Involvement of Mitochondrial Dysfunction in the Inflammatory Response in Human Mesothelial Cells from Peritoneal Dialysis Effluent.

Recent studies have related mitochondrial impairment with peritoneal membrane damage during peritoneal dialysis (PD) therapy. Here, we assessed the involvement of mitochondrial dysfunction in the inflammatory response in human mesothelial cells, a hallmark in the pathogenesis of PD-related peritoneal membrane damage. Our ex vivo studies showed that IL-1ß causes a drop in the mitochondrial membrane potential in cells from peritoneal effluent. Moreover, when mitochondrial damage was induced by inhibitors of mitochondrial function, a low-grade inflammatory response was generated. Interestingly, mitochondrial damage sensitized mesothelial cells, causing a significant increase in the inflammatory response induced by cytokines, in which ROS generation and NF-κB activation appear to be involved, since inflammation was counteracted by both mitoTEMPO (mitochondrial ROS scavenger) and BAY-117085 (NF-κB inhibitor). Furthermore, the natural anti-inflammatory antioxidant resveratrol significantly attenuated the inflammatory response, by reversing the decline in mitochondrial membrane potential and decreasing the expression of IL-8, COX-2 and PGE2 caused by IL-1ß. These findings suggest that IL-1ß regulates mitochondrial function in mesothelial cells and that mitochondrial dysfunction could induce an inflammatory scenario that sensitizes these cells, causing significant amplification of the inflammatory response induced by cytokines. Resveratrol may represent a promising strategy in controlling the mesothelial inflammatory response to PD.

Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis.

Control of excessive mitochondrial oxidative stress could provide new targets for both preventive and therapeutic interventions in the treatment of chronic inflammation or any pathology that develops under an inflammatory scenario, such as rheumatoid arthritis (RA). Increasing evidence has demonstrated the role of mitochondrial alterations in autoimmune diseases mainly due to the interplay between metabolism and innate immunity, but also in the modulation of inflammatory response of resident cells, such as synoviocytes. Thus, mitochondrial dysfunction derived from several danger signals could activate tricarboxylic acid (TCA) disruption, thereby favoring a vicious cycle of oxidative/mitochondrial stress. Mitochondrial dysfunction can act through modulating innate immunity via redox-sensitive inflammatory pathways or direct activation of the inflammasome. Besides, mitochondria also have a central role in regulating cell death, which is deeply altered in RA. Additionally, multiple evidence suggests that pathological processes in RA can be shaped by epigenetic mechanisms and that in turn, mitochondria are involved in epigenetic regulation. Finally, we will discuss about the involvement of some dietary components in the onset and progression of RA.

Clinical significance of high levels of soluble tumour necrosis factor-α receptor-2 produced by alternative splicing in rheumatoid arthritis: a longitudinal prospective cohort study.

OBJECTIVES: We investigated whether serum levels of an alternatively spliced soluble (s)TNF receptor-2 (DS-TNFR2) affected the clinical response to anti-TNF-α therapy, classical DMARDs or radiological evidence of disease progression in patients with RA. METHODS: We included 116 patients with RA. Cohort 1: 52 DMARD-naïve early RA patients [mean (s.d.) disease duration 8.5 (6.2) months] who started gold salts and MTX therapies. Cohort 2: 64 MTX-resistant established RA patients [144 (107) months] who started infliximab therapy. We evaluated the European League Against Rheumatism (EULAR) response to therapy and the serum levels of DS-TNFR2, sTNFR2 and ACPAs at baseline and at 12 months. In Cohort 1, radiological progression and levels of MMP-1 were also determined. RESULTS: In Cohort 1, 40% of patients had high baseline levels (HL > 50 ng/ml) of DS-TNFR2 with significantly higher RF and ACPA levels than patients with normal levels (NL ≤ 50 ng/ml) of DS-TNFR2. The EULAR response to DMARDs was similar in HL and NL patients. Radiographic progression was observed in 23.5% of all patients after 12 months. In Cohort 2, 26.6% of patients had HL of DS-TNFR2 with significantly higher RF and ACPA levels than patients with NLs. The EULAR response from 6 to 30 weeks was prolonged in the HL group compared with the NL group. CONCLUSIONS: Patients with HL of DS-TNFR2 maintained a prolonged therapeutic response to anti-TNF-α therapy and had proportionally less radiographic progression compared with patients with NLs.

