吸入一氧化氮和高氧对成熟肺炎症损伤时磷脂代谢的影响及机制
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摘要
背景:
急性肺损伤(ALI)是心源性以外的各种肺内外致病因素引起的弥漫性肺泡-毛细血管膜炎症性损伤,严重的ALI被定义为急性呼吸窘迫综合征(ARDS)。感染是ALI的主要诱因。其病理特征为严重的肺部炎症损伤,表现为肺泡换气功能受损、肺泡萎陷、继发于低氧性肺血管收缩的肺动脉高压、肺泡毛细血管膜通透性增加、肺表面活性物质功能及代谢受损及成分结构改变。
吸入一氧化氮(iNO)作为选择性肺血管扩张剂,常规用于治疗新生儿持续低氧血症及肺动脉高压。其选择性舒张肺血管,减少肺动静脉分流的效果得到大量实验及临床研究证实。但是iNO改善成人ALI/ARDS病人氧合的作用不能持久,且未能降低ALI/ARDS的病死率,推测可能与iNO导致肺泡腔第一道防线-肺表面活性物质(PS)的蛋白A(SP-A)硝基化损伤有关。但过度炎症反应及高氧应激本身即可使SP-A产生硝基化。iNO对炎症损伤肺PS的主要活性成分-磷脂酰胆碱(PC)的影响少有报道。对PC代谢的具体环节,如合成、分泌、清除的影响,尚是空白。在成熟肺PS磷脂合成主要经再循环(recycling)和由原料(de novo)合成二条途径,前者约占90%,后者约占10%;而在胎肺de novo合成占主要地位。成熟肺在弥漫性损伤时,再循环比例下降,de novo合成加强。PC 的de novo 合成在ALI时机体抗损伤机制中有重要地位,是肺泡II型上皮细胞(AEC-II)抗损伤机制的一个主要方面。
iNO治疗ALI/ARDS必定是和机械通气及高浓度氧气一起使用,长时间暴露会诱发肺损伤。有实验研究报道iNO可减轻动物肺高氧损伤并延长生存。但在肺部存在严重炎症损伤情况下,iNO加高氧对PS代谢的影响及其机制尚不清楚。
iNO能减轻肺部的炎症损伤,可能成为预防感染性ALI的有效手段。炎症损伤与PS的代谢密切相关。炎症对PC的合成及分解均有影响,对PC合成的影响表现在对PC合成的关键酶,磷脂酰胆碱胞苷二酰基转移酶(CCT)功能的抑制。外源性及内源性NO对炎症损伤肺的免疫调节作用,构成肺抗损伤及修复机制的一部分。PC合成功能是反映肺泡Ⅱ型上皮细胞(AEC-II)在炎症损伤时抗损伤及修复功能的一个重要指标。iNO与高氧对炎症损伤肺PC合成产生的影响是否与此时肺
部的炎症反应状态有关,尚未得到深入研究,值得探讨。
目的:
1. 从PC合成功能的角度,论证iNO在高氧条件下用于肺部炎症损伤的安全性。
2. 从PC合成关键酶的功能和表达水平,研究iNO在高氧条件下对PC合成功能的影响机制。
3. iNO及高氧对肺炎症反应的影响,及该影响与PC合成功能的关系。
方法:
清洁级成年雄性SD大鼠(180～200 g)先随机分组接受静脉注射内毒素2 mg/kg体重(简称LPS),和静脉注射等量生理盐水(作为对照组,简称C),24小时后LPS组及C组再分别随机给予吸空气(Air)、95%氧气(O)、20 ppm NO (NO)、20 ppm NO加95%氧气(ONO)4种干预。在开始气体干预的同时,大鼠尾静脉注射[3H]-氯化胆碱15 μCi,不同气体干预10分钟、及4、8、12和24小时(每组每时点n = 6~8 ),测各时点大鼠支气管肺泡灌洗液(BALF)及灌洗过的肺组织(LT)中总磷脂(TPL)和饱和磷脂酰胆碱(DSPC)放射活性,以反映合成及分泌TPL、DSPC的能力。并以生化方法检测BALF、LT磷脂代谢池中TPL、DSPC总量。并对BALF中白细胞计数(WCC)。另取大鼠,造模及分组干预同前,不注射示踪剂,不同气体干预4、24小时(每组每时点n = 6~8 )。以[14C]-磷酸胆碱为底物,测肺组织中CCT的活性。以RT-PCR、Western blot法测CCT mRNA与蛋白表达水平。以电泳迁移率法测肺组织核转录因子-κB(NF-κB)活性。以RT-PCR法测肿瘤坏死因子-α(TNF-α)、细胞因子诱导的中性粒细胞趋化因子-1(CINC-1)、白细胞介素-10(IL-10) mRNA表达水平;并检测肺组织湿干重比(W/D)、髓过氧化物酶(MPO)、丙二醛(MDA)水平。另取大鼠,造模及分组干预同前。不同气体干预4、24小时(每组每时点n = 5 )。全肺灌流固定用于组织形态学检查及损伤评分。
结果:
1. 肺PC合成代谢
不同干预组PC合成高峰均在注射示踪剂后4小时。此时在Air干预下,全肺TPL放射活性约占示踪剂2.4 ‰,全肺DSPC放射活性约占示踪剂0.5 ‰ 。
不同气体干预4小时后,LPS-NO组BALF与全肺(BALF+LT)中TPL(BALF 81±17.6 cpm/g,全肺931±158 cpm/g)、DSPC(BALF 21.2±4.3 cpm/g,全肺217±39.1 cpm/g)的放射活性均显著低于其它气体干预下的LPS大鼠(下降46～59%,P<0.01)。不同干预的LPS组之间,BALF与LT PC代谢池中TPL、DSPC总量,
其差异无显著性。
不同气体干预24小时后的LPS大鼠BALF与全肺中TPL、DSPC的放射活性均显著低于相同气体干预下的C组(下降24~47%)。LPS-O组BALF与全肺中TPL(BALF 68.8±17.5 cpm/g,全肺603±83.4 cpm/g)、DSPC(BALF 19.8±3.9 cpm/g,全肺102±13.6 cpm/g)的放射活性均显著低于其它气体干预下的LPS大鼠(下降42~53%,P<0.01)。LPS-NO及LPS-ONO组TPL、DSPC合成功能与LPS-Air组相比,其差异无显著性。LPS-O组BALF磷脂代谢池中TPL(4.1±0.8 mg/kg,下降35%)、DSPC总量(1.6±0.4 mg/kg,下降41%),及LT中DSPC(16.0±2.7 mg/kg)总量,显著低于LPS-Air组(TPL 6.3±1.6,DSPC 2.7±0.7,LT中DSPC 21.3±4.2 mg/kg)。LPS-NO、LPS-ONO组BALF及LT中TPL、DSPC总量与LPS-Air相比,其差异无显著性。
Background
Septic acute respiratory distress syndrome (ARDS) is often encountered as a complication of various diseases, such as pneumonia, pancreatitis, trauma, burn injury, cardiovascular and gastrointestinal operations, or as a part of multiple system organ failure. Pathogenesis of acute lung injury (ALI) and ARDS in septic patients is related to intrapulmonary neutrophil accumulation and inflammatory damage of lungs, especially in alveoli. Such changes lead to impairment of lung mechanics and gas exchange, surfactant dysfunction and deficiency, pulmonary hypertension secondary to hypoxic intrapulmonary vasoconstriction, and increased vascular-to-alveolar permeability.
