[en] Rheumatoid arthritis (RA) is one of the most common chronic and inflammatory diseases of the musculoskeletal system, capable of producing long-term joint damage associated with severe pain, progressive functional disability and even early death; in addition to the high socioeconomic costs that this entails. Although RA frequently shows systemic involvement, its main target is the synovial joints. Thus, the hyperplastic synovial membrane is one of its main pathological features, and it is associated both with the local infiltration and retention of inflammatory immune cells and with the activation and excessive proliferation of resident cells of the synovium. In relation to RA treatment, current drugs present numerous limitations, and consequently, in recent years, the possible therapeutic potential of natural products against this disease has been arousing great interest. In this line, the present work aimed to deepen the prophylactic effect of a compound of natural origin, such as resveratrol, in RA, using an animal model of antigen-induced arthritis in rats (AIA). To evaluate the effect of resveratrol in the in vivo study, it was administered orally during the two months prior to the induction of arthritis and continuing until the day of sacrifice, two days after induction, corresponding to the acute phase of the disease. In the first place, it was observed how resveratrol treatment was able to counteract the cardinal parameters of arthritic pathology (proliferation of the intimal layer, immune cellular infiltrate and cellularity) in the synovial tissue. In addition, it was evaluated how the possible involvement of two of the most relevant cell death mechanisms, type I cell death or apoptosis and/or type II cell death or autophagy, could play a fundamental role in the control of excessive cell proliferation of the synovial tissue of the arthritic joint. For this, the synovial expression of the active caspase-3 and its substrate PARP as intermediates of the apoptotic process and LC3, p62 and beclin-1 as mediators of the autophagic process were analyzed using immunohistochemical techniques; showing how resveratrol is capable of regulating the balance between autophagy and apoptosis, directing it towards autophagy and promoting, more specifically, the non-canonical pathway of autophagy. Furthermore, there is increasing evidence that a failure in autophagy could modulate inflammatory activity, promoting the development of multiple inflammatory and autoimmune diseases, such as RA. Thus, the serum concentration of three important mediators of inflammation at the systemic level, with great clinical relevance, was evaluated by means of immunoassays: interleukin (IL)-1β, prostaglandin (PG)E2 and C-reactive protein (CRP). The results obtained showed how those animals to which resveratrol was administered prophylactically had reduced levels of these markers; in the same way, when carrying out the correlation analysis between the levels of these and the synovial expression of p62, a strong positive correlation was obtained in all cases, highlighting the important relationship that autophagy maintains with the inflammatory process. Finally, the synovial expression of the transcription factor p65-NF-κB, key in the regulation of inflammation, and also of the markers VEGF and Ang-1, involved in the angiogenesis process, was evaluated, which contributed to obtaining a broader vision of the potential anti-inflammatory properties of resveratrol in the arthritic pathology. Our data showed that resveratrol down-regulated the expression levels of all these proteins in the synovial tissue of the animals in which arthritic disease was induced and, likewise, our results reflected the existence of a strong positive correlation between the synovial expression of p62 and factor p65-NF-κB. Based on the data obtained in the present work, we can suggest that the suppression of the inflammatory pathway, as a consequence of the inhibition of the transcription factor NF-ᴋB through the activation of the autophagic process, could be considered as a therapeutic strategy. The reason for this is due to the fact that a multitude of inflammatory mediators that are involved in its signaling pathway and that actively participate in the different events underlying RA are inhibited. To conclude, the data provided in this work suggest that the improvement of the autophagic process could be considered as a potential therapeutic target in the treatment of RA and, likewise, supports the use of compounds of natural origin, such as resveratrol, as a strategy in the treatment of this disease.

