Fig. 1

Origins of ongoing inflammatory processes in SCD patients. Endogenous stimuli arise due to erythrocyte membrane damage induced by a combination of background HbS polymerization and auto-oxidation. Exogenous stimuli contributing to the ongoing inflammatory process are due to increased intestinal permeability and enhanced translocation of bacteria/bacterial products into the systemic circulation to stimulate leukocytes and aged neutrophils. The inflammatory processes are compensated by various host adaptive mechanisms that prevent the progress of the process to VOC. Events such as infection/inflammation, stress, dehydration, increased hemolysis, and hypoxemia tilt the equilibrium and result in a decompensation state that precipitates the development of VOC. Cytokine reactions associated with ischemia/reperfusion injury induced by VOC may further feed into increasing the intestinal permeability (represented by dashed lines) and form part of the vicious cycle of vaso-occlusion