Inhaled nitric oxide (iNO) was introduced primarily as a selective pulmonary vasodilator to alter ventilation-perfusion mismatching in ALI/ARDS. It may also act to prevent development of ARDS from pulmonary infection and septic lung injury, Although in patients with ARDS, iNO significantly reduces the pulmonary hypertension and the intrapulmonary shunt, it has not yet proved to be effective in reducing mortality.
It has been speculated that iNO may cause secondary surfactant damage by formation of nitrotyrosine in its protein moiety due to production of peroxynitrite under hyperoxic condition. iNO is usually used in combination with high oxygen supply in critical conditions. Whether iNO alone or iNO together with hyperoxia would have any adverse effects on surfactant phosphatidylcholine (PC) de novo synthesis in inflammatory injury in the lungs remains an unanswered question, and of clinical importance in terms of new indication of iNO.
Recent studies showed that iNO attenuates lung inflammatory injury. Whether iNO alone or iNO plus hyperoxia would affect the course of lung inflammation is not clear. In ARDS patients, elevated levels of TNF-α may be primarily responsible for inhibition of surfactant phospholipid synthesis. In sepsis, bacterial lipopolysaccharide (LPS) triggers the release of TNF-α from alveolar macrophages and alveolar epithelial cells
and subsequently initiates an inflammatory cascade leading to diffusive lung injury. TNF-α inhibits PC synthesis via decreasing activity of cytidine triphosphorylate: phosphocholine cytidylyltransferase (CCT), a key rate-limiting enzyme in synthesis of PC. Our aim is to find out the mechanisms by which iNO alone or iNO plus hyperoxia affect PC de novo synthesis and its relation to the lung inflammatory injury.
Objectives
1. To explore safety and efficacy of iNO and/or hyperoxia in mature lungs with inflammatory injury in association with de novo synthesis and secretion of phosphatidylcholine (PC).
2. To determine function and expression of cytidine triphosphorylate: phosphocholine cytidylyltransferase (CCT), a key rate-limiting enzyme in synthesis of PC, and influence of iNO and hyperoxia on CCT.
3. Interaction between iNO and/or hyperoxia and lung inflammation in association with synthesis of PC.
Methods
Adult male SD rats (clean conventional rats, 180~200 g) were used to induce lung inflammatory injury with bolus LPS (2 mg/kg, i.v) 24 hours prior to experiment. A saline control group was used with identical manner for comparison. LPS-treated (LPS) and control (C) rats were randomly allocated to subgroups exposed to: air, 95% oxygen (O), 20 ppm iNO (NO), 95% oxygen and 20 ppm iNO (ONO).
PC de novo synthesis and secretion was determined by measurement of incorporated [3H]-choline chloride into PC. Each rat was injected intravenously with 15 μCi [3H]-choline chloride followed by exposure to various gases. They were sacrificed at 10 min, 4, 8, 12 and 24 hours after the exposure (n = 6~8). The radioactivity of 3H incorporated into total phospholipid (TPL) and disaturated phosphatidylcholine (DSPC) was measured in bronchoalveolar lavage fluid (BALF) and lung tissue (LT, after lavage) Pool size of PC was also measured in both BALF and LT.
In a separate cohort study, rats were exposed for 4 and 24 hours in the same protocol of gas exposure. Eight or six rats in each subgroup we
急性肺损伤(ALI)是心源性以外的各种肺内外致病因素引起的弥漫性肺泡-毛细血管膜炎症性损伤,严重的ALI被定义为急性呼吸窘迫综合征(ARDS)。感染是ALI的主要诱因。其病理特征为严重的肺部炎症损伤,表现为肺泡换气功能受损、肺泡萎陷、继发于低氧性肺血管收缩的肺动脉高压、肺泡毛细血管膜通透性增加、肺表面活性物质功能及代谢受损及成分结构改变。
吸入一氧化氮(iNO)作为选择性肺血管扩张剂,常规用于治疗新生儿持续低氧血症及肺动脉高压。其选择性舒张肺血管,减少肺动静脉分流的效果得到大量实验及临床研究证实。但是iNO改善成人ALI/ARDS病人氧合的作用不能持久,且未能降低ALI/ARDS的病死率,推测可能与iNO导致肺泡腔第一道防线-肺表面活性物质(PS)的蛋白A(SP-A)硝基化损伤有关。但过度炎症反应及高氧应激本身即可使SP-A产生硝基化。iNO对炎症损伤肺PS的主要活性成分-磷脂酰胆碱(PC)的影响少有报道。对PC代谢的具体环节,如合成、分泌、清除的影响,尚是空白。在成熟肺PS磷脂合成主要经再循环(recycling)和由原料(de novo)合成二条途径,前者约占90%,后者约占10%;而在胎肺de novo合成占主要地位。成熟肺在弥漫性损伤时,再循环比例下降,de novo合成加强。PC 的de novo 合成在ALI时机体抗损伤机制中有重要地位,是肺泡II型上皮细胞(AEC-II)抗损伤机制的一个主要方面。
