A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis

Tacrolimus (FK506) is an immunosuppressive drug, widely used for organ transplantation and atopic dermatitis. Tacrolimus exerts its immunosuppressive effects primarily by interfering with the activation of T cells, via inhibition of calcineurin. Recent clinical studies have also demonstrated the efficacy of tacrolimus in the treatment of rheumatoid arthritis (RA), an autoimmune disease in which T cells play a pivotal role in pathogenesis. Inflammatory cytokines such as TNF-, IL-1 , and IL-6 are involved in development of the disease. Recently, modes of action of tacrolimus on RA have been intensively studied in in vitro and animal arthritis models, demonstrating that tacrolimus exerts various novel actions as an anti-rheumatic drug. The pharmacological action of tacrolimus suggests that it has potential to specifically suppress the production of pathogenic inflammatory cytokines with a low frequency of infection, improve joint inflammation and bone/cartilage destruction, fully recover loss of functional status, exert rapid relief in arthritic pain, and promote osteogenic and chondrogenic differentiation. Here we review the action of tacrolimus on experimental models of RA, with a focus on our recent studies, and provide further insight into experimental models used for identifying efficacious anti-rheumatic drugs.Received 29 June 2004; returned for revision 19 July 2004; returned for final revision 6 September 2004; accepted by J. Hamilton 14 September 2004     

Toll 样受体信号转导通路与急性肺损伤的研究进展

急性肺损伤(ALI)是由感染性和非感染性的炎症刺激因子启动的细胞内“瀑布式”反应所产生的,是一种具有高发病率和死亡率的急性炎症性疾病,其进一步发展将演变为急性呼吸窘迫综合征(ARDS)。ALI作为一种复杂的临床综合征,发病率和病死率很高,目前发病机制仍不完全明确,大量研究表明细胞因子的过度表达及其相互作用是发生ALI的根本原因。Toll样受体(TLRs)是一类在先天免疫系统中起重要作用并参与炎症过程的跨膜蛋白,可识别外源性病原体或细胞损伤。近年来研究发现,TLRs在调节ALI后的炎症和修复机制方面扮演着重要的角色,是一个潜在的治疗靶点。本文将就TLRs在急性肺损伤中的研究进展作一综述。     

Cyclosporin a and tacrolimus (FK506) differentially alter T-cell receptor expression in vivo

Cyclosporin A (CSA) and tacrolimus (FK506) are two common immunosuppressive agents used post blood and marrow transplantation. Despite similarity in their accepted modes of action, we observed polarized effects of CSA and FK506 on the in vivo human T cell repertoire. To determine the possible mechanism for this difference, the effects of CSA and FK506 on cell viability, cell proliferation, interleukin-2 production, and calcineurin inhibition were determined in vitro. Our data suggest that a secondary mechanism of action exists for the different T-cell repertoire induced by exposure to CSA and FK506.     

Lung mechanics are both dose and tidal volume dependant in LPS-induced lung injury

Endotoxin stimulus plays a significant role in various forms of acute lung injury (ALI) which may be exacerbated by mechanical ventilation. Here, we identify the temporal pathophysiologic sequence following inhaled lipopolysaccharide (LPS) and subsequently examine both LPS dose and V_T relationships. Rats received intratracheal LPS (3, 9 or 15 mg/kg) prior to mechanical ventilation (V_T = 6, 9 or 12 ml/kg) and measurement of forced impedance mechanics for up to 4 h. LPS-induced lung injury was achieved within the 15 min of LPS instillation with a 78% decrease in PaO₂ promptly followed by 30% deterioration in tissue elastance. Despite a 41% increase in total surfactant, the active disaturated phospholipid fraction decreased 3–7% with decreasing PaO₂ and tissue mechanics and with increases in total lung lavage protein (150%) and wet-to-dry lung weight ratio (10%). V_T = 12 ml/kg resulted in an additional deterioration in tissue resistance (130%) and elastance (63%). These results suggest that LPS-induced lung injury is both LPS dose and V_T sensitive, supporting a ‘two hit’ model of ALI.     

