Factors in the ACS that contribute to intrapulmonary erythrocyte-endothelial adhesion are depicted. Hypoxia induces cytokine and endothelial-1 release, which singly and in combination upregulate VCAM-1. NO acts as a cytoprotective mediator that inhibits both endothelin-1 production and endothelial VCAM-1 expression under normal circumstances. However, during the pathophysiology of sickle cell ACS, sickled RBCs and hypoxia can both inhibit NO production (by decreasing cNOS transcription), leading to unopposed VCAM-1 upregulation and consequent RBC-endothelial adhesion.