iNO治疗ALI/ARDS必定是和机械通气及高浓度氧气一起使用,长时间暴露会诱发肺损伤。有实验研究报道iNO可减轻动物肺高氧损伤并延长生存。但在肺部存在严重炎症损伤情况下,iNO加高氧对PS代谢的影响及其机制尚不清楚。
iNO能减轻肺部的炎症损伤,可能成为预防感染性ALI的有效手段。炎症损伤与PS的代谢密切相关。炎症对PC的合成及分解均有影响,对PC合成的影响表现在对PC合成的关键酶,磷脂酰胆碱胞苷二酰基转移酶(CCT)功能的抑制。外源性及内源性NO对炎症损伤肺的免疫调节作用,构成肺抗损伤及修复机制的一部分。PC合成功能是反映肺泡Ⅱ型上皮细胞(AEC-II)在炎症损伤时抗损伤及修复功能的一个重要指标。iNO与高氧对炎症损伤肺PC合成产生的影响是否与此时肺
部的炎症反应状态有关,尚未得到深入研究,值得探讨。
目的:
1. 从PC合成功能的角度,论证iNO在高氧条件下用于肺部炎症损伤的安全性。
2. 从PC合成关键酶的功能和表达水平,研究iNO在高氧条件下对PC合成功能的影响机制。
3. iNO及高氧对肺炎症反应的影响,及该影响与PC合成功能的关系。
方法:
清洁级成年雄性SD大鼠(180～200 g)先随机分组接受静脉注射内毒素2 mg/kg体重(简称LPS),和静脉注射等量生理盐水(作为对照组,简称C),24小时后LPS组及C组再分别随机给予吸空气(Air)、95%氧气(O)、20 ppm NO (NO)、20 ppm NO加95%氧气(ONO)4种干预。在开始气体干预的同时,大鼠尾静脉注射[3H]-氯化胆碱15 μCi,不同气体干预10分钟、及4、8、12和24小时(每组每时点n = 6~8 ),测各时点大鼠支气管肺泡灌洗液(BALF)及灌洗过的肺组织(LT)中总磷脂(TPL)和饱和磷脂酰胆碱(DSPC)放射活性,以反映合成及分泌TPL、DSPC的能力。并以生化方法检测BALF、LT磷脂代谢池中TPL、DSPC总量。并对BALF中白细胞计数(WCC)。另取大鼠,造模及分组干预同前,不注射示踪剂,不同气体干预4、24小时(每组每时点n = 6~8 )。以[14C]-磷酸胆碱为底物,测肺组织中CCT的活性。以RT-PCR、Western blot法测CCT mRNA与蛋白表达水平。以电泳迁移率法测肺组织核转录因子-κB(NF-κB)活性。以RT-PCR法测肿瘤坏死因子-α(TNF-α)、细胞因子诱导的中性粒细胞趋化因子-1(CINC-1)、白细胞介素-10(IL-10) mRNA表达水平;并检测肺组织湿干重比(W/D)、髓过氧化物酶(MPO)、丙二醛(MDA)水平。另取大鼠,造模及分组干预同前。不同气体干预4、24小时(每组每时点n = 5 )。全肺灌流固定用于组织形态学检查及损伤评分。
结果:
1. 肺PC合成代谢
不同干预组PC合成高峰均在注射示踪剂后4小时。此时在Air干预下,全肺TPL放射活性约占示踪剂2.4 ‰,全肺DSPC放射活性约占示踪剂0.5 ‰ 。
不同气体干预4小时后,LPS-NO组BALF与全肺(BALF+LT)中TPL(BALF 81±17.6 cpm/g,全肺931±158 cpm/g)、DSPC(BALF 21.2±4.3 cpm/g,全肺217±39.1 cpm/g)的放射活性均显著低于其它气体干预下的LPS大鼠(下降46～59%,P<0.01)。不同干预的LPS组之间,BALF与LT PC代谢池中TPL、DSPC总量,
其差异无显著性。
不同气体干预24小时后的LPS大鼠BALF与全肺中TPL、DSPC的放射活性均显著低于相同气体干预下的C组(下降24~47%)。LPS-O组BALF与全肺中TPL(BALF 68.8±17.5 cpm/g,全肺603±83.4 cpm/g)、DSPC(BALF 19.8±3.9 cpm/g,全肺102±13.6 cpm/g)的放射活性均显著低于其它气体干预下的LPS大鼠(下降42~53%,P<0.01)。LPS-NO及LPS-ONO组TPL、DSPC合成功能与LPS-Air组相比,其差异无显著性。LPS-O组BALF磷脂代谢池中TPL(4.1±0.8 mg/kg,下降35%)、DSPC总量(1.6±0.4 mg/kg,下降41%),及LT中DSPC(16.0±2.7 mg/kg)总量,显著低于LPS-Air组(TPL 6.3±1.6,DSPC 2.7±0.7,LT中DSPC 21.3±4.2 mg/kg)。LPS-NO、LPS-ONO组BALF及LT中TPL、DSPC总量与LPS-Air相比,其差异无显著性。
Background
Septic acute respiratory distress syndrome (ARDS) is often encountered as a complication of various diseases, such as pneumonia, pancreatitis, trauma, burn injury, cardiovascular and gastrointestinal operations, or as a part of multiple system organ failure. Pathogenesis of acute lung injury (ALI) and ARDS in septic patients is related to intrapulmonary neutrophil accumulation and inflammatory damage of lungs, especially in alveoli. Such changes lead to impairment of lung mechanics and gas exchange, surfactant dysfunction and deficiency, pulmonary hypertension secondary to hypoxic intrapulmonary vasoconstriction, and increased vascular-to-alveolar permeability.
Inhaled nitric oxide (iNO) was introduced primarily as a selective pulmonary vasodilator to alter ventilation-perfusion mismatching in ALI/ARDS. It may also act to prevent development of ARDS from pulmonary infection and septic lung injury, Although in patients with ARDS, iNO significantly reduces the pulmonary hypertension and the intrapulmonary shunt, it has not yet proved to be effective in reducing mortality.
It has been speculated that iNO may cause secondary surfactant damage by formation of nitrotyrosine in its protein moiety due to production of peroxynitrite under hyperoxic condition. iNO is usually used in combination with high oxygen supply in critical conditions. Whether iNO alone or iNO together with hyperoxia would have any adverse effects on surfactant phosphatidylcholine (PC) de novo synthesis in inflammatory injury in the lungs remains an unanswered question, and of clinical importance in terms of new indication of iNO.