中性粒细胞胞外诱捕网在新生大鼠急性肺损伤中的作用

目的:探讨中性粒细胞胞外诱捕网(NETs)在新生大鼠急性肺损伤(ALI)中的作用。方法:取出生7 d的SD大鼠30只,按照随机数字表法分成生理盐水对照组、ALI组及ALI+脱氧核糖核酸酶(Dnase)组,每组10只。ALI组用脂多糖(LPS)以20 mg/kg的剂量腹腔注射,ALI+Dnase组则在注射LPS后即腹腔注射Dnase(5 mg/kg)。给药6 h后,水合氯醛麻醉大鼠,收集支气管肺泡灌洗液(BALF),荧光酶标仪检测BALF中游离DNA(cf-DNA)的含量;右肺组织固定于4%多聚甲醛中,HE染色观察各组大鼠肺组织形态结构;左肺组织制备肺组织匀浆,酶联免疫吸附测定(ELISA)法检测肺组织匀浆中白细胞介素6(IL-6)及肿瘤坏死因子α(TNF-α)的含量;使用免疫荧光法与Western blot检测各组大鼠肺组织中瓜氨酸化组蛋白H3(CitH3)及髓过氧化物酶(MPO)的生成情况。结果:与对照组相比,ALI组与ALI+Dnase组中cf-DNA、CitH3、MPO、IL-6及TNF-α水平均升高(P<0.05),肺组织中炎性细胞浸润严重;与ALI组相比,ALI+Dnase组新生大鼠肺组织中cf-DNA、Cith3、MPO、IL-6及TNF-α水平降低(P<0.05),ALI+Dnase组炎症浸润程度降低。结论:新生大鼠ALI中,NETs水平为反映肺组织损伤的重要指标,NETs可能为治疗新生儿ALI的新靶点。     

Degree of endothelium injury promotes fibroelastogenesis in experimental acute lung injury

We tested the hypothesis that at the early phase of acute lung injury (ALI) the degree of endothelium injury may predict lung parenchyma remodelling. For this purpose, two models of extrapulmonary ALI induced by Escherichia coli lipopolysaccharide (ALI-LPS) or cecal ligation and puncture (ALI-CLP) were developed in mice. At day 1, these models had similar degrees of lung mechanical compromise, epithelial damage, and intraperitoneal inflammation, but endothelial lesion was greater in ALI-CLP. A time course analysis revealed, at day 7: ALI-CLP had higher degrees of epithelial lesion, denudation of basement membrane, endothelial damage, elastic and collagen fibre content, neutrophils in bronchoalveolar lavage fluid (BALF), peritoneal fluid and blood, levels of interleukin-6, KC (murine analogue of IL-8), and transforming growth factor-β in BALF. Conversely, the number of lung apoptotic cells was similar in both groups. In conclusion, the intensity of fibroelastogenesis was affected by endothelium injury in addition to the maintenance of epithelial damage and intraperitoneal inflammation.     

LPS性肺损伤大鼠一氧化氮合酶表达和肺细胞凋亡变化

目的: 观察内毒素性肺损伤过程中肺细胞凋亡和一氧化氮合酶（NOS）mRNA表达的时程性变化及关系,探讨LPS性肺损伤（ALI）的发病机制。方法: 健康雄性SD大鼠48只,随机分成2组:①对照组：静注等量生理盐水；②模型组(LPS组)：静注LPS复制ALI模型,分别于给药1、3、6、9及12h后采集样品；逆转录聚合酶链反应（RT-PCR）法测定肺组织中NOSmRNA表达变化；电镜、流式细胞术检测肺细胞凋亡率；免疫组化法测定Bcl-2和Bax；光镜、电镜观察肺组织病理变化。结果: 与对照组比较，LPS组iNOSmRNA表达随时间延长而增强，给予LPS 3 h后有显著差异(P<0.05)，eNOSmRNA随时间延长而降低，给LPS 3 h时有显著差异(P<0.05)，nNOSmRNA在观察时间内没有变化；光镜和电镜下可见在观察时间内1 h起肺损伤随时间延长加重；流式细胞术显示LPS组凋亡细胞随时间延长增多，9 h达高峰，12 h有所降低；免疫组化结果显示，LPS组随时间延长Bcl-2减少，主要表现在肺上皮细胞，Bax增多；对照组无明显变化。结论: 不同一氧化氮合酶在ALI中表达强度不同；抗凋亡蛋白Bcl-2和促凋亡蛋白Bax是ALI时调节细胞凋亡的途径之一；一氧化氮合酶可能通过调节Bcl-2和Bax平衡而影响凋亡。     

急性肺损伤大鼠肺泡内中性粒细胞凋亡的延迟

目的 :观察急性肺损伤 (ALI)时中性粒细胞 (PMN)的凋亡情况 ,以阐明其在肺损伤中的作用。方法 :对盐酸内毒素造成的大鼠ALI模型行肺泡灌洗术 ,将其中的PMN及正常外周血PMN分别与ALI组及对照组的肺泡灌洗液 (BALF)孵育 ,用AnnexinV及形态学方法测其凋亡率 ,并观察白细胞介素 - 1β(IL - 1β)的表达情况。 结果 :同ALI的BALF孵育的PMN凋亡明显延迟 ,其IL - 1β的表达亦升高 ,IL - 1β与PMN的凋亡呈负相关。 结论 :ALI时 ,肺泡内PMN的渗出增加 ,凋亡延迟 ,可能与IL - 1β表达升高有关。     

