identified as the harmful component of NETs. NS1 injection into mouse sciatic nerves recruited neutrophils and triggered NET release and caspase-3 activation, events that were also elicited by the injection of purified MPO. In summary, we found that ZIKV NS1 protein induces NET formation, which causes nervous tissue damages. Our findings reveal new mechanisms leading to neuroinflammation by ZIKV.
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Trampas Extracelulares , Infección por el Virus Zika , Virus Zika , Animales , Ratones , Enfermedades Neuroinflamatorias , Nervio CiáticoRESUMEN
Early-stage professionals (ESPs) and senior scientists who want to transition from academia to the industry need support to develop new skills and know-how to endeavor this challenge. However, this topic is significantly underserved in the field of cell and gene therapy, slowing down ESPs' potential to make this step. The authors of this article, members of the ESPs in the South and Central America Subcommittee at the International Society for Cell and Gene Therapy, propose the concept of "scientific venturing," which stands for the process by which scientists become entrepreneurs or part of a company. In our article, we provide key aspects to understand this concept, considering key personality traits that need to be developed and a discussion about the "innovation ecosystem." Later, we consider how scientific venturing may result in an increase in difficulty in nascent innovation ecosystems such as Latin America, in comparison with those more advanced and mature in high-income countries. Finally, we provide key information for the ESPs and other professionals about the stages of private and public investment, including information about the resources needed for the sustainability of companies and startups. Understanding what scientific venturing involves for ESPs is key to taking advantage of the maturity of an innovation ecosystem, its network, and available opportunities.
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Movilidad Laboral , Emprendimiento , Humanos , Investigadores , CienciaRESUMEN
Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3' untranslated region miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells prevents tumour necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC-conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation in vitro When administered in vivo, MSC-conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b-deficient mice were resistant to pulmonary inflammation and injury induced by lipopolysaccharide (LPS) instillation. Silencing of Ocln in miR-193b-deficient mice partially recovered the susceptibility to LPS-induced lung injury. In vivo inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from acute respiratory distress syndrome patients who died with diffuse alveolar damage.
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Lesión Pulmonar Aguda , MicroARNs , Sepsis , Lesión Pulmonar Aguda/terapia , Animales , Tratamiento Basado en Trasplante de Células y Tejidos , Células Endoteliales , Humanos , Ratones , MicroARNs/genética , Sepsis/complicaciones , Sepsis/terapiaRESUMEN
Malaria is caused by Plasmodium infection and remains a serious public health problem worldwide, despite control efforts. Malaria can progress to severe forms, affecting multiple organs, including the brain causing cerebral malaria (CM). CM is the most severe neurological complication of malaria, and cognitive and behavior deficits are commonly reported in surviving patients. The number of deaths from malaria has been reducing in recent years, and as a consequence, neurological sequelae have been more evident. Neurological damage in malaria might be related to the neuroinflammation, characterized by glia cell activation, neuronal apoptosis and changes in the blood-brain barrier (BBB) integrity. The neurovascular unit (NVU) is responsible for maintaining the homeostasis of the BBB. Endothelial and pericytes cells in the cerebral microvasculature and neural cells, as astrocytes, neurons, and microglia, compose the NVU. The NVU can be disturbed by parasite metabolic products, such as heme and hemozoin, or cytokines that can promote activation of endothelial and glial cells and lead to increased BBB permeability and subsequently neurodegeneration. In this review, we will approach the main changes that happen in the cells of the NVU due to neuroinflammation caused by malaria infection, and elucidate how the systemic pathophysiology is involved in the onset and progression of CM.
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Barrera Hematoencefálica , Malaria , Astrocitos , Encéfalo , Humanos , Malaria/complicaciones , NeuronasRESUMEN
Infectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood-brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation.
