Thymulin, free or bound to PBCA nanoparticles, protects mice against chronic septic inflammation.

Elena G Novoselova,Svetlana B Parfenyuk,Nadezhda M Zakharova,Sergey M Lunin,Evgeny E Fesenko,Maxim O Khrenov,Olga V Glushkova,Bruno Lourenco Diaz

doi:10.1371/journal.pone.0197601

Abstract

In the present work, we aimed to study the effects of free and polybutylcyanoacrylate nanoparticle-bound thymulin on immune cell activity in mice with chronic inflammation. NF-κB, MAPK, and PKC-θ signaling pathway activity was assessed, alongside Hsp72, Hsp90-α, and TLR4 expression and levels of apoptosis. In addition, plasma cytokines and blood and brain melatonin and serotonin levels were measured. In mice treated with gradually raised doses of lipopolysaccharide, significant increases in the activity of the signaling pathways tested, heat-shock protein and TLR4 expression, lymphocyte apoptosis, and plasma proinflammatory cytokine levels were noted. Moreover, we observed significantly heightened serotonin concentrations in the plasma and especially the brains of mice with inflammation. In contrast, melatonin levels were reduced in the tissues examined, particularly so in the brain. Treatment of these mice with thymulin alleviated fever, reduced apoptosis, increased splenic cell number, and decreased cytokine production, Hsp72, Hsp90, and TLR4 expression, and the activity of the signaling pathways examined. In addition, thymulin partially restored brain and blood serotonin and melatonin levels. Thus, thymulin suppressed the proinflammatory response in LPS-treated mice, indicating the potential of thymulin co-therapy in the treatment of sepsis. Nanoparticle-bound thymulin was more effective in several respects.

Highlights

Chronic inflammatory diseases and their most severe complication, sepsis, are common causes of mortality
We revealed that the anti-inflammatory effects of such peptides are mediated by the activity of several intracellular signaling pathways [20], and that one of these peptides, thymulin, increases the anti-inflammatory activity of a specific inhibitor of the NF-κB signaling pathway, IκB kinase (IKK) inhibitor XII, in mice with acute septic inflammation [21]
Rectal temperature was measured throughout the study

Summary

Introduction

Chronic inflammatory diseases and their most severe complication, sepsis, are common causes of mortality. Sepsis may occur after surgery or trauma due to massive cell and tissue death, along with immune dysfunction, and has a fatal outcome in 40–60% of cases. The most severe form of sepsis develops during infection by gram-negative bacteria, and is commonly accompanied by severe immunodeficiency. Available treatments for sepsis, such as antibacterial therapy using antibiotics, infusion therapy with donor fresh frozen plasma, and therapies that alleviate hypercytokinemia by decreasing levels of cytokines [ tumor necrosis factor (TNF)-α], are not successful in all cases.

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