DARC on RBC limits lung injury by balancing compartmental distribution of CXC chemokines

The Duffy antigen receptor for chemokines (DARC) has a high affinity for CC and CXC chemokines. However, it lacks the ability to induce cell responses that are typical for classical chemokine receptors. The role of DARC in inflammatory conditions remains to be elucidated. We studied the role of DARC in a murine model of acute lung injury. We found that in Darc‐gene‐deficient (Darc^?/?) mice, LPS‐induced PMN migration into the alveolar space was elevated more than twofold. In contrast, PMN adhesion to endothelial cells and within the interstitial space was reduced in Darc^?/? mice. Darc^?/? mice also exhibited increased microvascular permeability. Elevated PMN migration in Darc^?/? mice was associated with increased concentrations of two essential CXCR2 ligands, CXCL1 and CXCL2/3 in the alveolar space. In the blood, CXCL1 was mostly associated with RBC in WT mice and with plasma in Darc^?/? mice. We found that DARC on RBC prevented excessive PMN migration into the alveolar space. In contrast, DARC on non‐hematopoietic cells appeared to have only minor effects on leukocyte trafficking in this model. These findings show how DARC regulates lung inflammation by controlling the distribution and presentation of chemokines that bind CXCR2.     

亚硝酸钠减轻脂多糖诱导的小鼠急性肺损伤

目的:明确亚硝酸钠对急性肺损伤(ALI)的治疗作用及可能机制。方法:用脂多糖(LPS4mg/kg)气道滴入制备小鼠ALI模型。随机分为生理盐水组、LPS模型组、亚硝酸钠4.8nmol/L、48nmol/L、480nmol/L治疗组。测定肺湿/干重比值、肺通透性,常规细胞形态学检测支气管肺泡灌洗液(BALF)中白细胞数量变化,苏木精曙红染色观察肺组织病理改变,用试剂盒检测肺组织白细胞介素-10(IL-10)、肿瘤坏死因子-α(TNF-α)、一氧化氮(NO)含量及一氧化氮合酶(NOS)活性。结果:腹腔注射4.8nmol/L、48nmol/L亚硝酸钠可明显降低LPS诱导的ALI小鼠肺湿/干重比值;减少BALF中的白细胞总数及中性粒细胞的比例;降低肺毛细血管通透性;改善肺组织病理变化;降低肺组织TNF-α/IL-10比值、抑制总NOS活性及诱导型NOS(iNOS)活性的增加。480nmol/L亚硝酸钠对LPS诱导的ALI小鼠肺组织上述指标除NOS活性外,均无显著影响(P0.05)。与对照组相比,480nmol/L亚硝酸钠显著增加了肺组织NO水平。结论:低、中剂量亚硝酸钠能够对抗LPS诱导的小鼠急性肺损伤,低剂量亚硝酸钠还原产生的NO对iNOS活性的抑制及下调TNF-α/IL-10比值可能在ALI中起重要作用。     

TNFR-Fc减轻LPS所致小鼠ALI炎症反应损伤

目的: 评价肿瘤坏死因子受体-Fc融合蛋白(TNFR-Fc)能否有效下调炎症反应而减轻急性肺损伤(ALI)小鼠的肺组织破坏。方法: 小鼠随机分为脂多糖(LPS)组、TNFR-Fc+LPS组和对照组。气管内滴入LPS复制ALI小鼠模型,TNFR-Fc组在滴入LPS前24 h腹膜腔注射TNFR-Fc (0.4 mg/kg),在滴入LPS后2 h收集标本,检测肺湿/干重、肺泡蛋白含量与肺组织病理评分;ELISA法检测血清TNF-α浓度及检测肺泡灌洗液与血清IL-1β、IL-6、IL-10与IFN-γ浓度。结果: TNFR-Fc显著降低血清TNF-α浓度(P＜0.05),轻度降低肺湿/干重比例,显著降低BALF蛋白浓度(P＜0.05),显著降低ALI评分数值(P＜0.05)。TNFR-Fc显著降低致炎症细胞因子IL-6在BALF(P＜0.05)与血清(P＜0.05)中的浓度,轻度提高BALF中IL-10浓度(P＞0.05),但其差异不显著,亦能显著提高血清IL-10浓度(P＜0.05)。IL-1β与IFN-γ水平处理前后变化不显著。结论: TNFR-Fc中和ALI中过度表达的TNF-α,下调以IL-6为代表的炎症反应,减轻ALI的肺组织破坏。     

