Heme Oxygenase and Spinal Cord Injury

脊髓损伤后的功能恢复归因于介导早期和延迟细胞损伤的继发性致病事件。 这项研究旨在探讨血红素氧合酶-1（HO-1）在创伤性脊髓早期和延迟性损伤中的作用。 血红素加氧酶是唯一的酶代谢的促氧化血红素胆色素，铁和一氧化碳。 细胞外血红素来源于脑实质内出血和死亡细胞释放的血红素蛋白。 虽然出血和持续的细胞死亡都是脊髓损伤的特征，但对血红素如何促进早期和延迟损伤知之甚少。 一般的假设是HO-1对受损脊髓中血红素的解毒至关重要。下面的实验将检验三个主要假设：假设：1。小胶质细胞通过代谢血红素和分隔血红素代谢产物游离铁，在受损脊髓中提供重要的防线。 实验：（1）我们将比较HO-1敲除（KO）和野生型（WT）小鼠中的小胶质细胞反应，并将确定在铁积累和出血区域中是否发生HO-1的急性诱导和小胶质细胞中的铁蛋白表达。 假设2.在小胶质细胞/巨噬细胞中诱导HO-1通过减少氧化应激/损伤促进伤口愈合和运动恢复。 实验：（1）我们将测量HO-1 WT和KO动物中氧化应激/损伤的指标并评价血管再生、白色损伤和运动恢复。 (2)将在脊髓损伤小鼠中评价类似的结果测量，用鞘内血红蛋白预处理，这是一种优先诱导神经胶质中HO-1的策略。 假设3.在损伤之前，脊髓血管中HO-1的诱导稳定血-脊髓屏障，减弱血管粘附分子的早期诱导和炎性细胞的浸润，并促进功能恢复。 实验：我们将确定是否在损伤前全身给予血红素，这是一种优先诱导内皮细胞中HO-1的策略，将限制蛋白质对屏障的破坏，通过调节血管粘附分子限制中性粒细胞的浸润，并促进运动恢复。总之，这些研究反映了集中努力联系出血，氧化应激和脊髓损伤后的功能结果，并将确定HO-1是否保护或损害细胞，调节血脊髓屏障功能和伤口愈合，并影响运动恢复。

Functional recovery after spinal cord injury is attributed to secondary pathogenic events that mediate early and delayed cell injury. The proposed studies examine the role of heme oxygenase-1 (HO-1) in both early and delayed injury in the traumatized spinal cord. Heme oxygenases are the only enzymes that metabolize the pro-oxidant heme to bile pigments, iron, and carbon monoxide. Extracellular heme is derived from intraparenchymal hemorrhage and heme proteins released from dying cells. Although both hemorrhage and ongoing cell death are features of the injured spinal cord, little is known about how heme contributes to early and delayed injury. The general hypothesis s that HO-1 is crucial for the detoxification of heme in the traumatized cord. The following experiments will test three major hypothesis: Hypothesis: 1. Microglia provide an important line of defense in the traumatized cord by metabolizing heme and compartmentalizing free iron, a product of heme metabolism. Experiments: (1) We will compare the microglial response in HO-1 knockout (KO) and wildtype (WT) mice and will determine if acute induction of HO-1 and ferritin expression in microglia occur in regions of iron accumulation and hemorrhage. Hypothesis 2. Induction of HO-1 in microglia/macrophages promotes wound healing and locomotor recovery by reducing oxidative stress/injury. Experiments: (1) We will measure indicators of oxidative stress/injury and evaluate revascularization, white matter injury, and locomotor recovery in HO-1 WT and KO animals. (2) Similar outcome measures will be evaluated in spinal cord injured mice, pretreated with intrathecal hemoglobin, a strategy that preferentially induces HO-1 in glia. Hypothesis 3. Induction of HO-1 in spinal cord blood vessels, prior to injury, stabilizes the blood-spinal cord barrier, attenuates the early induction of vascular adhesion molecules and infiltration of inflammatory cells, and promotes functional recovery. Experiments: We will determine if systemic administration of heme prior to injury, a strategy which preferentially induces HO-1 in endothelium, will restrict barrier disruption to proteins, limit the infiltration of neutrophils through the modulation of vascular adhesion molecules, and promote locomotor recovery. In summary, these studies reflect a focused effort to link hemorrhage, oxidative stress and functional outcome after spinal cord injury and will determine if HO-1 protects or harm cells, modulates blood-spinal cord barrier function and wound healing, and influences locomotor recovery.