Inflammatory and oxidative stress phenotypes in transgenic sickle cell mice

Abstract

The Townes mouse model of homozygous sickle cell disease (SS) has emerged as the major experimental model for studying pathophysiological mechanisms of human sickle cell disease (SCD). We therefore investigated hematological and hemorheological parameters as well as organ-specific inflammatory and oxidative stress molecular profiles in these animals in steady state conditions. Evidences of SCD-related intravascular hemolysis, impaired red blood cell (RBC) deformability, leukocytosis and altered plasma nitric oxide byproducts (NOx) level were found in the SS mice. The SS mice have damaged, enlarged and dysfunctional spleen as attested by high AOPP levels, low SOD and GPx activities and low pro-inflammatory cytokines mRNA expression. SS mice exhibited cardiomegaly, high cardiac mRNA levels of proinflammatory markers and low cardiac GPx activity. While lungs did not display any noticeable defects, liver and kidney were particularly sensitive to oxidative stress and inflammation as suggested by high AOPP levels in both organs, elevated renal NF-κB and TNF-α, and increased hepatic VCAM-1 and IL-1β. Our data indicate a tissue-specific phenotype regarding oxidative stress and inflammation in SS mice that may help to optimize the development of novel potential drug treatments.

Keywords: Inflammation; Nitric oxide; Oxidative stress; Sickle cell disease.