Molecular Modulation Of Traumatic Edema And Peri-tumor Edema In Human Brain: Roles Of 5-lipoxygenase/cysteinyl Leukotriene Receptors And Aquapotin 4 (AQP4)

Both traumatic brain injury and brain tumor cause brain edema, which subsequently lead to neurological dysfunction, intracranial pressure increase, cerebral hernia and even death in severe cases. Therefore, brain edema is the common pathological and physiological basis for these diseases. Investigation of the mechanisms underlying brain edema is very important for understanding pathogenesis and developing treatments of such diseases.There are two types of brain edema: cytotoxic and vasogenic edemas. The causes are multiple and the mechanisms underlying brain edema are complicated. Among these mechanisms, aquaporins (AQPs), which is widely distributed in tissues (including in human tissues), is thought to play an important role in normal balance of intracellular water, and therefore in the formation and decay of brain edema. AQPs are a superfamily of transmembrane proteins that modulate water balance. Up to date, 11subtypes of AQPs have been cloned. AQPs are widely distributed in almost all the tissues from bacteria to mammals. In human brain, 6 subtypes of AQPs are expressed. Among these subtypes, AQP1 and AQP4 are the most important types. AQP1 is mostly expressed in choroids plexus, regulating the secretion of cerebro-spinal fluid (CSF); while AQP4 is normally distributed in the brain parenchyma. AQP4 is primarily expressed in glial cells surrounding the blood-brain and the brain-CSF interfaces. At the blood-brain barrier (BBB), AQP4 is expressed in the astrocytic foot processes adjacent to vascular endothelial cells. At the brain-CSF interface, AQP4 is found in the ependymal cells on the basal side of the plasma membrane. From AQP4 distribution, it can be inferred that AQP4 may play an important role in water transport between fluid compartments within the brain and maintain the water balance.Following traumatic cortical contusions in rats, the amount of AQP4 mRNA was significantly higher in the site of injury than that in non-injured sites in the same brain. Furthermore, the expression level of AQP4 correlates with the degree of brain edema indicated by MRI. In AQP4-knockout mice with cerebral ischemia and water intoxication, brain edema was significantly decreased, neurological outcomes were improved, and survival rate was elevated as compared to wild-type mice. In human autopsy brain samples from patients with cerebral ischemic infarction, AQP4 immunoreactivity was more intense at the periphery of ischemic foci. There is also reported that AQP4 protein expression was decreased after brain injury in rats, especially at the traumatic hemisphere. However, how AQP4 is expression in the human brain following injuries is still unknown. Therefore, the expression of AQP4 in human brain with traumatic injury and brain tumor remains to be determined.In addition, 5-lipoxygenase (5-LOX) and its products, cysteinyl leukotrienes (CysLTs, including LTC4, LTD4 and LTE4), are potent inflammatory mediators. They also increase the permeability of BBB and cause brain edema. The effects of CysLTs are mediated by CysLT receptors. Pharmacological studies have shown that CysLT receptors have two types, CysLTi and CysLT2 receptors, in the lungs. In the past decade, CysLT 1 and CysLT2 receptors are cloned; they are typical Gq protein-coupledreceptors with seven transmembrane domains, which can increase calcium level when activated. CysLT1 receptor is highly expressed in the spleen, peripheral blood leukocytes, while weakly in the brain, lung, heart, colon, pancreas, prostatic gland, kidney and liver. CysLT2 receptor is highly expressed in the spleen, heart and peripheral blood leukocytes, and weakly in the brain, prostate, kidney and ovary. CysLT2 receptor is expressed much more than CysLTi receptor in the brain as detected by Northern blot and RT-PCR. However, the expressions of CysLTi and CysLT2 receptors in the human brain are not yet reported, especially in the patients with traumatic brain injury and tumors. As the rate-limited enzyme in biosynthesis of CysLTs, 5-LOX is expressed in normal brains, and hypoxia, cerebral ischemia and...