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

Roberto Nicolete,Carlos A Sorgi,Peter J Jose,Cristina Rius,Laura Piqueras,Edson G Soares,Maria J Sanz,Lúcia H Faccioli

doi:10.1186/1471-2172-9-36

Roberto Nicolete, Carlos A Sorgi + Show 6 more

Open Access

https://doi.org/10.1186/1471-2172-9-36

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Abstract

BackgroundLeukotriene 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.ResultsIn 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.ConclusionLTB4-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.

Highlights

Leukotriene B4 (LTB4) is a potent inflammatory mediator that stimulates the immune response
Effect of the LTB4-loaded MS administration on leukocyte infiltration into the lungs and leukocyte-endothelial cell interactions To investigate whether microspheres could release the encapsulated LTB4 during days, we assessed the leukocyte infiltration into the lung parenchyma of 5-LO knockout (5-LO-/-) mice submitted to the evaluated administrations
We previously demonstrated that the LTB4 released from microspheres recruited high numbers of mononuclear cells and neutrophils to the bronchoalveolar space of 5-LO-/- mice [27]

Summary

Introduction

Leukotriene B4 (LTB4) is a potent inflammatory mediator that stimulates the immune response. It promotes polymorphonuclear leukocyte phagocytosis, chemotaxis, chemokinesis and modulates cytokines release. In addition to its direct impact on leukocyte effector functions, leukotrienes promote innate immune responses indirectly by stimulating the production of other inflammatory mediators [4,5], inducing phagocytosis [6] and activating antimicrobial mechanisms [7,8]. PPARs have been reported to regulate inflammatory responses, both in vivo and in vitro In this context, PPARα activation by LTB4 binding affects the duration of the inflammatory response induced by this eicosanoid [12]

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