Recent studies showed that iNO attenuates lung inflammatory injury. Whether iNO alone or iNO plus hyperoxia would affect the course of lung inflammation is not clear. In ARDS patients, elevated levels of TNF-α may be primarily responsible for inhibition of surfactant phospholipid synthesis. In sepsis, bacterial lipopolysaccharide (LPS) triggers the release of TNF-α from alveolar macrophages and alveolar epithelial cells
and subsequently initiates an inflammatory cascade leading to diffusive lung injury. TNF-α inhibits PC synthesis via decreasing activity of cytidine triphosphorylate: phosphocholine cytidylyltransferase (CCT), a key rate-limiting enzyme in synthesis of PC. Our aim is to find out the mechanisms by which iNO alone or iNO plus hyperoxia affect PC de novo synthesis and its relation to the lung inflammatory injury.
Objectives
1. To explore safety and efficacy of iNO and/or hyperoxia in mature lungs with inflammatory injury in association with de novo synthesis and secretion of phosphatidylcholine (PC).
2. To determine function and expression of cytidine triphosphorylate: phosphocholine cytidylyltransferase (CCT), a key rate-limiting enzyme in synthesis of PC, and influence of iNO and hyperoxia on CCT.
3. Interaction between iNO and/or hyperoxia and lung inflammation in association with synthesis of PC.
Methods
Adult male SD rats (clean conventional rats, 180~200 g) were used to induce lung inflammatory injury with bolus LPS (2 mg/kg, i.v) 24 hours prior to experiment. A saline control group was used with identical manner for comparison. LPS-treated (LPS) and control (C) rats were randomly allocated to subgroups exposed to: air, 95% oxygen (O), 20 ppm iNO (NO), 95% oxygen and 20 ppm iNO (ONO).
PC de novo synthesis and secretion was determined by measurement of incorporated [3H]-choline chloride into PC. Each rat was injected intravenously with 15 μCi [3H]-choline chloride followed by exposure to various gases. They were sacrificed at 10 min, 4, 8, 12 and 24 hours after the exposure (n = 6~8). The radioactivity of 3H incorporated into total phospholipid (TPL) and disaturated phosphatidylcholine (DSPC) was measured in bronchoalveolar lavage fluid (BALF) and lung tissue (LT, after lavage) Pool size of PC was also measured in both BALF and LT.
In a separate cohort study, rats were exposed for 4 and 24 hours in the same protocol of gas exposure. Eight or six rats in each subgroup we
引文
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10. Troncy E, Collet JP, Shapiro S, et al. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study. Am J Respir Crit Care Med 1998; 157: 1483-1488
11. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med 1998; 26: 15-23
12. Lundin S, Mang H, Smithies M, et al. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of
Inhaled Nitric Oxide. Intensive Care Med 1999; 25: 911-919
13. Zhu S, Ware LB, Geiser T, et al. Increased levels of nitrate and surfactant protein a nitration in the pulmonary edema fluid of patients with acute lung injury. Am J Respir Crit Care Med 2001; 163: 166-172
14. Lamb NJ, Quinlan GJ, Westerman ST, et al. Nitration of proteins in bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome receiving inhaled nitric oxide. Am J Respir Crit Care Med 1999; 160: 1031-1034
15. Honda K, Kobayashi H, Hataishi R, et al. Inhaled nitric oxide reduces tyrosine nitration after lipopolysaccharide instillation into lungs of rats. Am J Respir Crit Care Med 1999; 160: 678-688
16. Jacobs H, Jobe A, Ikegami M, Jones S. Surfactant phosphatidylcholine source, fluxes, and turnover times in 3-day-old, 10-day-old, and adult rabbits. J Biol Chem 1982; 257: 1805-1810.
17. Bartlett GR. Phosphorous assay in column chromatography. J Biol Chem 1959; 234: 466-468
18. Mason RJ, Nellenbogen J, Clements JA. Isolation of disaturated phosphatidyl-choline with osmium tetroxide. J Lipid Res 1976; 17: 281-284
19. Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with the folin phenol reagent. J Biol Chem 1951; 193: 265-275
20. Zhou ZH, Sun B, Lin K, et al. Prevention of rabbit acute lung injury by surfactant, inhaled nitric oxide, and pressure support ventilation. Am J Respir Crit Care Med 2000; 161: 581-588
21. Xing Z, Kirpalani H, Torry D, et al. Polymorphonuclear leukocytes as a significant source of tumor necrosis factor-alpha in endotoxin-challenged lung tissue. Am J Pathol 1993;143:1009-1015
22. Ulich TR, Watson LR, Yin S, et al. The intratracheal administration of endotoxin and cytokines. I. Characterization of LPS-induced IL-1 and TNF mRNA expression and the LPS, IL-1, TNF-induced inflammatory infiltrate. Am J Pathol 1991;138:1485-1496
