Monocyte Chemotactic Protein-1-Interleukin-6-Osteopontin Pathway of Intra-Aneurysmal Tissue Healing.

BACKGROUND AND PURPOSE: We have previously demonstrated that the local delivery of monocyte chemotactic protein-1 (MCP-1) via an MCP-1-releasing poly(lactic-co-glycolic acid)-coated coil promotes intra-aneurysmal tissue healing. In this study, we demonstrate that interleukin-6 (IL-6) and osteopontin are downstream mediators in the MCP-1-mediated aneurysm-healing pathway. METHODS: Murine carotid aneurysms were created in C57BL/6 mice. Drug-releasing coils (MCP-1, IL-6, and osteopontin) and control poly(lactic-co-glycolic acid) coils were created and then implanted into the aneurysms to evaluate their intra-aneurismal-healing capacity. To investigate the downstream mediators for aneurysm healing, blocking antibodies for IL-6 receptor and osteopontin were given to the mice implanted with the MCP-1-releasing coils. A histological analysis of both murine and human aneurysms was utilized to cross-validate the data. RESULTS: We observed increased expression of IL-6 in MCP-1-coil-treated aneurysms and not in control-poly(lactic-co-glycolic acid)-only-treated aneurysms. MCP-1-mediated intra-aneurysmal healing is inhibited in mice given blocking antibody to IL-6 receptor. MCP-1-mediated intra-aneurysmal healing is also inhibited by blocking antibody to osteopontin. The role of IL-6 in intra-aneurysmal healing is in recruiting of endothelial cells and fibroblasts. Local delivery of osteopontin to murine carotid aneurysms via osteopontin-releasing coil significantly promotes intra-aneurysmal healing, but IL-6-releasing coil does not, suggesting that IL-6 cannot promote aneurysm healing independent of MCP-1. In the MCP-1-mediated aneurysm healing, osteopontin expression is dependent on IL-6; inhibition of IL-6 receptor significantly inhibits osteopontin expression in MCP-1-mediated aneurysm healing. CONCLUSIONS: Our findings suggest that IL-6 and osteopontin are key downstream mediators of MCP-1-mediated intra-aneurysmal healing.

Idiopathic Thrombocytopenic Purpura Induced by Synthetic Cannabinoid.

: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder defined as low platelet count with normal bone marrow in the absence of other causes of thrombocytopenia. It is caused by autoantibodies binding to several platelet surface antigens which lead to premature destruction of the platelet by the reticuloendothelial system. ITP can be primary or secondary, and it is known to be associated with various infections and drugs. K2/Spice, or synthetic marijuana, acts on cannabinoid receptors CB1 (cannabinoid type-1) and CB2 (cannabinoid type-2) with increased binding capacity compared to marijuana. A white male was brought to the emergency department with signs of acute drug toxicity. His urine drug test was negative but he admitted to a year long history of synthetic marijuana use. His platelet count was 12,000/mm and he was diagnosed with ITP. After receiving 2 doses of oral dexamethasone his platelets improved. Synthetic cannabinoids are widely available and used psychoactive drugs. Little is known about the complete chemical composition of the synthetic products thus there is relatively little information available on the pharmacodynamic and pharmacokinetic effects. A high index of suspicion is needed to diagnose toxicity to these drugs since there are no readily available on-site lab tests. Currently there exists 1 case report of ITP induced by K2/Spice. Here, we discuss another case of K2/Spice a as a potential cause of immune thrombocytopenia.

Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin-17A Which Downregulates E-Cadherin.

BACKGROUND: Estrogen deficiency is associated with the development of cerebral aneurysms; however, the mechanism remains unknown. We explored the pathway of cerebral aneurysm development by investigating the potential link between estrogen deficiency and inflammatory factors. METHODS AND RESULTS: First, we established the role of interleukin-17 (IL-17)A. We performed a cytokine screen demonstrating that IL-17A is significantly expressed in mouse and human aneurysms (P=0.03). Likewise, IL-17A inhibition was shown to prevent aneurysm formation by 42% (P=0.02) and rupture by 34% (P<0.05). Second, we found that estrogen deficiency upregulates T helper 17 cells and IL-17A and promotes aneurysm rupture. Estrogen-deficient mice had more ruptures than control mice (47% versus 7%; P=0.04). Estradiol supplementation or IL-17A inhibition decreased the number of ruptures in estrogen-deficient mice (estradiol 6% versus 37%; P=0.04; IL-17A inhibition 18% versus 47%; P=0.018). Third, we found that IL-17A-blockade protects against aneurysm formation and rupture by increased E-cadherin expression. IL-17-inhibited mice had increased E-cadherin expression (P=0.003). E-cadherin inhibition reversed the protective effect of IL-17A inhibition and increased the rate of aneurysm formation (65% versus 28%; P=0.04) and rupture (12% versus 0%; P=0.22). However, E-cadherin inhibition alone does not significantly increase aneurysm formation in normal mice or in estrogen-deficient mice. In cell migration assays, E-cadherin inhibition promoted macrophage infiltration across endothelial cells (P<0.05), which may be the mechanism for the estrogen deficiency/IL-17/E-cadherin aneurysm pathway. CONCLUSIONS: Our data suggest that estrogen deficiency promotes cerebral aneurysm rupture by upregulating IL-17A, which downregulates E-cadherin, encouraging macrophage infiltration in the aneurysm vessel wall.