| The decompression sickness (DCS) occurs due to a sudden or excessively rapidreduction in ambient pressure. DCS manifestations range from simple joint pain to severeinjury, including cardiopulmonary failure and neurologic deficits. Neurological deficits,such as sensory abnormalities, difficulty walking, and paraplegia, are attributed to spinalcord injury. The spinal cord white matter is, therefore, considered a major target organ forDCS. While there is no definitive etiology of neurologic DCS, bubbles in the tissue andblood vessels after decompression are purported to be responsible for DCS inducedneurological symptoms. Bubbles may play a role in DCS spinal cord injury in two possibleways: first, intravascular or extravascular bubbles may directly cause mechanical damageto blood vessels and decrease the spinal cord perfusion resulting in neurological damage.Second, bubbles may also initiate biochemical cascades such as leukocyte adhesion,platelet aggregation, or complement activation, which, in turn, lead to ischemic damage.Although the significance of ischemia in the spinal cord injury pathogenesis after fastdecompression is still debated, several publications clearly demonstrated that spinal cordischemia is responsible for the neurological deficits. The beneficial effects of treatmentsfor ischemia have also been shown to be beneficial in animal models of DCS.Treatment with helium inhalation has been proven effective for spinal cord DCS afterair dives by divers not responding to treatment with oxygen. Helium inhalation afterdecompression can also improve spinal conductive functions in animal models of DCS.The effect of helium inhalation on the development of DCS can be explained by helium’sphysical properties. Furthermore, recent publications have shown that biochemical actionsof helium also underlie its beneficial effects. HPC, on the other hand, can reduce ischemicdamage in cardiac and brain tissues, indicating that HPC may have additional benefits forDCS treatment. Several molecular pathways are implicated in beneficial effects of HPC,but specific mechanisms and signaling pathways responsible for HPC actions remainpoorly understood. Ischemia/reperfusion (IR) injury in the liver/brain is a major complication of organtransplantation, organ resection and trauma. The pathophysiology of IR injury includesboth direct cellular damage as the result of the ischemic insult and delayed dysfunction,which is a consequence of inflammatory pathways activation. Histopathological changesafter IR injury include: cellular swelling, vacuolization, endothelial cell disruption,neutrophil infiltration, necrosis and apoptosis. Despite improved preservation andsurgical techniques, IR injury resulting from donor organ retrieval, cold storage, andwarm ischemia during the surgery often leads to dysfunction, a predisposition to chronicrejection and ultimately contributes to the acute shortage of donor organs available fortransplantation. New therapeutic strategies preventing or attenuating the harmfulprocesses triggered by reperfused ischemic tissues are, therefore, urgently needed.Helium is safe for use in clinical and diving because of its favorable characteristicsand the lack of hemodynamic side effects. Recent experimental research hasconvincingly shown helium’s protective properties against ischemia in the heart and thebrain. These organs can be protected against IR injury by subjecting them to several shorthelium episodes according to a specific protocol, known as helium preconditioning(HPC). However, the specific mechanisms and signaling pathways responsible forHPC-induced protections remain poorly understood. The phosphatidylinositol-3-kinasePI3K/Akt pathway is a survival pathway, involved in protection against various stressors.Activation of Akt promotes cell survival by modulation of various downstream elements,including glycogen synthase kinase-3β (GSK-3β) and Bcl-2-associated death promoter(BAD). Phosphorylation of GSK-3β and BAD by Akt can suppress caspase-3activityand inhibit cell apoptosis. Additionally, Akt inhibits activation of NF-κB, which results inthe suppression of hepatic inflammation. Activation of Akt also inhibits the activity ofc-Jun N-terminal kinase (JNK) and ameliorates cell necrosis. PI3K acts as an upstreamtrigger for p38mitogen-activated protein kinase (p38-MAPK) activation, which caninterfere with the processes leading to cell necrosis. Thus, activation of the PI3K/Aktpathway plays an important protective role during IR.Part1Beneficial effects of helium preconditioning on decompression inducedneurological deficits in ratsMethods: Fifty male Sprague-Dawley rats were divided into two groups:1) the DCS group (n=25) and2) the DCS+helium preconditioning (HPC) group (n=25). Toinduce DCS, rats underwent the compression to a pressure of709kPa at a rate of101kPa/min and kept by the pressure for60min. Then animals were decompressed at a rateof203kPa/min. Animals in the preconditioning group were subjected to three episodesof helium inhalation (70%of helium and30%of oxygen, five minutes each expose)interspersed with5minutes air inhalation before compression. Additionally5naiveanimals were sacrificed for histological examination. Clinical monitoring, neurologicaltesting, biochemical and histological assay as well as ultrasound Doppler technique wereused as measurements.Results: HPC significantly decreased the incidence of DCS, and delayed the onsettime of DCS. HPC also significantly ameliorated the neurological deficits at15minutesafter decompression. The number of platelets was significantly decreased in both theDCS and DCS+HPC groups compared with the baseline values, but HPC had no effecton DCS-induced decrease of platelets numbers. HPC neither affect bubble formationafter fast decompression. Foci of demyelination could be found in luxol fast blue-stainedspinal cord sections from severe-DCS rats.Conclusion: Helium preconditioning decreased the occurrence of DCS andameliorated DCS-induced neurological deficits.Part2Helium preconditioning protects mouse liver against ischemia andreperfusion injury through PI3k-Akt pathwayMethods: We employed a model of segmental warm hepatic IR on BALb/c mice.Serum Alt was measured and livers were analyzed by histology, RT-PCR, western blot.HPC was induced by inhalation of70%helium-30%oxygen mixture for three5-minperiods interspersed in between with three5-min washout periods by room air. We alsotested which component of HPC (the mixture of helium/air inhalation, the air room gap,or the interaction of these two factors) is protective.Results: We found out that HPC caused a significant increase in Aktphosphorylation in hepatocytes. The HPC-induced Akt phosphorylation resulted indecreased hepatocellular injury and improved survival rate of treated animals. PI3kinhibitors abolished HPC induced effects. HPC-induced Akt phosphorylation affectedexpression of it’s downstream molecules. The effects of HPC on the PI3K/Akt pathway were attenuated by adenosine A2a receptor blockade, but can be re-established by PTENinhibitor. We demonstrated the interaction effect of helium/air breathing and air gap isresponsible for observed effects of HPC.Conclusion:1) HPC reduced IR-induced liver injury in mice;2) The protective effects induced by HPC are mediated through PI3k-Akt pathwayactivation, probably via adenosine A2a receptor activation;3) The interaction effect of helium/air inhalation and the air room gap, rather thanthese two factors alone, is responsible for the HPC-induced protection.Part3Protective effects of helium preconditioning on focal cerebralischemia-reperfusion injury in ratsMethods: To study the effects and the possible mechanisms of HPC on the rats withacute transient focal cerebral IR injury, the rat model of focal cerebral IR model wasestablished by middle cerebral artery occlusion (2h) and reperfusion (24h). Healthyadult SD rats were divided into3groups: Control group, IR group and HPC group. Thedegree of cerebral injury was evaluated by neurological deficit score, infarct volume,superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Themorphological changes of the brain were observed by HE staining.Results: Compared with IR group, the neurological deficit score, infracted volumeand the content of MDA were decreased, and the SOD activity was increased in HPCtreated groups.Conclusion: HPC has a protective effect against acute focal cerebral IR injury. Themechanisms may be related to scavenging of free radicals by spermine. |
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