23. Martin TR. Recognition of bacterial endotoxin in the lungs. Am J Respir Cell Mol Biol 2000; 23: 128-132
24. Batenburg JJ. Surfactant phospholipids: synthesis and storage. Am J Physiol 1992; 262: L367-L385
25. Rooney SA. The surfactant system and lung phospholipid biochemistry. Am Rev Respir Dis 1985; 131: 439-460.
26. Attalah HL, Wu Y, Alaoui-El-Azher M, et al. Induction of type-IIA secretory phospholipase A2 in animal models of acute lung injury. Eur Respir J 2003; 21: 1040-1045
27. Gunther A, Ruppert C, Schmidt R,et al. Surfactant alteration and replacement in acute respiratory distress syndrome. Respir Res 2001; 2: 353-364
28. Fehrenbach H, Brasch F, Uhlig S, et al. Early alterations in intracellular and alveolar surfactant of the rat lung in response to endotoxin. Am J Respir Crit Care Med 1998; 157 : 1630-1639
29. Anonymous. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med 1997; 336: 597-604
30. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med 2000; 342: 469-474
31. Zhu GF, Sun B, Niu SF, et al. Combined surfactant therapy and inhaled nitric oxide in rabbits with oleic acid-induced acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 158: 437-443
32. Cassina A, Rado R. Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 1996; 328: 309-316
33. Beckman TS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 1996; 271: C1424-C1437
34. Gaston B, Drazen JM, Loscalzo J, et al. The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 1994; 149: 538-551
35. Frostell CG. Reassessment of inhaled nitric oxide in acute lung injury. Acta Pharmacol Sin 2003; 24: 1314-1315
36. Jobe A, Kirkpatrick E, Gluck L. Labeling of phospholipids in the surfactant and subcellular fractions of rabbit lung. J Biol Chem 1978; 253: 3810-3816
37. Bosch MA, Risco C, Martin-Municio A. Effect of Escherichia coli lipopolysaccharide on phosphatidylcholine biosynthesis by rat lung and alveolar type II cells. Mol Cell Biochem 1990; 93: 167-172
38. Matalon S, DeMarco V, Haddad IY, et al. Inhaled nitric oxide injures the
pulmonary surfactant system of lambs in vivo. Am J Physiol 1996; 270: L273- L280
39. Miles PR, Bowman L, Huffman L. Nitric oxide alters metabolism in isolated alveolar type II cells. Am J Physiol 1996; 271: L23-30.
40. Ward JA, Roberts RJ. Effect of hyperoxia on phosphatidylcholine synthesis, secretion, uptake and stability in the newborn rabbit lung. Biochim Biophys Acta 1984; 796: 42-50
41. Wink DA, Hanbauer I, Krishna MC, et al. Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. Proc Natl Acad Sci USA 1993; 90: 9813-9817
42. Rubbo H, Radi R, Trujillo M, et al. Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives. J Biol Chem 1994; 269: 26066-26075
43. Wink DA, Cook JA, Krishna MC, et al. Nitric oxide protects against alkyl peroxide-mediated cytotoxicity: further insights into the role nitric oxide plays in oxidative stress. Arch Biochem Biophys 1995; 319: 402-407
44. Rodenas J, Mitjavila MT, Carbonell T. Nitric oxide inhibits superoxide production by inflammatory polymorphonuclear leukocytes. Am J Physiol 1998; 274: C827-C830
45. Turanlahti M, Pesonen E, Lassus P, et al. Nitric oxide and hyperoxia in oxidative lung injury. Acta Paediatr 2000; 89: 966-970
46. Nelin LD, Welty SE, Morrisey JF, et al. Nitric oxide increases the survival of rats with a high oxygen exposure. Pediatr Res 1998; 43: 727-732
47. Howlett CE, Hutchison JS, Veinot JP, et al. Inhaled nitric oxide protects against hyperoxia-induced apoptosis in rat lungs. Am J Physiol 1999; 277: L596-L605
48. Lightfoot RT, Khov S, Ischiropoulos H. Transient injury to rat lung mitochondrial DNA after exposure to hyperoxia and inhaled nitric oxide. Am J Physiol Lung Cell Mol Physiol 2004; 286: L23-L29
49. Charafeddine L, D'Angio CT, Richards JL, et al. Hyperoxia increases keratinocyte growth factor mRNA expression in neonatal rabbit lung. Am J Physiol 1999; 276: L105- L113
50. Ikegami M, Jobe AH, Havill AM. Keratinocyte growth factor increases surfactant pool sizes in premature rabbits. Am J Respir Crit Care Med 1997; 155:
1155-1158
51. Post M, Batenburg JJ, Schuurmans EA, et al. The rate-limiting step in the biosynthesis of phosphatidylcholine by alveolar type II cells from adult rat lung. Biochim Biophys Acta 1982; 712: 390-394
52. Kalmar GB, Kay RJ, Lachance A, et al. Cloning and expression of rat liver CTP: phosphocholine cytidylyltransferase: an amphipathic protein that controls phosphatidylcholine synthesis. Proc Natl Acad Sci USA 1990; 87: 6029-6033
53. Weinhold PA, Rounsifer ME, Feldman DA. The purification and characterization of CTP:phosphorylcholine cytidylyltransferase from rat liver. J Biol Chem 1986; 261: 5104-5110.
54. Spragg RG, Li J. Effect of phosphocholine cytidylyltransferase overexpression on phosphatidylcholine synthesis in alveolar type II cells and related cell lines. Am J Respir Cell Mol Biol 2000; 22: 116-124.
55. Mallampalli RK, Mathur SN, Warnock LJ, et al. Betamethasone modulation of sphingomyelin hydrolysis up-regulates CTP:cholinephosphate cytidylyltransferase activity in adult rat lung. Biochem J 1996; 318: 333-341
56. Kent C. CTP:phosphocholine cytidylyltransferase. Biochim Biophys Acta 1997; 1348: 79-90
57. Mallampalli RK, Salome RG, Hunninghake GW. Lung CTP:choline-phosphate cytidylyltransferase: activation of cytosolic species by unsaturated fatty acid. Am J Physiol 1993; 265: L158-L163
58. Hogan M, Zimmermann LJ, Wang J, et al. Increased expression of CTP:phosphocholine cytidylyltransferase in maturing type II cells. Am J Physiol 1994; 267: L25-L32
59. Tronchere H, Record M, Terce F, et al. Phosphatidylcholine cycle and regulation of phosphatidylcholine biosynthesis by enzyme translocation. Biochim Biophys Acta 1994; 1212: 137-151
60. MacDonald JI, Kent C. Identification of phosphorylation sites in rat liver CTP: phosphocholine cytidylyltransferase. J Biol Chem 1994; 269: 10529-10537
61. Mallampalli RK, Ryan AJ, Salome RG, et al. Tumor necrosis factor-alpha inhibits expression of CTP:phosphocholine cytidylyltransferase. J Biol Chem 2000; 275: 9699-9708
62. Blackwell TS, Christman JW. The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell Mol Biol 1997; 17: 3-9
63. Kang JL, Park W, Pack IS, et al. Inhaled nitric oxide attenuates acute lung injury via inhibition of nuclear factor-kappa B and inflammation. J Appl Physiol 2002; 92: 795-801
64. Cao L, Qian LL, Zhu RY, et al. Regulation of activity of nuclear factor-kappa B and activator protein-1 by nitric oxide, surfactant and glucocorticoids in alveolar macrophages from piglets with acute lung injury. Acta Pharmacol Sin 2003; 24: 1316-1323
65. Ennema JJ, Kobayashi T, Robertson B, et al. Inactivation of exogenous surfactant in experimental respiratory failure induced by hyperoxia. Acta Anaesthesiol Scand 1988; 32: 665-671
66. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351-358
67. Sato Y, Walley KR, Klut ME, et al. Nitric oxide reduces the sequestration of polymorphonuclear leukocytes in lung by changing deformability and CD18 expression. Am J Respir Crit Care Med 1999; 159: 1469-1476
68. Haddad el-B, McCluskie K, Birrell MA, et al. Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation. J Immunol 2002; 169: 974-982
69. Narasaraju TA, Jin N, Narendranath CR, et al. Protein nitration in rat lungs during hyperoxia exposure: a possible role of myeloperoxidase. Am J Physiol Lung Cell Mol Physiol. 2003; 285: L1037- L1045
70. Kobayashi H, Hataishi R, Mitsufuji H, et al. Antiinflammatory properties of inducible nitric oxide synthase in acute hyperoxic lung injury. Am J Respir Cell Mol Biol 2001; 24: 390-397
71. Schwartz MD, Moore EE, Moore FA, et al. Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Crit Care Med 1996; 24: 1285-1292
72. Abraham E, Arcaroli J, Shenkar R. Activation of extracellular signal-regulated kinases, NF-kappa B, and cyclic adenosine 5'-monophosphate response element-binding protein in lung neutrophils occurs by differing mechanisms after hemorrhage or endotoxemia. J Immunol 2001; 166: 522-530