Evidencia de mecanismos inflamatorios en la osteoartritis / Evidence of inflammatory mechanisms in osteoarthritis

Clásicamente, la artrosis (OA) no ha sido considerada una artropatía inflamatoria por la escasez de neutrófilos en el líquido sinovial y la ausencia de manifestaciones sistémicas de inflamación. Además, las características del cartílago articular (avascular, alinfático y aneural) impiden cumplir los signos clásicos de la inflamación (enrojecimiento, hinchazón, calor y dolor). Sin embargo, gracias a los avances en biología molecular y celular, son múltiples los estudios que demuestran que diversos mediadores proinflamatorios, como las citocinas interleucina 1 y factor de necrosis tumoral , pueden ser importantes en el desarrollo de esta enfermedad. Así, la estimulación de condrocitos, único representante del cartílago articular y por ello principal encargado de mantener la matriz extracelular del cartílago, con estas citocinas proinflamatorias incrementa la producción de las metaloproteasas, enzimas proteolíticas clave en la degradación irreversible de la arquitectura articular normal. También inhiben la síntesis de proteoglucanos y colágeno tipo II, estimulan la producción de especies reactivas de oxígeno como el óxido nítrico e incrementan la producción de prostaglandina E2. Asimismo, es evidente que los efectos de la inflamación sinovial favorecen la desregulación en la función del condrocito y la pérdida del equilibrio entre las actividades anabólicas y catabólicas del condrocito, imprescindibles para mantener la integridad articular normal (AU)

Classically, osteoarthritis (OA) is not considered an inflammatory arthropathy, because of the presence of a small number of neutrophils in the synovial fluid and the absence of systemic manifestations of inflammation. Besides, the characteristics of articular cartilage (avascular, alymphatic and aneural) do disable to fulfill with the classical signs of inflammation (redness, swelling, heat, pain). However, thanks to development of molecular and cellular biology, there are multiple studies which shown that different proinflammatory mediators, such as the cytokines IL-1 and TNF, could be important in the development of this disease. Therefore, the stimulation of chondrocytes, the only cell type living in the cartilage matrix and for this reason the principal responsible of integrity of cartilage matrix extracellular, with these proinflamatory cytokines increases the production of metalloproteinases, keys molecules in the irreversible degradation of normal architecture of cartilage. As well, inhibits the synthesis of cartilage proteoglycans and type II collagen, stimulates the production of reactive oxygen species such as nitric oxide, and increases the production of prostaglandin E2. Likewise, the effects of synovial inflammation expected contribute to deregulation of chondrocyte function in a similar fashion, favouring the lost of equilibrium between the catabolic and anabolic activities of the chondrocyte necessary for maintaining the extracellular cartilage matrix (AU)

[Evidence of inflammatory mechanisms in osteoarthritis]. / Evidencia de mecanismos inflamatorios en la osteoartritis.

Classically, osteoarthritis (OA) is not considered an inflammatory arthropathy, because of the presence of a small number of neutrophils in the synovial fluid and the absence of systemic manifestations of inflammation. Besides, the characteristics of articular cartilage (avascular, alymphatic and aneural) do disable to fulfill with the classical signs of inflammation (redness, swelling, heat, pain). However, thanks to development of molecular and cellular biology, there are multiple studies which shown that different proinflammatory mediators, such as the cytokines IL-1ß and TNFα, could be important in the development of this disease. Therefore, the stimulation of chondrocytes, the only cell type living in the cartilage matrix and for this reason the principal responsible of integrity of cartilage matrix extracellular, with these proinflamatory cytokines increases the production of metalloproteinases, keys molecules in the irreversible degradation of normal architecture of cartilage. As well, inhibits the synthesis of cartilage proteoglycans and type II collagen, stimulates the production of reactive oxygen species such as nitric oxide, and increases the production of prostaglandin E(2). Likewise, the effects of synovial inflammation expected contribute to deregulation of chondrocyte function in a similar fashion, favouring the lost of equilibrium between the catabolic and anabolic activities of the chondrocyte necessary for maintaining the extracellular cartilage matrix.