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Encefalopatías/inmunología , COVID-19/complicaciones , Citocinas/inmunología , Gripe Humana/complicaciones , Malaria/complicaciones , Sepsis/complicaciones , Barrera Hematoencefálica/inmunología , Encefalopatías/prevención & control , COVID-19/inmunología , Humanos , Gripe Humana/inmunología , Malaria/inmunología , Sepsis/inmunologíaRESUMEN
OBJECTIVES: Survivors of sepsis are frequently left with significant cognitive and behavioral impairments. These complications derive from nonresolving inflammation that persists following hospital discharge. To date, no study has investigated the effects of mesenchymal stromal cell therapy on the blood-brain barrier, astrocyte activation, neuroinflammation, and cognitive and behavioral alterations in experimental sepsis. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Government-affiliated research laboratory. SUBJECTS: Male Swiss Webster mice (n = 309). INTERVENTIONS: Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. All animals received volume resuscitation (1 mL saline/mouse subcutaneously) and antibiotics (meropenem 10 mg/kg intraperitoneally at 6, 24, and 48 hours). Six hours after surgery, mice were treated with mesenchymal stromal cells IV (1 × 10 cells in 0.05 mL of saline/mouse) or saline (0.05 mL IV). MEASUREMENTS AND MAIN RESULTS: At day 1, clinical score and plasma levels of inflammatory mediators were increased in cecal ligation and puncture mice. Mesenchymal stromal cells did not alter clinical score or survival rate, but reduced levels of systemic interleukin-1ß, interleukin-6, and monocyte chemoattractant protein-1. At day 15, survivor mice completed a battery of cognitive and behavioral tasks. Cecal ligation and puncture mice exhibited spatial and aversive memory deficits and anxiety-like behavior. These effects may be related to increased blood-brain barrier permeability, with altered tight-junction messenger RNA expression, increased brain levels of inflammatory mediators, and astrogliosis (induced at day 3). Mesenchymal stromal cells mitigated these cognitive and behavioral alterations, as well as reduced blood-brain barrier dysfunction, astrocyte activation, and interleukin-1ß, interleukin-6, tumor necrosis factor-α, and interleukin-10 levels in vivo. In cultured primary astrocytes stimulated with lipopolysaccharide, conditioned media from mesenchymal stromal cells reduced astrogliosis, interleukin-1ß, and monocyte chemoattractant protein-1, suggesting a paracrine mechanism of action. CONCLUSIONS: In mice who survived experimental sepsis, mesenchymal stromal cell therapy protected blood-brain barrier integrity, reduced astrogliosis and neuroinflammation, as well as improved cognition and behavior.
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Barrera Hematoencefálica , Trastornos del Conocimiento , Gliosis , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Sepsis , Animales , Masculino , Ratones , Conducta Animal , Barrera Hematoencefálica/metabolismo , Trastornos del Conocimiento/prevención & control , Modelos Animales de Enfermedad , Gliosis/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Estudios Prospectivos , Sepsis/terapiaRESUMEN
RATIONALE: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. OBJECTIVES: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis. METHODS: We used cell and murine models with gain- and loss-of-function experiments, plasma, and cells from patients with sepsis. MEASUREMENTS AND MAIN RESULTS: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1-/- mice had improved survival and bacterial clearance. DJ-1-/- macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1-/- bone marrow-derived mononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of the NADPH oxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking down DJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst. DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. CONCLUSIONS: These novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.
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Proteína Desglicasa DJ-1/sangre , Sepsis/sangre , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Especies Reactivas de Oxígeno/sangreAsunto(s)
Células Madre Mesenquimatosas , Sepsis , Animales , Barrera Hematoencefálica , Cognición , Gliosis , RatonesRESUMEN
PURPOSE OF REVIEW: Acute respiratory distress syndrome (ARDS) is a multifaceted lung disease with no current effective therapy. Many clinical trials using conventional pharmacologic therapies have failed, suggesting the need to examine alternative approaches. Thus, attention has focused on the therapeutic potential of cell-based therapies for ARDS, with promising results demonstrated in relevant preclinical disease models. We review data concerning the therapeutic promise of cell-based therapies for ARDS. RECENT FINDINGS: Recent experimental studies provide further evidence for the potential of cell-based therapies in ARDS. A number of cell types, particularly mesenchymal stem/stromal cells (MSCs), bone marrow-derived mononuclear cells, endothelial progenitor cells, and embryonic stem cells have been demonstrated to reduce mortality and modulate the inflammatory and remodeling processes in relevant preclinical ARDS models. Multiple insights have emerged in regard to the mechanisms by which cell therapies - particularly MSCs - exert their effects, with evidence supporting direct cell-mediated and paracrine-mediated mechanisms of action. Diverse paracrine mechanisms exist, including the release of cytokines, growth factors (such as keratinocyte growth factor), and antimicrobial peptides, and transfer of cellular contents such as peptides, nucleic acids, and mitochondria via either microvesicular or direct cell-cell contact-mediated transfer. SUMMARY: Cell-based therapies offer considerable promise for the treatment of ARDS. While MSC-based therapies are being rapidly advanced toward clinical testing, clear therapeutic potential exists for other cell types for ARDS. A greater understanding of current knowledge gaps should further enhance the therapeutic potential of cell-based therapies for ARDS.
