Role of O2-sensitive K and Ca channels in the regulation of the pulmonary circulation: Potential role of caveolae and implications for high altitude pulmonary edema

High altitude pulmonary edema (HAPE) is a potentially fatal complication in response to exposure to low O₂ at high altitudes. Hypoxia, by causing pulmonary vasoconstriction, increases pulmonary vascular resistance and pulmonary arterial pressure, both of which are features in the pathogenesis of HAPE. Uneven hypoxic pulmonary vasoconstriction is thought to be responsible for increased capillary pressure and leakage, resulting in edema. O₂-sensitive ion channels are known to play pivotal roles in determining vascular tone in response to hypoxia. K⁺, Ca²⁺ and Na⁺ channels are ubiquitously expressed in both endothelial and smooth muscle cells of the pulmonary microvasculature, subfamilies of which are regulated by local changes in P_O2. Hypoxia reduces activity of voltage-gated K⁺ channels and down-regulates their expression leading to membrane depolarization, Ca²⁺ influx in pulmonary artery smooth muscle cells (by activating voltage-dependent Ca²⁺ channels) and vasoconstriction. Hypoxia up-regulates transient receptor potential channels (TRPC) leading to enhanced Ca²⁺ entry through receptor- and store-operated Ca²⁺ channels. Altered enrichment of ion channels in membrane microdomains, in particular in caveolae, may play a role in excitation–contraction coupling and perhaps in O₂-sensing in the pulmonary circulation and thereby may contribute to the development of HAPE. We review the role of ion channels, in particular those outlined above, in response to low O₂ on vascular tone and pulmonary edema. Advances in the understanding of ion channels involved in the physiological response to hypoxia should lead to a greater understanding of the pathogenesis of HAPE and perhaps in the identification of new therapies.     

NADPH oxidase inhibition improves neurological outcomes in surgically-induced brain injury

Neurosurgical procedures can result in brain injury by various means including direct trauma, hemorrhage, retractor stretch, and electrocautery. This surgically-induced brain injury (SBI) can cause post-operative complications such as brain edema. By creating a mouse model of SBI, we tested whether NADPH oxidase, an important reactive oxygen species producing enzyme, is involved in SBI using transgenic mice lacking gp91^phox subunit of NADPH oxidase (gp91^phox KO) and apocynin, a specific inhibitor of NADPH oxidase. Neurological function and brain edema were evaluated at 24 h post-SBI in gp91^phox KO and wild-type littermates grouped into SBI and sham-surgery groups. Alternatively, mice were grouped into vehicle- and apocynin-treated (5 mg/kg, i.p. 30 min before SBI) groups. Oxidative stress indicated by lipid peroxidation (LPO) was measured at 3 and 24 h post-SBI. The gp91^phox KO mice, but not the apocynin-treated mice showed significantly improved neurological scores. Brain edema was observed in both gp91^phox KO and wild-type groups after SBI; however, there was no significant difference between these two groups. Brain edema was also not affected by apocynin-pretreatment. LPO levels were significantly higher in SBI group in both gp91^phox KO and wild-type groups as compared to sham group. A trend, although without statistical significance, was noted towards attenuation of LPO in the gp91^phox KO animals as compared to wild-type group. LPO levels were significantly attenuated at 3 h post-SBI by apocynin-pretreatment but not at 24 h post-SBI. These results suggest that chronic and acute inhibition of NADPH oxidase activity does not reduce brain edema after SBI. Long-term inhibition of NADPH oxidase, however improves neurological functions after SBI.     

