Abstract
IntroductionGlucocorticoids are commonly used as therapeutic agents in many acute and chronic inflammatory and auto-immune diseases. The current study investigated the effects of methylprednisolone (a synthetic glucocorticoid) on aortic distensibility and vascular resistance in lipopolysaccharide-induced chronic inflammation in male Wistar rats.MethodsChronic inflammation was induced by implanting a subcutaneous slow-release ALZET osmotic pump (1 mg kg−1 day−1 lipopolysaccharide) for either 2 or 4 weeks. Arterial wave transit time (τ) was derived to describe the elastic properties of aortas using the impulse response function of the filtered aortic input impedance spectra.ResultsLong-term lipopolysaccharide challenge enhanced the expression of advanced glycation end products (AGEs) in the aortas. Lipopolysaccharide also upregulated the inducible form of nitric oxide synthase to produce high levels of nitric oxide (NO), which resulted in vasodilation, as evidenced by the fall in total peripheral resistance (Rp). However, lipopolysaccharide challenge did not influence the elastic properties of aortas, as shown by the unaltered τ. The NO-mediated vascular relaxation may counterbalance the AGEs-induced arterial stiffening so that the aortic distensibility remained unaltered. Treating lipopolysaccharide-challenged rats with methylprednisolone prevented peripheral vasodilation because of its ability to increase Rp. However, methylprednisolone produced an increase in aorta stiffness, as manifested by the significant decline in τ. The diminished aortic distensibility by methylprednisolone paralleled a significant reduction in NO plasma levels, in the absence of any significant changes in AGEs content.ConclusionMethylprednisolone stiffens aortas and elastic arteries in lipopolysaccharide-induced chronic inflammation in rats, for NO activity may be dominant as a counteraction of AGEs.
Highlights
Glucocorticoids are commonly used as therapeutic agents in many acute and chronic inflammatory and autoimmune diseases
nuclear factor-kB (NF-kB) activation enhances the expression of receptor for advanced glycation end products (RAGE) as NF-kB
The LPS-challenged animals exhibited no significant difference in body weight (BW), LV weight (LVW) and LVW/BW ratio from that of the age-matched shams
Summary
Glucocorticoids are commonly used as therapeutic agents in many acute and chronic inflammatory and autoimmune diseases. An in vivo animal model of systemic inflammation in which lipopolysaccharide (LPS) is infused is useful for studying the integrative mediator pathways of inflammation as well as hemodynamic and functional changes in acute and chronic inflammatory disorders. When LPS binding protein binds LPS to its receptors, especially Toll-like receptor (TLR)-4, downstream intracellular signaling pathways are initiated; the ultimate result is the activation of nuclear factor-kB (NF-kB) [2]. NF-kB activation enhances the expression of receptor for advanced glycation end products (RAGE) as NF-kB possesses a binding site for the RAGE gene [4]. Binding of RAGE by its ligands such as advanced glycation end products (AGEs) produces reactive oxygen species, which further activates NF-kB to amplify RAGE signal transduction. The RAGE-AGE interaction associated with LPS stimulation may maintain and even amplify inflammatory activities, critically leading to vascular dysfunction
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