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Lesión Pulmonar Aguda/terapia , Tratamiento Basado en Trasplante de Células y Tejidos , Trasplante de Células Madre Mesenquimatosas , Síndrome de Dificultad Respiratoria/terapia , Adulto , Tratamiento Basado en Trasplante de Células y Tejidos/tendencias , Femenino , Humanos , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Trasplante de Células Madre Mesenquimatosas/tendencias , Células Madre MesenquimatosasRESUMEN
BACKGROUND/AIMS: Diabetic nephropathy is one of the main causes of end-stage renal disease. The present study investigated the effect of mononuclear cell (MC) therapy in rats subjected to diabetic nephropathy. METHODS: Male Wistar rats were divided into control (CTRL), diabetic (DM), CTRL+MC and DM+MC groups. Diabetes was induced by a single injection of streptozotocin (45 mg/kg, i.p.) and, 4 weeks later, 2×10(7) MCs were injected via the jugular vein. RESULTS: The rats in the DM and DM+MC groups showed increased glycemia, glomerular filtration rate and glomerular tuff area versus control groups. The glomerular filtration rate and glomerular tuff area were normalized in the DM+MC group. No alterations were observed in the fractional excretion of electrolytes and proteinuria between the DM and DM+MC groups. TGF-ß1 protein levels in the DM group were significantly increased versus control animals and normalized in the DM+MC group. An increase in ED1(+)/arginase I(+) macrophages and IL-10 renal expression was observed in the DM+MC group versus DM group. CONCLUSIONS: Bone marrow-derived MC therapy was able to prevent glomerular alterations and TGF-ß1 protein overexpression and modulated glomerular arginase I(+) macrophage infiltration in rats subjected to early diabetic nephropathy.
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Células de la Médula Ósea/citología , Diabetes Mellitus Experimental/cirugía , Nefropatías Diabéticas/cirugía , Leucocitos Mononucleares/trasplante , Animales , Arginasa/metabolismo , Glucemia/análisis , Peso Corporal , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Ectodisplasinas/metabolismo , Tasa de Filtración Glomerular , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Riñón/patología , Leucocitos Mononucleares/citología , Macrófagos/metabolismo , Masculino , Proteinuria , Ratas , Ratas Wistar , Factor de Crecimiento Transformador beta1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: Recent evidence suggests that mesenchymal stem cells may attenuate lung inflammation and fibrosis in acute lung injury. However, so far, no study has investigated the effects of mesenchymal stem cell therapy on the time course of the structural, mechanical, and remodeling properties in pulmonary or extrapulmonary acute lung injury. DESIGN: Prospective randomized controlled experimental study. SETTING: University research laboratory. SUBJECTS: One hundred forty-three females and 24 male C57BL/6 mice. INTERVENTIONS: Control mice received saline solution intratracheally (0.05 mL, pulmonary control) or intraperitoneally (0.5 mL, extrapulmonary control). Acute lung injury mice received Escherichia coli lipopolysaccharide intratracheally (2 mg/kg in 0.05 mL of saline/mouse, pulmonary acute lung injury) or intraperitoneally (20 mg/kg in 0.5 mL of saline/mouse, extrapulmonary acute lung injury). Mesenchymal stem cells were intravenously injected (IV, 1 × 10 cells in 0.05 mL of saline/mouse) 1 day after lipopolysaccharide administration. MEASUREMENTS AND MAIN RESULTS: At days 1, 2, and 7, static lung elastance and the amount of alveolar collapse were similar in pulmonary and extrapulmonary acute lung injury groups. Inflammation was