Abstract
The aim of the current study was to investigate the effects of glucosamine (GlcN) on septic lethality and sepsis-induced inflammation using animal models of mice and zebrafish. GlcN pretreatment improved survival in the cecal ligation and puncture (CLP)-induced sepsis mouse model and attenuated lipopolysaccharide (LPS)-induced septic lung injury and systemic inflammation. GlcN suppressed LPS-induced M1-specific but not M2-specific gene expression. Furthermore, increased expressions of inflammatory genes in visceral tissue of LPS-injected zebrafish were suppressed by GlcN. GlcN suppressed LPS-induced activation of mitogen-activated protein kinase (MAPK) and NF-κB in lung tissue. LPS triggered a reduction in O-GlcNAc levels in nucleocytoplasmic proteins of lung, liver, and spleen after 1 day, which returned to normal levels at day 3. GlcN inhibited LPS-induced O-GlcNAc down-regulation in mouse lung and visceral tissue of zebrafish. Furthermore, the O-GlcNAcase (OGA) level was increased by LPS, which were suppressed by GlcN in mouse and zebrafish. OGA inhibitors suppressed LPS-induced expression of inflammatory genes in RAW264.7 cells and the visceral tissue of zebrafish. Stable knockdown of Oga via short hairpin RNA led to increased inducible nitric oxide synthase (iNOS) expression in response to LPS with or without GlcN in RAW264.7 cells. Overall, our results demonstrate a protective effect of GlcN on sepsis potentially through modulation of O-GlcNAcylation of nucleocytoplasmic proteins.
Highlights
The aim of the current study was to investigate the effects of glucosamine (GlcN) on septic lethality and sepsis-induced inflammation using animal models of mice and zebrafish
GlcN pretreatment decreases mortality and systemic inflammation in septic mice To examine the effects of GlcN on septic mortality, we monitored mouse survival after cecal ligation and puncture (CLP) with or without GlcN (200 mg/kg) for 12 days (Fig. 1A)
In the present study, we employed the CLP model to examine the effect of GlcN on lethality, whereas the LPS model for moderate sepsis was applied to examine the inhibitory effect of GlcN on lung and systemic inflammation in mice
Summary
The aim of the current study was to investigate the effects of glucosamine (GlcN) on septic lethality and sepsis-induced inflammation using animal models of mice and zebrafish. Increased expressions of inflammatory genes in visceral tissue of LPS-injected zebrafish were suppressed by GlcN. GlcN suppressed LPS-induced activation of mitogen-activated protein kinase (MAPK) and NF-B in lung tissue. GlcN inhibited LPS-induced O-GlcNAc down-regulation in mouse lung and visceral tissue of zebrafish. OGA inhibitors suppressed LPS-induced expression of inflammatory genes in RAW264.7 cells and the visceral tissue of zebrafish. LPS induces ALI in animal models by promoting pulmonary microvascular permeability and recruiting activated neutrophils and macrophages to the lung [6]. Macrophages circulating in blood or residing in tissues represent the first barrier against external infection through controlling both innate and acquired immunity. Because of their diversity and plasticity, macrophages undergo heterogeneous activation and polarization. M1 macrophages release proinflammatory molecules such as IL-1, IL-6, TNF-␣, and reactive nitrogen and oxygen intermediates, which cause tissue damage, whereas M2 macrophages release anti-inflammatory cytokines that promote wound healing and tissue repair [8]
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