神经调节素-1β对小鼠脑缺血再灌注损伤的干预作用及可能的机制

目的 研究神经调节素-1β(NRG-1β)对小鼠脑缺血再灌注后神经行为功能,脑梗死体积,脑组织含水量,神经细胞凋亡以及胶质细胞水通道蛋白-4(AQP-4)表达的影响和神经保护的作用机制.方法 应用线栓法建立小鼠大脑中动脉闭塞再灌注(MCAO/R)模型,经颈内动脉微量注射NRG-1β(2μg/kg)干预治疗,Bederson法评价动物的神经行为功能;氯化三苯基四氮唑(TTC)染色,观察脑梗死体积;干湿重法测定脑组织含水量;免疫荧光染色检测神经细胞凋亡;免疫组织化学检测AQP-4的表达.结果 脑缺血再灌注损伤后,动物均表现神经行为功能障碍,缺血侧出现脑梗塞病灶,脑组织含水量、神经细胞凋亡数量和胶质细胞AQP-4表达均高于假手术组.与对照组相比较,NRG-1β治疗组缺血24h,动物神经行为功能损伤明显改善,凋亡神经细胞数明显减少,脑梗塞体积显著缩小(P<0.05);但脑组织含水量和AQP-4表达与对照组比较无显著性差异(P>0.05).缺血再灌注22h、46h和70h组,上述5项指标较相应的对照组均有显著性差异(P<0.05).结论 NRC-1β可能通过下调脑缺血再灌注损伤诱导的胶质细胞AQP-4表达和抑制细胞凋亡,减轻脑水肿和缩小梗死体积,从而改善动物的神经行为功能.     

Dielectric behavior of pulmonary edema induced in the rat lung

The dielectric properties (conductivity, kappa and relative permittivity, epsilon) of excised rat lung are modified by lung air and water content. The measurements of these quantities were made over the frequency range of 10 kHz to 100 MHz with an open-ended coaxial probe. The following relationships were analyzed in an oleic acid-induced pulmonary edema model using 18 animals: the spectra of kappa, epsilon and the loss tangent as a function of lung air and water content. Secondly, an isolated-perfused lung system was produced to induce a gradual increase in lung water. The time course of kappa, epsilon and the loss tangent for one excised lung was analyzed. The principal findings were: (i) a decrease in kappa and epsilon with increasing air content, (ii) an increase in kappa and epsilon with increasing water content, and (iii) a good correlation between lung water content and maximum loss tangent that was insensitive to changes in air content. We conclude that this technique could provide a quantitative assessment of lung water during pulmonary edema formation.     

Suprachoroidal Injection of Triamcinolone Acetonide Injectable Suspension for the Treatment of Macular Edema Associated With Uveitis in the United States: A Cost-Effectiveness Analysis

ObjectivesSuprachoroidal injection of triamcinolone acetonide is the first Food and Drug Administration–approved treatment for macular edema associated with uveitis. A cost-effectiveness analysis was performed comparing this treatment with best supportive care (BSC) for the management of this indication from US Medicare and commercial payer perspectives.MethodsA patient-level simulation was developed per the patient characteristics and changes in best-corrected visual acuity letter scores observed in a phase III study of triamcinolone acetonide (PEACHTREE). The wholesale acquisition cost of triamcinolone acetonide was $1650/injection; suprachoroidal injection cost was assumed at $200/injection. Healthcare costs were informed by a US claims–based analysis. Mortality risk associated with severe vision loss and blindness was modeled by applying a hazard ratio to all-cause mortality rates of the US general population. Health-related quality of life weights, obtained from a regression model fitted to the Visual Function Questionnaire-25 data from PEACHTREE, were applied based on the best-corrected visual acuity scores of both eyes. Costs (2020 US dollar) and benefits were discounted at 3% annually. Incremental cost-effectiveness ratios were estimated over a 10-year horizon.ResultsIn the base-case, the incremental cost-effectiveness ratio comparing triamcinolone acetonide with BSC was $28 479 per quality-adjusted life-year gained. The wholesale acquisition cost for triamcinolone acetonide for suprachoroidal use was ～68%, ～56%, and ～27% below the willingness-to-pay thresholds of $150 000, $100 000, and $50 000 per quality-adjusted life-year gained, respectively. Results were robust in sensitivity and scenario analyses.ConclusionsTriamcinolone acetonide for suprachoroidal use is cost-effective compared with BSC for patients with macular edema associated with uveitis.     

High-altitude pulmonary edema

Lay summary: High Altitude Pulmonary Edema (HAPE) is a potentially fatal disease of altitude, in which the lungs can become filled with fluid. In this article we explore the mechanisms causing this condition and how it can be viewed as a condition of a mismatch between current environment and evolutionary experience.     