markedly increased at day 2 in both acute lung injury groups as evidenced by neutrophil infiltration and levels of cytokines in bronchoalveolar lavage fluid and lung tissue. Conversely, collagen deposition was only documented in pulmonary acute lung injury. Mesenchymal stem cell mitigated changes in elastance, alveolar collapse, and inflammation at days 2 and 7. Compared with extrapulmonary acute lung injury, mesenchymal stem cell decreased collagen deposition only in pulmonary acute lung injury. Furthermore, mesenchymal stem cell increased metalloproteinase-8 expression and decreased expression of tissue inhibitor of metalloproteinase-1 in pulmonary acute lung injury, suggesting that mesenchymal stem cells may have an effect on the remodeling process. This change may be related to a shift in macrophage phenotype from M1 (inflammatory and antimicrobial) to M2 (wound repair and inflammation resolution) phenotype. CONCLUSIONS: Mesenchymal stem cell therapy improves lung function through modulation of the inflammatory and remodeling processes. In pulmonary acute lung injury, a reduction in collagen fiber content was observed associated with a balance between metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 expressions.
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Lesión Pulmonar Aguda/terapia , Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Trasplante de Células Madre Mesenquimatosas/métodos , Lesión Pulmonar Aguda/fisiopatología , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Colágeno/efectos de los fármacos , Colágeno/metabolismo , Femenino , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/farmacología , Pulmón/patología , Masculino , Metaloproteinasas de la Matriz/efectos de los fármacos , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Mecánica RespiratoriaRESUMEN
Acute cerebral dysfunction is a pathological state common in severe infections and a pivotal determinant of long-term cognitive outcomes. Current evidence indicates that a loss of synaptic contacts orchestrated by microglial activation is central in sepsis-associated encephalopathy. However, the upstream signals that lead to microglial activation and the mechanism involved in microglial-mediated synapse dysfunction in sepsis are poorly understood. This study investigated the involvement of the NLRP3 inflammasome in microglial activation and synaptic loss related to sepsis. We demonstrated that septic insult using the cecal ligation and puncture (CLP) model induced the expression of NLRP3 inflammasome components in the brain, such as NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), caspase-1, and IL-1ß. Immunostaining techniques revealed increased expression of the NLRP3 inflammasome in microglial cells in the hippocampus of septic mice. Meanwhile, an in vitro model of primary microglia stimulated with LPS exhibited an increase in mitochondrial reactive oxygen species (ROS) production, NLRP3 complex recruitment, and IL-1ß release. Pharmacological inhibition of NLRP3, caspase-1, and mitochondrial ROS all decreased IL-1ß secretion by microglial cells. Furthermore, we found that microglial NLRP3 activation is the main pathway for IL-1ß-enriched microvesicle (MV) release, which is caspase-1-dependent. MV released from LPS-activated microglia induced neurite suppression and excitatory synaptic loss in neuronal cultures. Moreover, microglial caspase-1 inhibition prevented neurite damage and attenuated synaptic deficits induced by the activated microglial MV. These results suggest that microglial NLRP3 inflammasome activation is the mechanism of IL-1ß-enriched MV release and potentially synaptic impairment in sepsis.
