RESUMO
Macrophage activation is, in part, regulated via hydrolysis of oxidised low density lipoproteins by Lipoprotein-Associated phospholipase A2 (Lp-PLA2), resulting in increased macrophage migration, pro-inflammatory cytokine release and chemokine expression. In uveitis, tissue damage is mediated as a result of macrophage activation; hence inhibition of Lp-PLA2 may limit macrophage activation and protect the tissue. Utilising Lp-PLA2 gene-deficient (KO) mice and a pharmacological inhibitor of Lp-PLA2 (SB-435495) we aimed to determine the effect of Lp-PLA2 suppression in mediating retinal protection in a model of autoimmune retinal inflammation, experimental autoimmune uveoretinitis (EAU). Following immunisation with RBP-3 (IRBP) 1-20 or 161-180 peptides, clinical disease was monitored and severity assessed, infiltrating leukocytes were enumerated by flow cytometry and tissue destruction quantified by histology. Despite ablation of Lp-PLA2 enzyme activity in Lp-PLA2 KO mice or wild-type mice treated with SB-435495, the number of infiltrating CD45+ cells in the retina was equivalent to control EAU animals, and there was no reduction in disease severity. Thus, despite the reported beneficial effects of therapeutic Lp-PLA2 depletion in a variety of vascular inflammatory conditions, we were unable to attenuate disease, show delayed disease onset or prevent progression of EAU in Lp-PLA2 KO mice. Although EAU exhibits inflammatory vasculopathy there is no overt defect in lipid metabolism and given the lack of effect following Lp-PLA2 suppression, these data support the hypothesis that sub-acute autoimmune inflammatory disease progresses independently of Lp-PLA2 activity.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Doenças Autoimunes/metabolismo , Retinite/metabolismo , Uveíte/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/prevenção & controle , Compostos de Bifenilo/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Expressão Gênica/genética , Imunização , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Peptídeos/imunologia , Fosfolipases A2/genética , Fosfolipases A2/metabolismo , Pirimidinonas/farmacologia , Retinite/genética , Retinite/prevenção & controle , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Uveíte/genética , Uveíte/prevenção & controleRESUMO
One approach to treatment of internal derangements of the temporomandibular joint (TMJ) is surgical remodeling and repositioning of the disk and its attachments. Nine joints exhibiting disk displacements (four histological series and five magnetic resonance imagining (MRI) series) were studied to analyze the geometrical and mechanical implications of surgical repositioning. In the central tomographic plane, for example, these cases would have required repositioning the disk 6.9 mm posteriorly (+/- 3.3 mm), removing 5.2 mm (+/- 1.6 mm) of remodeled retrodiskal tissue, and trimming 2.1 mm (+/- 2.0 mm) of disk. This suggests that from gross geometric considerations alone, there is not sufficient viable joint tissue to recommend disk repositioning as a routine procedure.