Leukotriene B4-loaded microspheres: a new therapeutic strategy to modulate cell activation

Abstract Background Leukotriene B4 (LTB4) is a potent inflammatory mediator that also stimulates the immune response. In addition, it promotes polymorphonuclear leukocyte phagocytosis, chemotaxis, chemokinesis and modulates cytokines release. Regarding chemical instability of the leukotriene molecule, in the present study we assessed the immunomodulatory activities conferred by LTB4 released from microspheres (MS). A previous oil-in-water emulsion solvent extraction-evaporation method was chosen to prepare LTB4-loaded MS. Results In the mice cremasteric microcirculation, intraescrotal injection of 0.1 ml of LTB4-loaded MS provoked significant increases in leukocyte rolling flux, adhesion and emigration besides significant decreases in the leukocyte rolling velocity. LTB4-loaded MS also increase peroxisome proliferator-activated receptor-α (PPARα) expression by murine peritoneal macrophages and stimulate them to generate nitrite levels. Monocyte chemoattractant protein-1 (MCP-1) and nitric oxide (NO) productions were also increased when human umbilical vein and artery endothelial cells (HUVECs and HUAECs, respectively) were stimulated with LTB4-loaded MS. Conclusion LTB4-loaded MS preserve the biological activity of the encapsulated mediator indicating their use as a new strategy to modulate cell activation, especially in the innate immune response.

We are grateful to the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 02/12856-2 and 05/00110-4), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPp) and grants SAF 2005-01649, CICYT, Spanish Ministerio de Educación y Ciencia; Research Group 03/166 of Conselleria de Cultura y Educación (Generalitat Valenciana). RN was supported by a grant of Programa de Mobilidade Internacional, Banco Santander. CR and LP were supported by a grant from Spanish Ministerio de Educacion y Ciencia. PJJ was supported by a grant from the University of Valencia, Spain.

We are grateful to the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 02/128562 and 05/001104), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPp) and grants SAF 200501649, CICYT, Spanish Ministerio de Educación y Ciencia; Research Group 03/166 of Conselleria de Cultura y Educación (Generalitat Valenciana). RN was supported by a grant of Programa de Mobilidade Internacional, Banco Santander. CR and LP were supported by a grant from Spanish Ministerio de Educacion y Ciencia. PJJ was supported by a grant from the University of Valencia, Spain.