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Encefalopatía Asociada a la Sepsis , Sepsis , Animales , Ratones , Caspasa 1/metabolismo , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Ratones Endogámicos NOD , Microglía/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sepsis/complicaciones , Sepsis/metabolismo , Encefalopatía Asociada a la Sepsis/metabolismoRESUMEN
Introduction: Sepsis is defined as a multifactorial debilitating condition with high risks of death. The intense inflammatory response causes deleterious effects on the brain, a condition called sepsis-associated encephalopathy. Neuroinflammation or pathogen recognition are able to stress cells, resulting in ATP (Adenosine Triphosphate) release and P2X7 receptor activation, which is abundantly expressed in the brain. The P2X7 receptor contributes to chronic neurodegenerative and neuroinflammatory diseases; however, its function in long-term neurological impairment caused by sepsis remains unclear. Therefore, we sought to evaluate the effects of P2X7 receptor activation in neuroinflammatory and behavioral changes in sepsis-surviving mice. Methods: Sepsis was induced in wild-type (WT), P2X7-/-, and BBG (Brilliant Blue G)-treated mice by cecal ligation and perforation (CLP). On the thirteenth day after the surgery, the cognitive function of mice was assessed using the novel recognition object and Water T-maze tests. Acetylcholinesterase (AChE) activity, microglial and astrocytic activation markers, and cytokine production were also evaluated. Results: Initially, we observed that both WT and P2X7-/- sepsis-surviving mice showed memory impairment 13 days after surgery, once they did not differentiate between novel and familiar objects. Both groups of animals presented increased AChE activity in the hippocampus and cerebral cortex. However, the absence of P2X7 prevented partly this increase in the cerebral cortex. Likewise, P2X7 absence decreased ionized calcium-binding protein 1 (Iba-1) and glial fibrillary acidic protein (GFAP) upregulation in the cerebral cortex of sepsis-surviving animals. There was an increase in GFAP protein levels in the cerebral cortex but not in the hippocampus of both WT and P2X7-/- sepsis-surviving animals. Pharmacological inhibition or genetic deletion of P2X7 receptor attenuated the production of Interleukin-1ß (IL-1ß), Tumor necrosis factor-α (TNF-α), and Interleukin-10 (IL-10). Conclusion: The modulation of the P2X7 receptor in sepsis-surviving animals may reduce neuroinflammation and prevent cognitive impairment due to sepsis-associated encephalopathy, being considered an important therapeutic target.
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Knowledge of the mechanisms that trigger infection-related encephalopathies is still very limited and cell therapies are one of the most promising alternatives for neurodegenerative diseases, and its application in infectious diseases can be of great relevance. Mesenchymal stromal cells are cells with great immunomodulatory potential; therefore, their use in clinical and preclinical studies in a variety of diseases, including central nervous system diseases, increased in the last decade. Mesenchymal stromal cells can exert their beneficial effects through several mechanisms, such as direct cell contact, through surface receptors, and also through paracrine or endocrine mechanisms. The paracrine mechanism is widely accepted by the scientific community and involves the release of soluble factors, which include cytokines, chemokines and trophic factors, and extracellular vesicles. This mini review discusses mesenchymal stromal cells mechanisms of action in neurological disorders, the neuroinflammatory process that takes place in the brain as a result of peripheral inflammation and changes in the brain's cellular scenario as a common factor in central nervous system diseases, and mesenchymal stromal cells therapy in encephalopathies. Mesenchymal stromal cells have been shown to act in neuroinflammation processes, leading to improved survival and mitigating behavioral damage. More recently, these cells have been tested in preclinical models of infectious diseases-associated encephalopathies (e.g., cerebral malaria and sepsis associated encephalopathy) and have shown satisfactory results.
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Infectious diseases of different etiologies have been associated with acute and long-term neurological consequences. The primary cause of these consequences appears to be an inflammatory process characterized primarily by a pro-inflammatory microglial state. Microglial cells, the local effectors' cells of innate immunity, once faced by a stimulus, alter their morphology, and become a primary source of inflammatory cytokines that increase the inflammatory process of the brain. This inflammatory scenario exerts a critical role in the pathogenesis of neurodegenerative diseases. In recent years, several studies have shown the involvement of the microglial inflammatory response caused by infections in the development of neurodegenerative diseases. This has been associated with a transitory microglial state subsequent to an inflammatory response, known as microglial priming, in which these cells are more responsive to stimuli. Thus, systemic inflammation and infections induce a transitory state in microglia that may lead to changes in their state and function, making priming them for subsequent immune challenges. However, considering that microglia are long-lived cells and are repeatedly exposed to infections during a lifetime, microglial priming may not be beneficial. In this review, we discuss the relationship between infections and neurodegenerative diseases and how this may rely on microglial priming.
