RESUMEN
Higher levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a TLR4 agonist, are associated with poor clinical outcomes in sepsis-induced acute lung injury (ALI). Little is known regarding the mechanisms by which eNAMPT is involved in ALI. Our recent work has identified a crucial role for mitochondrial dysfunction in ALI. Thus, this study aimed to determine if eNAMPT-mediated inflammatory injury is associated with the loss of mitochondrial function. Our data show that eNAMPT disrupted mitochondrial bioenergetics. This was associated with cytoskeleton remodeling and the loss of endothelial barrier integrity. These changes were associated with enhanced mitochondrial fission and blocked when Rho-kinase (ROCK) was inhibited. The increases in mitochondrial fission were also associated with the nitration-mediated activation of the small GTPase activator of ROCK, RhoA. Blocking RhoA nitration decreased eNAMPT-mediated mitochondrial fission and endothelial barrier dysfunction. The increase in fission was linked to a RhoA-ROCK mediated increase in Drp1 (dynamin-related protein 1) at serine(S)616. Another TLR4 agonist, lipopolysaccharide (LPS), also increased mitochondrial fission in a Drp1 and RhoA-ROCK-dependent manner. To validate our findings in vivo, we challenged C57BL/6 mice with eNAMPT in the presence and absence of the Drp1 inhibitor, Mdivi-1. Mdivi-1 treatment protected against eNAMPT-induced lung inflammation, edema, and lung injury. These studies demonstrate that mitochondrial fission-dependent disruption of mitochondrial function is essential in TLR4-mediated inflammatory lung injury and identify a key role for RhoA-ROCK signaling. Reducing mitochondrial fission could be a potential therapeutic strategy to improve ARDS outcomes.
Asunto(s)
Lesión Pulmonar Aguda , Citoesqueleto , Células Endoteliales , Dinámicas Mitocondriales , Receptor Toll-Like 4 , Quinasas Asociadas a rho , Proteína de Unión al GTP rhoA , Animales , Proteína de Unión al GTP rhoA/metabolismo , Ratones , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células Endoteliales/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Quinasas Asociadas a rho/metabolismo , Humanos , Citoesqueleto/metabolismo , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Mitocondrias/metabolismo , Mitocondrias/patología , Ratones Endogámicos C57BL , Lipopolisacáridos , Masculino , Transducción de SeñalRESUMEN
Once thought of in terms of bioenergetics, mitochondria are now widely accepted as both the orchestrator of cellular health and the gatekeeper of cell death. The pulmonary disease field has performed extensive efforts to explore the role of mitochondria in regulating inflammation, cellular metabolism, apoptosis, and oxidative stress. However, a critical component of these processes needs to be more studied: mitochondrial network dynamics. Mitochondria morphologically change in response to their environment to regulate these processes through fusion, fission, and mitophagy. This allows mitochondria to adapt their function to respond to cellular requirements, a critical component in maintaining cellular homeostasis. For that reason, mitochondrial network dynamics can be considered a bridge that brings multiple cellular processes together, revealing a potential pathway for therapeutic intervention. In this review, we discuss the critical modulators of mitochondrial dynamics and how they are affected in pulmonary diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), and pulmonary arterial hypertension (PAH). A dysregulated mitochondrial network plays a crucial role in lung disease pathobiology, and aberrant fission/fusion/mitophagy pathways are druggable processes that warrant further exploration. Thus, we also discuss the candidates for lung disease therapeutics that regulate mitochondrial network dynamics.
Asunto(s)
Dinámicas Mitocondriales , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Estrés Oxidativo , Inflamación , Metabolismo EnergéticoRESUMEN
Resumen El objetivo de este trabajo fue sistematizar las especies apropiadas, formas de apropiación y valores de uso asignados a la fauna silvestre en comunidades de la Reserva de la Biosfera Sierra de Huautla, México, mediante un análisis documental y trabajo de campo. Se registraron 46 especies con valor de uso pertenecientes a 31 familias. La clase con mayor número de especies apropiadas son las aves (42.5%), seguidas de los mamíferos (34%). El 64% de las especies se apropian con fines alimentarios y el 38.3% se utilizan para el tratamiento de enfermedades en la medicina tradicional. Otros usos son adornos, amuletos, elaboración de herramientas y como animal de compañía. La apropiación de fauna silvestre se realiza por medio de la cacería, la recolección y la pesca. Las armas de fuego como la escopeta es el principal instrumento para la cacería. También se utilizan perros, machetes, resorteras, tarrayas, anzuelos, nudos corredizos y se capturan manualmente. La apropiación puede ser una actividad oportunista u organizada por medio de las arreadas, espiadas, lampareadas, campeadas, acorralamiento y recolección manual. La apropiación de fauna silvestre es una actividad culturalmente arraigada en las comunidades de la reserva. Sin embargo, el análisis de la relación sociedad-fauna en la región es limitado, por lo que es necesario generar información que promueva el manejo sostenible del recurso faunístico.
