Abstract
Leukocyte adhesion to vascular endothelium contributes to vaso-occlusion and widespread organ damage in sickle cell disease (SCD). Previously, we found high expression of the adhesion molecules αMβ2 integrin and L-selectin in HbSS individuals with severe disease. The n-6 and n-3 polyunsaturated fatty acids (FA) are vital structural and functional components of cell and sub-cellular membranes. They modulate cell adhesion, inflammation, aggregation and vascular tone. We investigated the FA composition of mononuclear cells (MNC) and platelets of HbSS patients in steady-state (n = 28); and racially matched, healthy HbAA controls (n = 13). MNC phospholipids of the patients had low levels of docosahexanoic acid (DHA, p<0.01), n-3 metabolites (p<0.05) and total n-3 polyunsaturated FA (p<0.05); table 1. In contrast, arachidonic (AA, p<0.005), AA:DHA ratio (p<0.005, fig 1) and total n-6 metabolites (p<0.05) were increased in the patients. Similarly, platelets from HbSS patients had low levels of eicosapentanoic acid (EPA, p<0.05), and raised AA (p<0.05) in choline phosphoglycerides (CPG); with reduced linoleic acid (LA, p<0.005) and DHA (p<0.05) in ethanolamine phosphoglycerides. Platelet CPG had lower DHA levels in HbSS individuals with complications of SCD compared to those who had no complications (p<0.05, fig.2). Reduced EPA and DHA relative to AA favours the production of aggregatory and pro-inflmmatory eicosanoids that activate leukocytes and platelets. This may lead to enhanced inflammation, leukocyte adhesion, platelet aggregation and vaso-occlusion in SCD.
Table 1: Fatty Acid Composition of MNC Total Phospholipids in HbSS Patients and HbAA Controls
Fatty Acids HbSS Patients HbAA Controls Values are Means [SD}. *p<0.05, **p<0.01, ***p<0.005, ****p<0.001 24:0 0.71 [0.30]*** 1.3 [0.4] saturates ∑ 38.2 [3.6] 39.1 [1.7] 16:1 0.69 [0.45] 0.56 [0.11] 18:1 14.4 [1.8]* 12.9 [1.9] 24:1 1.2 [0.3] 1.1 [0.4] ∑monoenes 16.2 [2.1]** 14.3 [1.4] 18:2n-6 6.1 [0.9] 7.0 [1.4] 18:3n-6 0.11 [0.04]* 0.23 [0.17] 20:2n-6 0.56 [0.18]** 0.83 [0.32] 20:3n-6 (DHGLA) 1.2 [0.2]* 1.4 [0.2] 20:4n-6 20.2 [1.7]*** 18.1 [1.8] 22:4n-6 1.7 [0.4] 1.6 [0.4] 22:5n-6 0.3 [0.21] 0.24 [0.14] n-6 metabolites ∑ 24.1 [1.9]* 22.6 [1.7] n-6 ∑ 30.2 [2.0] 29.7 [2.2] 20:5n-3 (EPA) 0.43 [0.16] 0.61 [0.35] 22:6n-3 (DHA) 1.9 [0.4]** 2.5 [0.6] ∑n-3metabolites 4.3 [0.9]* 4.8 [0.4] n-3 ∑ 4.5 [0.9]* 5.0 [0.4] DHGLA:AA ratio 0.06 [0.01]**** 0.08 [0.01] AA:EPA ratio 52.4 [20.9] 38.6 [18.4]
Sickle Cell Disease Activates Peripheral Blood Mononuclear Cells to Induce Cathepsins K and V Activity in Endothelial Cells