73. Moine P, McIntyre R, Schwartz MD, et al. NF-kappa B regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome.
Shock 2000; 13: 85-91
74. Blackwell TS, Blackwell TR, Holden EP, et al. In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation. J Immunol 1996; 157: 1630-1637
75. Thomassen MJ, Buhrow LT, Connors MJ, et al. Nitric oxide inhibits inflammatory cytokine production by human alveolar macrophages. Am J Respir Cell Mol Biol 1997; 17: 279-283
76. Umansky V, Hehner SP, Dumont A, et al. Co-stimulatory effect of nitric oxide on endothelial NF-kappaB implies a physiological self-amplifying mechanism. Eur J Immunol 1998; 28: 2276-2282
77. Shin WS, Hong YH, Peng HB, et al. Nitric oxide attenuates vascular smooth muscle cell activation by interferon-gamma. The role of constitutive NF-kappa B activity. J Biol Chem 1996; 271: 11317-11324
78. Peng HB, Libby P, Liao JK. Induction and stabilization of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B. J Biol Chem 1995; 270: 14214-14219
79. Park SK, Lin HL, Murphy S. Nitric oxide regulates nitric oxide synthase-2 gene expression by inhibiting NF-kappa B binding to DNA. Biochem J 1997; 322: 609-613
80. Spiecker M, Peng HB, Liao JK. Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of IkappaBalpha. J Biol Chem 1997; 272: 30969-30974
81. D'Angio CT, LoMonaco MB, Johnston CJ, et al. Differential roles for NF-kappa B in endotoxin and oxygen induction of interleukin-8 in the macrophage. Am J Physiol Lung Cell Mol Physiol 2004; 286: L30-L36
82. Burner U, Furtmuller PG, Kettle AJ, et al. Mechanism of reaction of myeloperoxidase with nitrite. J Biol Chem 2000; 275: 20597-20601
83. Stuber F, Wrigge H, Schroeder S, et al. Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury. Intensive Care Med 2002; 28: 834-841
84. Gerlach H, Keh D, Semmerow A, et al. Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. Am J Respir Crit Care Med 2003; 167: 1008-1015
2. Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004; 291: 1603-1609
3. Zhang H, Lindwall R, Zhu L, et al. Lung physiology and histopathology during cumulated exposure to nitric oxide in combination with assisted ventilation in healthy piglets. Pulm Pharmacol Ther 2003; 16: 163-169
4. Gutierrez HH, Nieves B, Chumley P, Rivera A, et al. Nitric oxide regulation of superoxide-dependent lung injury: oxidant-protective actions of endogenously produced and exogenously administered nitric oxide. Free Radic Biol Med 1996; 21: 43-52
5. Issa A, Lappalainen U, Kleinman M, et al. Inhaled nitric oxide decreases hyperoxia-induced surfactant abnormality in preterm rabbits. Pediatr Res 1999; 45: 247-254
6. Chollet-Martin S, Gatecel C, Kermarrec N, et al. Alveolar neutrophil functions and cytokine levels in patients with the adult respiratory distress syndrome during nitric oxide inhalation. Am J Respir Crit Care Med 1996; 153: 985-990
7. Salome RG, McCoy DM, Ryan AJ, et al. Effects of intratracheal instillation of TNF-alpha on surfactant metabolism. J Appl Physiol 2000; 88: 10-16
8. Walley KR, McDonald TE, Higashimoto Y, et al. Modulation of proinflammatory cytokines by nitric oxide in murine acute lung injury. Am J Respir Crit Care Med 1999; 160: 698-704
9. Krafft P, Fridrich P, Fitzgerald RD, et al. Effectiveness of nitric oxide inhalation in septic ARDS. Chest 1996; 109: 486-493
10. Troncy E, Collet JP, Shapiro S, et al. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study. Am J Respir Crit Care Med 1998; 157: 1483-1488
11. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med 1998; 26: 15-23
12. Lundin S, Mang H, Smithies M, et al. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of
Inhaled Nitric Oxide. Intensive Care Med 1999; 25: 911-919
13. Zhu S, Ware LB, Geiser T, et al. Increased levels of nitrate and surfactant protein a nitration in the pulmonary edema fluid of patients with acute lung injury. Am J Respir Crit Care Med 2001; 163: 166-172
14. Lamb NJ, Quinlan GJ, Westerman ST, et al. Nitration of proteins in bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome receiving inhaled nitric oxide. Am J Respir Crit Care Med 1999; 160: 1031-1034
15. Honda K, Kobayashi H, Hataishi R, et al. Inhaled nitric oxide reduces tyrosine nitration after lipopolysaccharide instillation into lungs of rats. Am J Respir Crit Care Med 1999; 160: 678-688
16. Jacobs H, Jobe A, Ikegami M, Jones S. Surfactant phosphatidylcholine source, fluxes, and turnover times in 3-day-old, 10-day-old, and adult rabbits. J Biol Chem 1982; 257: 1805-1810.