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OBJECTIVE: To investigate the effects of the rate of airway pressure increase and duration of recruitment maneuvers on lung function and activation of inflammation, fibrogenesis, and apoptosis in experimental acute lung injury. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: Thirty-five Wistar rats submitted to acute lung injury induced by cecal ligation and puncture. INTERVENTIONS: After 48 hrs, animals were randomly distributed into five groups (seven animals each): 1) nonrecruited (NR); 2) recruitment maneuvers (RMs) with continuous positive airway pressure (CPAP) for 15 secs (CPAP15); 3) RMs with CPAP for 30 secs (CPAP30); 4) RMs with stepwise increase in airway pressure (STEP) to targeted maximum within 15 secs (STEP15); and 5) RMs with STEP within 30 secs (STEP30). To perform STEP RMs, the ventilator was switched to a CPAP mode and positive end-expiratory pressure level was increased stepwise. At each step, airway pressure was held constant. RMs were targeted to 30 cm H2O. Animals were then ventilated for 1 hr with tidal volume of 6 mL/kg and positive end-expiratory pressure of 5 cm H2O. MEASUREMENTS AND MAIN RESULTS: Blood gases, lung mechanics, histology (light and electronic microscopy), interleukin-6, caspase 3, and type 3 procollagen mRNA expressions in lung tissue. All RMs improved oxygenation and lung static elastance and reduced alveolar collapse compared to NR. STEP30 resulted in optimal performance, with: 1) improved lung static elastance vs. NR, CPAP15, and STEP15; 2) reduced alveolar-capillary membrane detachment and type 2 epithelial and endothelial cell injury scores vs. CPAP15 (p < .05); and 3) reduced gene expression of interleukin-6, type 3 procollagen, and caspase 3 in lung tissue vs. other RMs. CONCLUSIONS: Longer-duration RMs with slower airway pressure increase efficiently improved lung function, while minimizing the biological impact on lungs.
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Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/terapia , Presión de las Vías Aéreas Positiva Contínua/métodos , Pulmón/metabolismo , Lesión Pulmonar Aguda/complicaciones , Lesión Pulmonar Aguda/mortalidad , Animales , Caspasa 3/análisis , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Interleucina-6/análisis , Interleucina-6/metabolismo , Pulmón/fisiopatología , Masculino , Microscopía Electrónica de Transmisión , Procolágeno , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/patología , Distribución Aleatoria , Ratas , Ratas Wistar , Mecánica Respiratoria , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y Especificidad , Sepsis/complicaciones , Tasa de Supervivencia , Factores de TiempoRESUMEN
Oxidative stress is considered one of the early underlying contributors of acute lung injury (ALI) and ventilator-induced lung injury (VILI). DJ-1, also known as PARK7, has a well-established role as an antioxidant. We have previously shown maintaining oxidative balance via the ATF3-Nrf2 axis was important in protection from ALI. Here, we exclusively characterize the role of DJ-1 in sterile LPS-induced ALI and VILI. DJ-1 protein expression was increased after LPS treatment in human epithelial and endothelial cell lines and lungs of wild-type mice. DJ-1 deficient mice exhibited greater susceptibility to LPS-induced acute lung injury as demonstrated by increased cellular infiltration, augmented levels of pulmonary cytokines, enhanced ROS levels and oxidized by-products, increased pulmonary edema and cell death. In a two-hit model of LPS and mechanical ventilation (MV), DJ-1 deficient mice displayed enhanced susceptibility to inflammation and lung injury. Collectively, these results identify DJ-1 as a negative regulator of ROS and inflammation, and suggest its expression protects from sterile lung injury driven by high oxidative stress.
