RESUMO
The formylpeptide receptor 2 (FPR2/ALX) is a very promiscuous receptor, utilized by lipid and protein ligands that trigger pro- or anti-inflammatory responses. FPR2/ALX expression is increased in lung tissues of septic animals and its activation has a beneficial therapeutic effect by controlling exacerbated inflammation. Although FPR2/ALX expression was observed in vascular smooth muscle cells, its role in vascular reactivity in inflammatory conditions has not been studied. In this study, we report that LPS increases FPR2/ALX expression in vascular smooth muscle cells (A7r5 cells) and aorta tissue, and that the selective agonist WKYMVm reverses LPS-induced vascular hyporeactivity in mouse aorta rings. Mice bearing pneumosepsis by Klebsiella pneumoniae and treated with WKYMVm recovered the reactivity to vasoconstrictors and the survival improved by 40%. As for the mechanisms involved, FPR2/ALX activation decreases NO production in LPS-stimulated cells and aorta, but it does not seem involve the regulation of NOS-2 expression. The molecular mechanism by which the peptide inhibits NO production still needs to be elucidated, but our data suggests an important role for NO in the WKYMVm beneficial effect observed in LPS injury and sepsis. In conclusion, our data suggest, for the first time, that a receptor, primarily described as a mediator of immune responses, may have an important role in the vascular dysfunctions observed in sepsis and may be a possible target for new therapeutic interventions.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Oligopeptídeos/uso terapêutico , Receptores de Formil Peptídeo/agonistas , Sepse/tratamento farmacológico , Vasculite/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aorta/efeitos dos fármacos , Aorta/imunologia , Aorta/metabolismo , Linhagem Celular , Endotélio Vascular/fisiologia , Endotélio Vascular/fisiopatologia , Técnicas In Vitro , Infecções por Klebsiella/metabolismo , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/fisiopatologia , Klebsiella pneumoniae/crescimento & desenvolvimento , Klebsiella pneumoniae/imunologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/metabolismo , Óxido Nítrico/agonistas , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Oligopeptídeos/farmacologia , Ratos , Receptores de Formil Peptídeo/metabolismo , Sepse/metabolismo , Sepse/microbiologia , Sepse/fisiopatologia , Análise de Sobrevida , Resistência Vascular/efeitos dos fármacos , Vasculite/etiologia , Vasculite/imunologiaRESUMO
In this article, we review the current status of inflammation linked to percutaneous transluminal angioplasty with stent implantation, especially as it relates to restenosis and its clinical implications. Common to multiple vascular diseases, including atherosclerosis, interventional restenosis is a localized inflammatory reaction. Activated smooth muscle cells respond to local inflammation and migrate from the media into the lumen of the vessel, where they proliferate and synthesize cytokines which they respond to in an autocrine manner, sustaining the progression of the lesion. The deleterious effects of proinflammatory cytokines, particularly immunomodulatory interleukins, on vascular pathophysiology and development of these maladaptive processes have been the subject of intense study. Matrix metalloproteinases and tissue inhibitors of metalloproteinases are important in many physiologic and pathologic processes and their expression is related with the classic cardiovascular risk factors as well as with inflammation. They seem to play a central role in atherosclerosis and restenosis. The primary use of drug-eluting stents has become routine clinical practice for coronary artery disease, but the use in peripheral arteries remains to be further studied, like that demonstrated in sirolimus-coated Cordis trials. New studies to understand this complex process in peripheral arteries are warranted.