17. Bartlett GR. Phosphorous assay in column chromatography. J Biol Chem 1959; 234: 466-468
18. Mason RJ, Nellenbogen J, Clements JA. Isolation of disaturated phosphatidyl-choline with osmium tetroxide. J Lipid Res 1976; 17: 281-284
19. Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with the folin phenol reagent. J Biol Chem 1951; 193: 265-275
20. Zhou ZH, Sun B, Lin K, et al. Prevention of rabbit acute lung injury by surfactant, inhaled nitric oxide, and pressure support ventilation. Am J Respir Crit Care Med 2000; 161: 581-588
21. Xing Z, Kirpalani H, Torry D, et al. Polymorphonuclear leukocytes as a significant source of tumor necrosis factor-alpha in endotoxin-challenged lung tissue. Am J Pathol 1993;143:1009-1015
22. Ulich TR, Watson LR, Yin S, et al. The intratracheal administration of endotoxin and cytokines. I. Characterization of LPS-induced IL-1 and TNF mRNA expression and the LPS, IL-1, TNF-induced inflammatory infiltrate. Am J Pathol 1991;138:1485-1496
23. Martin TR. Recognition of bacterial endotoxin in the lungs. Am J Respir Cell Mol Biol 2000; 23: 128-132
24. Batenburg JJ. Surfactant phospholipids: synthesis and storage. Am J Physiol 1992; 262: L367-L385
25. Rooney SA. The surfactant system and lung phospholipid biochemistry. Am Rev Respir Dis 1985; 131: 439-460.
26. Attalah HL, Wu Y, Alaoui-El-Azher M, et al. Induction of type-IIA secretory phospholipase A2 in animal models of acute lung injury. Eur Respir J 2003; 21: 1040-1045
27. Gunther A, Ruppert C, Schmidt R,et al. Surfactant alteration and replacement in acute respiratory distress syndrome. Respir Res 2001; 2: 353-364
28. Fehrenbach H, Brasch F, Uhlig S, et al. Early alterations in intracellular and alveolar surfactant of the rat lung in response to endotoxin. Am J Respir Crit Care Med 1998; 157 : 1630-1639
29. Anonymous. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med 1997; 336: 597-604
30. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med 2000; 342: 469-474
31. Zhu GF, Sun B, Niu SF, et al. Combined surfactant therapy and inhaled nitric oxide in rabbits with oleic acid-induced acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 158: 437-443
32. Cassina A, Rado R. Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 1996; 328: 309-316
33. Beckman TS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 1996; 271: C1424-C1437
34. Gaston B, Drazen JM, Loscalzo J, et al. The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 1994; 149: 538-551
35. Frostell CG. Reassessment of inhaled nitric oxide in acute lung injury. Acta Pharmacol Sin 2003; 24: 1314-1315
36. Jobe A, Kirkpatrick E, Gluck L. Labeling of phospholipids in the surfactant and subcellular fractions of rabbit lung. J Biol Chem 1978; 253: 3810-3816
37. Bosch MA, Risco C, Martin-Municio A. Effect of Escherichia coli lipopolysaccharide on phosphatidylcholine biosynthesis by rat lung and alveolar type II cells. Mol Cell Biochem 1990; 93: 167-172
38. Matalon S, DeMarco V, Haddad IY, et al. Inhaled nitric oxide injures the
pulmonary surfactant system of lambs in vivo. Am J Physiol 1996; 270: L273- L280
39. Miles PR, Bowman L, Huffman L. Nitric oxide alters metabolism in isolated alveolar type II cells. Am J Physiol 1996; 271: L23-30.
40. Ward JA, Roberts RJ. Effect of hyperoxia on phosphatidylcholine synthesis, secretion, uptake and stability in the newborn rabbit lung. Biochim Biophys Acta 1984; 796: 42-50
41. Wink DA, Hanbauer I, Krishna MC, et al. Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. Proc Natl Acad Sci USA 1993; 90: 9813-9817
42. Rubbo H, Radi R, Trujillo M, et al. Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives. J Biol Chem 1994; 269: 26066-26075
43. Wink DA, Cook JA, Krishna MC, et al. Nitric oxide protects against alkyl peroxide-mediated cytotoxicity: further insights into the role nitric oxide plays in oxidative stress. Arch Biochem Biophys 1995; 319: 402-407
44. Rodenas J, Mitjavila MT, Carbonell T. Nitric oxide inhibits superoxide production by inflammatory polymorphonuclear leukocytes. Am J Physiol 1998; 274: C827-C830
45. Turanlahti M, Pesonen E, Lassus P, et al. Nitric oxide and hyperoxia in oxidative lung injury. Acta Paediatr 2000; 89: 966-970
46. Nelin LD, Welty SE, Morrisey JF, et al. Nitric oxide increases the survival of rats with a high oxygen exposure. Pediatr Res 1998; 43: 727-732
47. Howlett CE, Hutchison JS, Veinot JP, et al. Inhaled nitric oxide protects against hyperoxia-induced apoptosis in rat lungs. Am J Physiol 1999; 277: L596-L605
48. Lightfoot RT, Khov S, Ischiropoulos H. Transient injury to rat lung mitochondrial DNA after exposure to hyperoxia and inhaled nitric oxide. Am J Physiol Lung Cell Mol Physiol 2004; 286: L23-L29
49. Charafeddine L, D'Angio CT, Richards JL, et al. Hyperoxia increases keratinocyte growth factor mRNA expression in neonatal rabbit lung. Am J Physiol 1999; 276: L105- L113
50. Ikegami M, Jobe AH, Havill AM. Keratinocyte growth factor increases surfactant pool sizes in premature rabbits. Am J Respir Crit Care Med 1997; 155:
1155-1158
51. Post M, Batenburg JJ, Schuurmans EA, et al. The rate-limiting step in the biosynthesis of phosphatidylcholine by alveolar type II cells from adult rat lung. Biochim Biophys Acta 1982; 712: 390-394
52. Kalmar GB, Kay RJ, Lachance A, et al. Cloning and expression of rat liver CTP: phosphocholine cytidylyltransferase: an amphipathic protein that controls phosphatidylcholine synthesis. Proc Natl Acad Sci USA 1990; 87: 6029-6033
53. Weinhold PA, Rounsifer ME, Feldman DA. The purification and characterization of CTP:phosphorylcholine cytidylyltransferase from rat liver. J Biol Chem 1986; 261: 5104-5110.