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Lesión Pulmonar Aguda , Proteína Desglicasa DJ-1 , Lesión Pulmonar Inducida por Ventilación Mecánica , Lesión Pulmonar Aguda/genética , Animales , Línea Celular , Humanos , Lipopolisacáridos , Pulmón , Ratones , Ratones Endogámicos C57BL , Proteína Desglicasa DJ-1/genética , Lesión Pulmonar Inducida por Ventilación Mecánica/genética , Ventiladores MecánicosRESUMEN
OBJECTIVE: In acute lung injury, recruitment maneuvers have been used to open collapsed lungs and set positive end-expiratory pressure, but their effectiveness may depend on the degree of lung injury. This study uses a single experimental model with different degrees of lung injury and tests the hypothesis that recruitment maneuvers may have beneficial or deleterious effects depending on the severity of acute lung injury. We speculated that recruitment maneuvers may worsen lung mechanical stress in the presence of alveolar edema. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: Thirty-six Wistar rats randomly divided into three groups (n = 12 per group). INTERVENTIONS: In the control group, saline was intraperitoneally injected, whereas moderate and severe acute lung injury animals received paraquat intraperitoneally (20 mg/kg [moderate acute lung injury] and 25 mg/kg [severe acute lung injury]). After 24 hrs, animals were further randomized into subgroups (n = 6/each) to be recruited (recruitment maneuvers: 40 cm H2O continuous positive airway pressure for 40 secs) or not, followed by 1 hr of protective mechanical ventilation (tidal volume, 6 mL/kg; positive end-expiratory pressure, 5 cm H2O). MEASUREMENTS AND MAIN RESULTS: Only severe acute lung injury caused alveolar edema. The amounts of alveolar collapse were similar in the acute lung injury groups. Static lung elastance, viscoelastic pressure, hyperinflation, lung, liver, and kidney cell apoptosis, and type 3 procollagen and interleukin-6 mRNA expressions in lung tissue were more elevated in severe acute lung injury than in moderate acute lung injury. After recruitment maneuvers, static lung elastance, viscoelastic pressure, and alveolar collapse were lower in moderate acute lung injury than in severe acute lung injury. Recruitment maneuvers reduced interleukin-6 expression with a minor detachment of the alveolar capillary membrane in moderate acute lung injury. In severe acute lung injury, recruitment maneuvers were associated with hyperinflation, increased apoptosis of lung and kidney, expression of type 3 procollagen, and worsened alveolar capillary injury. CONCLUSIONS: In the presence of alveolar edema, regional mechanical heterogeneities, and hyperinflation, recruitment maneuvers promoted a modest but consistent increase in inflammatory and fibrogenic response, which may have worsened lung function and potentiated alveolar and renal epithelial injury.
Asunto(s)
Lesión Pulmonar Aguda/terapia , Presión de las Vías Aéreas Positiva Contínua , Atelectasia Pulmonar/etiología , Edema Pulmonar/etiología , Lesión Pulmonar Aguda/complicaciones , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/fisiopatología , Animales , Colágeno Tipo III/biosíntesis , Interleucina-6/biosíntesis , Riñón/patología , Hígado/patología , Pulmón/patología , Microscopía Electrónica de Transmisión , Alveolos Pulmonares/lesiones , Alveolos Pulmonares/patología , Alveolos Pulmonares/fisiopatología , Atelectasia Pulmonar/terapia , Edema Pulmonar/terapia , Ratas , Ratas Wistar , Respiración Artificial , Mecánica Respiratoria/fisiologíaRESUMEN
OBJECTIVE: To hypothesize that bone marrow-derived mononuclear cell (BMDMC) therapy might act differently on lung and distal organs in models of pulmonary or extrapulmonary acute lung injury with similar mechanical compromises. The pathophysiology of acute lung injury differs according to the type of primary insult. DESIGN: Prospective, randomized, controlled, experimental study. SETTING: University research laboratory. MEASUREMENTS AND MAIN RESULTS: In control animals, sterile saline solution was intratracheally (0.05 mL) or intraperitoneally (0.5 mL) injected. Acute lung injury animals received Escherichia coli lipopolysaccharide intratracheally (40 microg, ALIp) or intraperitoneally (400 microg, ALIexp). Six hours after lipopolysaccharide administration, ALIp and