Characteristic chronic hemolysis in sickle cell anemia is presumed to induce an inflammatory response through sub-clinical vasooclusion. Acute phase reactants such as C-reactive protein are elevated in both stable patients and during vasoocusive crisis. However, the role and pattern of inflammatory cytokines, which are generally depressed in stable HbSS patients, remains inconclusive and there is very limited information about the inflammatory response in organs, e.g. liver, where acute phase proteins and cytokine production are initiated. In sickle cell anemia patients, abnormal adherence of 'sickled'red cells to vascular endothelium induces local inflammation via sub-clinical ischemia, vasoocclusion, reperfusion and hemolysis. In our preliminary studies, we have found that in asymptomatic sickle cell children and a transgenic sickle cell mouse model, plasma L-arginine concentration is significantly low compared with healthy controls. Also sickle cell transgenic mice grew faster on a 35% (high) protein diet and this diet was associated with reduced concentrations of inflammatory indicators CRP and IL6, compared with sickle cell transgenics on a 20% (normal) diet. It is our hypothesis that the sickle cell mice on the high protein diet have less inflammation due to increased L-arginine availability from their diet for nitric oxide production and subsequent repair functions. We will test this hypothesis by studying a transgenic mouse model with human sickle cell hemoglobin over three months, to determine the effect of short term and chronic sub-clinical ischemia on the production of acute phase proteins and cytokines. Experiments will include blood chemistry, enzyme activity, and RNA and protein expression analysis of plasma, liver, spleen and kidney, plus histopathology of these organs.
Specific aims are: 1) to determine the temporal changes of proinflammatory and anti-inflammatory markers affecting nitric oxide production in weanling transgenic sickle cell mice versus control mice, fed standard and high protein diets and 2) to determine the effect of supplementing the standard diet for sickle cell mice with L-arginine, thus investigating the mechanism for the reduced inflammation observed on the high protein diet. This research will assist in seeking nutritional remedies for reducing sub-clinical tissue injury in sickle cell disease.
Chronic inflammation is a component of sickle cell anemia, demonstrated by high levels of white blood cells and inflammatory proteins. However, the role and pattern of inflammatory proteins in sickle cell anemia remain inconclusive, and the development of the chronic inflammation over time is unknown. In our preliminary data, a high protein diet reduces circulating and liver inflammation in the Berkeley sickle cell mouse model. The use of this mouse model is important for investigating the time course of sickle cell induced tissue inflammation, and for seeking practical and effective dietary treatment to reduce the tissue injury.
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