54. Spragg RG, Li J. Effect of phosphocholine cytidylyltransferase overexpression on phosphatidylcholine synthesis in alveolar type II cells and related cell lines. Am J Respir Cell Mol Biol 2000; 22: 116-124.
55. Mallampalli RK, Mathur SN, Warnock LJ, et al. Betamethasone modulation of sphingomyelin hydrolysis up-regulates CTP:cholinephosphate cytidylyltransferase activity in adult rat lung. Biochem J 1996; 318: 333-341
56. Kent C. CTP:phosphocholine cytidylyltransferase. Biochim Biophys Acta 1997; 1348: 79-90
57. Mallampalli RK, Salome RG, Hunninghake GW. Lung CTP:choline-phosphate cytidylyltransferase: activation of cytosolic species by unsaturated fatty acid. Am J Physiol 1993; 265: L158-L163
58. Hogan M, Zimmermann LJ, Wang J, et al. Increased expression of CTP:phosphocholine cytidylyltransferase in maturing type II cells. Am J Physiol 1994; 267: L25-L32
59. Tronchere H, Record M, Terce F, et al. Phosphatidylcholine cycle and regulation of phosphatidylcholine biosynthesis by enzyme translocation. Biochim Biophys Acta 1994; 1212: 137-151
60. MacDonald JI, Kent C. Identification of phosphorylation sites in rat liver CTP: phosphocholine cytidylyltransferase. J Biol Chem 1994; 269: 10529-10537
61. Mallampalli RK, Ryan AJ, Salome RG, et al. Tumor necrosis factor-alpha inhibits expression of CTP:phosphocholine cytidylyltransferase. J Biol Chem 2000; 275: 9699-9708
62. Blackwell TS, Christman JW. The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell Mol Biol 1997; 17: 3-9
63. Kang JL, Park W, Pack IS, et al. Inhaled nitric oxide attenuates acute lung injury via inhibition of nuclear factor-kappa B and inflammation. J Appl Physiol 2002; 92: 795-801
64. Cao L, Qian LL, Zhu RY, et al. Regulation of activity of nuclear factor-kappa B and activator protein-1 by nitric oxide, surfactant and glucocorticoids in alveolar macrophages from piglets with acute lung injury. Acta Pharmacol Sin 2003; 24: 1316-1323
65. Ennema JJ, Kobayashi T, Robertson B, et al. Inactivation of exogenous surfactant in experimental respiratory failure induced by hyperoxia. Acta Anaesthesiol Scand 1988; 32: 665-671
66. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351-358
67. Sato Y, Walley KR, Klut ME, et al. Nitric oxide reduces the sequestration of polymorphonuclear leukocytes in lung by changing deformability and CD18 expression. Am J Respir Crit Care Med 1999; 159: 1469-1476
68. Haddad el-B, McCluskie K, Birrell MA, et al. Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation. J Immunol 2002; 169: 974-982
69. Narasaraju TA, Jin N, Narendranath CR, et al. Protein nitration in rat lungs during hyperoxia exposure: a possible role of myeloperoxidase. Am J Physiol Lung Cell Mol Physiol. 2003; 285: L1037- L1045
70. Kobayashi H, Hataishi R, Mitsufuji H, et al. Antiinflammatory properties of inducible nitric oxide synthase in acute hyperoxic lung injury. Am J Respir Cell Mol Biol 2001; 24: 390-397
71. Schwartz MD, Moore EE, Moore FA, et al. Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Crit Care Med 1996; 24: 1285-1292
72. Abraham E, Arcaroli J, Shenkar R. Activation of extracellular signal-regulated kinases, NF-kappa B, and cyclic adenosine 5'-monophosphate response element-binding protein in lung neutrophils occurs by differing mechanisms after hemorrhage or endotoxemia. J Immunol 2001; 166: 522-530
73. Moine P, McIntyre R, Schwartz MD, et al. NF-kappa B regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome.
Shock 2000; 13: 85-91
74. Blackwell TS, Blackwell TR, Holden EP, et al. In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation. J Immunol 1996; 157: 1630-1637
75. Thomassen MJ, Buhrow LT, Connors MJ, et al. Nitric oxide inhibits inflammatory cytokine production by human alveolar macrophages. Am J Respir Cell Mol Biol 1997; 17: 279-283
76. Umansky V, Hehner SP, Dumont A, et al. Co-stimulatory effect of nitric oxide on endothelial NF-kappaB implies a physiological self-amplifying mechanism. Eur J Immunol 1998; 28: 2276-2282
77. Shin WS, Hong YH, Peng HB, et al. Nitric oxide attenuates vascular smooth muscle cell activation by interferon-gamma. The role of constitutive NF-kappa B activity. J Biol Chem 1996; 271: 11317-11324
78. Peng HB, Libby P, Liao JK. Induction and stabilization of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B. J Biol Chem 1995; 270: 14214-14219
79. Park SK, Lin HL, Murphy S. Nitric oxide regulates nitric oxide synthase-2 gene expression by inhibiting NF-kappa B binding to DNA. Biochem J 1997; 322: 609-613
80. Spiecker M, Peng HB, Liao JK. Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of IkappaBalpha. J Biol Chem 1997; 272: 30969-30974
81. D'Angio CT, LoMonaco MB, Johnston CJ, et al. Differential roles for NF-kappa B in endotoxin and oxygen induction of interleukin-8 in the macrophage. Am J Physiol Lung Cell Mol Physiol 2004; 286: L30-L36
82. Burner U, Furtmuller PG, Kettle AJ, et al. Mechanism of reaction of myeloperoxidase with nitrite. J Biol Chem 2000; 275: 20597-20601
83. Stuber F, Wrigge H, Schroeder S, et al. Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury. Intensive Care Med 2002; 28: 834-841
84. Gerlach H, Keh D, Semmerow A, et al. Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. Am J Respir Crit Care Med 2003; 167: 1008-1015