[gl] A artrite reumatoide (AR) é unha das enfermidades crónicas e inflamatorias máis comúns do sistema músculo-esquelético, capaz de producir danos articulares a longo prazo asociados a dor severa, discapacidade funcional progresiva e mesmo a morte precoz; ademáis dos elevados custos socioeconómicos que isto supón. Aínda que a AR mostra frecuentemente unha afectación sistémica, o seu principal obxectivo son as articulacións sinoviais. Así, a membrana sinovial hiperplásica é unha das súas principais características patolóxicas, e está asociada tanto coa infiltración e retención local de células inmunes inflamatorias como coa activación e proliferación excesiva de células residentes da sinovial. En relación co seu tratamento, os fármacos actuais presentan numerosas limitacións, razón pola cal, nos últimos anos, existe un auxe de interese no posible potencial terapéutico dos productos naturais fronte a esta enfermidade. Nesta liña, o presente traballo pretendeu afondar no efecto profiláctico dun composto de orixe natural, como é o resveratrol, na AR, empregando un modelo animal de artrite inducida por antíxeno en ratas (AIA). Para avaliar o efecto do resveratrol no estudo in vivo, éste administrouse por vía oral durante os dous meses previos á indución da artrite e continuándose ata o día do sacrificio, dous días despois da indución, correspondéndose coa fase aguda da enfermidade. En primeiro lugar, observouse como o tratamento con resveratrol foi capaz de contrarrestar os parámetros cardinais da patoloxía artrítica (proliferación da capa íntima, infiltrado celular inmune e celularidade) no tecido sinovial. Ademais disto, avaliouse como a posible implicación de dous dos mecanismos de morte celular máis relevantes, a morte celular de tipo I ou apoptose e/ou a morte celular de tipo II ou autofaxia, podería xogar un papel fundamental no control da proliferación celular excesiva do tecido sinovial da articulación artrítica. Para iso, analizouse mediante técnicas inmunohistoquímicas a expresión sinovial dos marcadores caspase-3 activa e do seu substrato PARP como intermediarios do proceso apoptótico e LC3, p62 e beclin-1 como mediadores do proceso autofáxico; amosando como o resveratrol é capaz de regular o equilibrio entre a autofaxia e a apoptose, dirixindoo cara a autofaxia e promovendo, máis concretamente, a vía non canónica da autofaxia. Así mesmo, cada vez hai máis evidencia de que un fallo na autofaxia podería modular a actividade inflamatoria, favorecendo así o desenvolvemento de múltiples enfermidades inflamatorias e autoinmunes, como a AR. Deste xeito, avaliouse mediante inmunoensaios a concentración sérica de tres importantes mediadores da inflamación a nivel sistémico e con gran relevancia clínica: interleucina (IL)-1β, prostaglandina (PG)E2 e a proteína C reactiva (PCR). Os resultados obtidos mostraron como aqueles animais aos que se lles administrou profilácticamente resveratrol tiñan niveis reducidos destes marcadores; Do mesmo xeito, ao realizar a análise de correlación entre os niveis destes e a expresión sinovial de p62, obtívose en todos os casos unha forte correlación positiva, evidenciando a importante relación que mantén a autofaxia co proceso inflamatorio. Finalmente, avaliouse a expresión sinovial do factor de transcrición p65-NF-κB, clave na regulación da inflamación, e tamén dos marcadores VEGF e Ang-1, implicados no proceso de anxioxénese, o que contribuíu a obter unha visión máis amplia das potenciais propiedades antiinflamatorias do resveratrol na patoloxía artrítica. Os nosos datos mostraron que o resveratrol regulaba á baixa os niveis de expresión de todas estas proteínas no tecido sinovial dos animais nos que se inducía a enfermidade artrítica e, así mesmo, os nosos resultados reflexaron a existencia dunha forte correlación positiva entre a expresión sinovial de p62 e o factor p65-NF-κB. En base a estes datos, podemos suxerir que a supresión da vía inflamatoria, como consecuencia da inhibición do factor de transcrición NF-ᴋB mediante a activación do proceso autofáxico, podería considerarse como unha estratexia terapéutica. A razón disto débese ao feito de que se inhiben multitude de mediadores inflamatorios que están implicados na súa vía de sinalización e que participan activamente nos diferentes eventos subxacentes á AR. Para concluír, os datos achegados neste traballo suxiren que a mellora do proceso autofáxico podería considerarse como unha potencial diana terapéutica no tratamento da AR e, así mesmo, apoia o uso de compostos de orixe natural, coma o resveratrol, como estratexia no tratamento desta enfermidade.