肾综合征出血热(HFRS)并发ARDS临床特征及抢救

目的　探讨肾综合征出血热 (HFRS)并发急性呼吸窘迫综合征 (ARDS)临床特征及诊断和抢救措施。方法　对 8例HFRS并发ADRS临床特征及血气、X检查进行分析诊断及其抢救措施。结果　 8例中 3例治愈(早期 2例 ,中期 1例 )。 5例死亡 (皆为中晚期 )。治愈率为 37 5% (3/ 8) ;病死率 6 2 5% (5/ 8)。结论　ARDS发病期别与预后关系较大。其发病机理主要是各种致病因素 ,尤其是严重感染和休克 ,使体内产生大量炎性介质、可使毛细血管扩张 ,通透性增加 ,引起间质性肺水肿。由于中性粒细胞和血小板被活化 ,可释放大量自由基 ,使肺微血管损伤和通透性增加 ,使肺含水量增高所致。救治措施 ,积极治疗和纠正原发病 ,迅速纠正缺氧 ,限制液体入量 ,早期使用胶体液 ,减轻肺水肿。早期大量肾上腺皮质激素应用 ;α受体阻滞剂 -酚氨拉明及抗胆碱能药物 -东莨菪碱应用 ,均对改善肺水肿有益。     

葛根素对星形胶质细胞肿胀及大鼠脑水肿的对抗作用

为观察葛根素是否有对抗星形胶质细胞肿胀及脑水肿的作用 ,体外实验用培养的星形胶质细胞进行 ,整体实验用Wistar雄性大鼠tACPD(5 0 0nmol,2 μL)尾状核内微量注射的方法 ,分别测定星形胶质细胞水含量、脑组织水含量和Na+ 、K+ 、Ca2 + 含量 ,部分脑组织进行电镜观察。结果显示葛根素可以阻断tACPD引起的星形胶质细胞水含量增加 ,减轻由tACPD尾状核内注射引起的脑组织水含量和Na+ 含量增加 ,电镜检查证实葛根素可以减轻tACPD引起的星形胶质细胞肿胀及足突肿胀对毛细血管的挤压。提示葛根素可以对抗星形胶质细胞肿胀及脑水肿。     

不同药物治疗创伤性脑水肿的动物实验研究

为研究临床常用的甘露醇和速尿对创伤性脑水肿的治疗作用 ,因改良Feeney自由落体装置致大鼠创伤性脑水肿 ,分别用不同剂量的甘露醇、速尿及 2药合用进行治疗。通过对血 脑脊液屏障通透性的观察、脑组织含水量的测定及光镜、电镜下的病理组织学检查 ,判定各治疗组的疗效。结果 :大剂量甘露醇治疗组的脑水肿蓝染面积和脑组织含水量下降最明显 ,光镜及电镜下观察脑组织损伤最轻 ,但随着治疗次数的增加 ,其治疗效果反而下降 ;小剂量甘露醇和速尿合用组的脱水作用虽不如大剂量甘露醇组强 ,但随着治疗次数的增加 ,其治疗效果并未明显下降。结果提示 :甘露醇对于急性创伤性脑水肿的治疗效果最佳 ,使用甘露醇 5～ 6次后应使用小剂量甘露醇 +速尿治疗 ,单独应用速尿效果欠佳。     

急性肺水肿不同湿化剂吸氧疗效的实验研究

目的通过对急性肺水肿不同湿化剂吸氧疗效的动物实验,筛选一种合适的湿化剂.方法复制急性肺水肿的动物模型,给予蒸馏水及不同浓度的乙醇、丁醇湿化吸氧,观察吸氧前后PaO2变化及支气管肺泡灌注液(BALF)中SOD及血浆NO变化情况.结果各组PaO2在吸氧后明显增高,尤以15%、25%乙醇组增高显著(P均<0.01),肺系数显著低于未吸氧组(P<0.01);15%乙醇组BALF中SOD显著高于其它各组(P<0.05),血浆NO在吸氧后亦明显升高,但与其它各组无显著性差异.结论①低浓度乙醇(15%～25%)为最佳湿化剂浓度,丁醇不适合作湿化剂;②不同湿化剂对肺水肿吸氧疗效的影响除与其消泡作用有关外,尚与水肿液成份及其它因素有关.