ALIexp animals were further randomized into subgroups receiving saline (0.05 mL) or BMDMC (2 x 10) intravenously. On day 7, BMDMC led to the following: 1) increase in survival rate; 2) reduction in static lung elastance, alveolar collapse, and bronchoalveolar lavage fluid cellularity (higher in ALIexp than ALIp); 3) decrease in collagen fiber content, cell apoptosis in lung, kidney, and liver, levels of interleukin-6, KC (murine interleukin-8 homolog), and interleukin-10 in bronchoalveolar lavage fluid, and messenger RNA expression of insulin-like growth factor, platelet-derived growth factor, and transforming growth factor-beta in both groups, as well as repair of basement membrane, epithelium and endothelium, regardless of acute lung injury etiology; 4) increase in vascular endothelial growth factor levels in bronchoalveolar lavage fluid and messenger RNA expression in lung tissue in both acute lung injury groups; and 5) increase in number of green fluorescent protein-positive cells in lung, kidney, and liver in ALIexp. CONCLUSIONS: BMDMC therapy was effective at modulating the inflammatory and fibrogenic processes in both acute lung injury models; however, survival and lung mechanics and histology improved more in ALIexp. These changes may be attributed to paracrine effects balancing pro- and anti-inflammatory cytokines and growth factors, because a small degree of pulmonary BMDMC engraftment was observed.
Asunto(s)
Lesión Pulmonar Aguda/terapia , Apoptosis/fisiología , Trasplante de Médula Ósea/métodos , Citocinas/metabolismo , Mecánica Respiratoria/fisiología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/mortalidad , Lesión Pulmonar Aguda/fisiopatología , Animales , Líquido del Lavado Bronquioalveolar/citología , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Escherichia coli , Femenino , Leucocitos Mononucleares/trasplante , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal , Microscopía Electrónica , Factor de Crecimiento Derivado de Plaquetas/metabolismo , ARN Mensajero/metabolismo , Distribución Aleatoria , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
INTRODUCTION: Recruitment maneuvers (RMs) seem to be more effective in extrapulmonary acute lung injury (ALI), caused mainly by sepsis, than in pulmonary ALI. Nevertheless, the maintenance of adequate volemic status is particularly challenging in sepsis. Since the interaction between volemic status and RMs is not well established, we investigated the effects of RMs on lung and distal organs in the presence of hypovolemia, normovolemia, and hypervolemia in a model of extrapulmonary lung injury induced by sepsis. METHODS: ALI was induced by cecal ligation and puncture surgery in 66 Wistar rats. After 48 h, animals were anesthetized, mechanically ventilated and randomly assigned to 3 volemic status (n = 22/group): 1) hypovolemia induced by blood drainage at mean arterial pressure (MAP) approximately 70 mmHg; 2) normovolemia (MAP approximately 100 mmHg), and 3) hypervolemia with colloid administration to achieve a MAP approximately 130 mmHg. In each group, animals were further randomized to be recruited (CPAP = 40 cm H2O for 40 s) or not (NR) (n = 11/group), followed by 1 h of protective mechanical ventilation. Echocardiography, arterial blood gases, static lung elastance (Est,L), histology (light and electron microscopy), lung wet-to-dry (W/D) ratio, interleukin (IL)-6, IL-1beta, caspase-3, type III procollagen (PCIII), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) mRNA expressions in lung tissue, as well as lung and distal organ epithelial cell apoptosis were analyzed. RESULTS: We observed that: 1) hypervolemia increased lung W/D ratio with impairment of oxygenation and Est,L, and was associated with alveolar and endothelial cell damage and increased IL-6, VCAM-1, and ICAM-1 mRNA expressions; and 2) RM reduced alveolar collapse independent of volemic status. In hypervolemic animals, RM improved oxygenation above the levels observed with the use of positive-end expiratory pressure (PEEP), but increased lung injury and led to higher inflammatory and fibrogenetic responses. CONCLUSIONS: Volemic status should be taken into account during RMs, since in this sepsis-induced ALI model hypervolemia promoted and potentiated lung injury compared to hypo- and normovolemia.