Abstract The aims of this paper were the systematization of appropriated species, appropriation forms and assigned use values of wildlife species in the Biosphere Reserve of the Sierra de Huautla, Mexico, by means of documentary analysis and field work. We recorded 46 species with use value pertaining to 31 families. Birds accounted for the highest number of appropriated species (42.5%), followed by mammals (34%). Of the total species, 64% are appropriated for alimentary purposes and are used in the treatment of diseases in traditional medicine. Others are used as ornaments, talismans, in tool manufacture and as pet animals. Wildlife appropriation is achieved by hunting, collection and fishing. Fire arms such as shotguns are the main instrument used in hunting. Dogs, machetes, slingshots, nets, hooks, slipknots, are also used, or they are captured by hand. Appropriation can be an opportunistic or organized activity by means of "arreadas" (herding), "espiadas" (opportunistic observation), "lampareadas" (spotlighting), "campeadas" (scouring), "acorralamiento" (cornering) and manual collection. Wildlife appropriation is a culturally rooted activity in the reserve communities. Nevertheless, the analysis of the relationship society-fauna in the region is limited and this is why the generation of information that may enable a sustainable management of the faunistic resource is necessary.
RESUMEN
Resumen El objetivo de la investigación fue analizar el conocimiento etnozoológico que conservan de los vertebrados silvestres los habitantes de la comunidad Bonifacio García en Morelos, México. Se aplicaron entrevistas semiestructuradas a 30 informantes clave, mediante la observación participante y recorridos guiados se buscaron rastros como huellas, excretas, madrigueras, pieles y observación in vivo para la identificación de las especies citadas y se calcularon los siguientes índices: valor de diversidad de uso para cada especie (VDE) y de uso medicinal (VDM), así como el índice de diversidad de las enfermedades tratadas (IVDE). Se reportan 41 especies de vertebrados que los entrevistados reconocen, de los cuales 28 son aprovechados: mamíferos 39.3%, aves 32%, reptiles 18%, peces 7.1% y anfibios 3.6%. Los principales valores de uso fueron alimentario (0.54), medicinal (0.46) y ornamental (0.43). El venado cola blanca, la iguana negra y la víbora de cascabel registraron 0.57 de VDE y un VDM de 0.19. Las principales enfermedades tratadas son: cáncer, afecciones respiratorias, enfermedades de la piel y reumatismo con un IVDE de 0.17. La apropiación de los vertebrados silvestres se lleva a cabo por medio de la cacería de subsistencia en el campo (50%), terrenos de cultivo (43%) y el traspatio (7%) utilizando con mayor frecuencia escopeta como arma de captura. Se concluye que la apropiación de vertebrados permite complementar necesidades básicas de alimentación y salud; por lo que los conocimientos etnozoológicos deben de integrarse a políticas públicas que permitan la conservación y manejo de la fauna silvestre en la comunidad.
Abstract The aim of this study was to analyze the ethnozoological knowledge that the inhabitants of the Bonifacio García community, Morelos, Mexico, conserve about wild vertebrate. Semi-structured interviews were applied to 30 key informants, through participant observation and guided tours, traces such as footprints, excreta, burrows and pelts and in vivo observation were researched for the identification of the mentioned species and the following indexes were calculated: value of diversity of use for each species (VDS) and of medicinal uses (DVM), as well as the diversity index of the treated diseases (DITD). The study recorded a total of 42 wild vertebrate species, of these 28 are used: mammals 39.3%, birds 32%, reptiles 18%, fish 7.1% and amphibia 3.6%. The main use values were alimentary (0.54), medicinal (0.46) and ornamental (0.43). The white-tailed deer, the black iguana and the rattlesnake registered 0.57 of VDS and a DVM of 0.19. The main diseases treated are cancer, respiratory and skin diseases and rheumatism with an DITD of 0.17. The animals are obtained by means of subsistence hunting in the fields (50%), croplands (43%) and backyards (7%), using most frequently shotguns as arms for capture. We conclude that the appropriation of vertebrates complements basic needs for food and health; therefore, ethnozoological knowledge must be integrated into public policies that enable the conservation and management of wild fauna in the community.