Estudo da resposta inflamatória na artrite induzida por antígeno e o papel de mediadores endógenos na sua resolução: importância das espécies reativas de oxigênio

Abstract

During inflammatory response there an important accumulation (arrival and permanence at inflamed site) of leukocytes, production of inflammatory mediators and, conse quently, loss of function of involved organ. Neutrophils are effector cells of innate immune response and are the most abundant leukocyte in joints of mice with antigen-induced arthritis. This study evaluated inflammatory characteristics during antigen-induced arthritis in mice and mechanisms that influence hypernociception during AIA. Furthermore, we evaluated the importance of endogenous mediators, such as emphasis on reactive oxygen species and intracellular signaling pathways for apoptosis of neutrophils and their relevance to resolution of inflammatory response: elimination of neutrophils and control hypernociception. First, we demonstrated that during the AIA has an accumulation of neutrophils associated with local production of TNF-, IL-1 and CXCL-1 and hypernociception. The next time was to evaluate the importance of resolution of inflammatory response to control AIA. Thus, we demonstrated that production of reactive oxygen species precede natural resolution of inflammatory response observed 48 hours after challenge with antigen. Furthermore, it was observed that in mice deficient in gp91 phox or treated with apocynin or catalase presented a delay in resolution of inflammatory response. Increased reactive oxygen species generated pharmacologically advancing the resolution of inflammatory response by inhibiting signal transduction pathways such as PI3K, ERK1/2 and P38, as well as activation of NF-kB, linked to these survival leukocytes into inflammatory sites. Advance of time resolution of inflammatory response decreases production of chemokines CCL1, CCL5 and CXCL1, which contributes to preservation of structures commonly affected by antigen-induced arthritis, as well as reducing hypernociception. Pharmacological inhibition of these pathways was also able to advance the resolution of inflammatory response. Human neutrophil also advance apoptosis when cultured with H2O2, by this inhibit cell survival pathways. The modulation of production of reactive oxygen species may represent a new strategy to control neutrophilic inflammation in the joints.