Effect of hypertonic saline treatment on the inflammatory response after hydrochloric acid-induced lung injury in pigs

OBJECTIVES:

Hypertonic saline has been proposed to modulate the inflammatory cascade in certain experimental conditions, including pulmonary inflammation caused by inhaled gastric contents. The present study aimed to assess the potential anti-inflammatory effects of administering a single intravenous dose of 7.5% hypertonic saline in an experimental model of acute lung injury induced by hydrochloric acid.

METHODS:

Thirty-two pigs were anesthetized and randomly allocated into the following four groups: Sham, which received anesthesia and were observed; HS, which received intravenous 7.5% hypertonic saline solution (4 ml/kg); acute lung injury, which were subjected to acute lung injury with intratracheal hydrochloric acid; and acute lung injury + hypertonic saline, which were subjected to acute lung injury with hydrochloric acid and treated with hypertonic saline. Hemodynamic and ventilatory parameters were recorded over four hours. Subsequently, bronchoalveolar lavage samples were collected at the end of the observation period to measure cytokine levels using an oxidative burst analysis, and lung tissue was collected for a histological analysis.

RESULTS:

Hydrochloric acid instillation caused marked changes in respiratory mechanics as well as blood gas and lung parenchyma parameters. Despite the absence of a significant difference between the acute lung injury and acute lung injury + hypertonic saline groups, the acute lung injury animals presented higher neutrophil and tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and IL-8 levels in the bronchoalveolar lavage analysis. The histopathological analysis revealed pulmonary edema, congestion and alveolar collapse in both groups; however, the differences between groups were not significant. Despite the lower cytokine and neutrophil levels observed in the acute lung injury + hypertonic saline group, significant differences were not observed among the treated and non-treated groups.

CONCLUSIONS:

Hypertonic saline infusion after intratracheal hydrochloric acid instillation does not have an effect on inflammatory biomarkers or respiratory gas exchange.     

Effect of tacrolimus on endotoxin-induced lung injury in sheep

Since tacrolimus (FK-506) is known to suppress the proliferation and generation of T cells and to inhibit the production of T cell derived cytokines, we examined the effect of FK-506 on endotoxin-induced lung injury. We administered FK-506 (0.1 mg/kg) intravenously before the infusion of endotoxin (1 microgram/kg) into conscious sheep. We measured pulmonary hemodynamics, lung fluid balance, circulating leukocyte count and arterial blood gas tensions. The increase in pulmonary arterial pressure was significantly attenuated by FK-506 during the late period (3-5 h after endotoxin). Arterial oxygen gas tension was significantly higher in the FK-506 treated sheep during this phase. However, no significant differences were observed in lung lymph balance and circulating leukocyte count between the endotoxin alone group and the FK-506 treated group. These findings suggest that FK-506 may improve gas exchange in acute lung injury although there is an increased pulmonary vascular leakage. It is probable that FK-506 may have a beneficial potential on endotoxin-induced lung injury in sheep.     

Quercetin protects against lipopolysaccharide-induced acute lung injury in rats through suppression of inflammation and oxidative stress

Introduction

Acute lung injury (ALI) is an acute inflammatory disease characterized by excess production of inflammatory factors in lung tissue. Quercetin, a herbal flavonoid, exhibits anti-inflammatory and anti-oxidative properties. This study was performed to assess the effects of quercetin on lipopolysaccharide (LPS)-induced ALI.

Material and methods

Sprague-Dawley rats were randomly divided into 3 groups: the control group (saline alone), the LPS group challenged with LPS (Escherichia coli 026:B6; 100 µg/kg), and the quercetin group pretreated with quercetin (50 mg/kg, by gavage) 1 h before LPS challenge. Bronchoalveolar lavage fluid (BALF) samples and lung tissues were collected 6 h after LPS administration. Histopathological and biochemical parameters were measured.

Results

The LPS treatment led to increased alveolar wall thickening and cellular infiltration in the lung, which was markedly prevented by quercetin pretreatment. Moreover, quercetin significantly (p < 0.05) attenuated the increase in the BALF protein level and neutrophil count and lung wet/dry weight ratio and myeloperoxidase activity in LPS-challenged rats. The LPS exposure evoked a 4- to 5-fold rise in BALF levels of tumor necrosis factor-α and interleukin-6, which was significantly (p < 0.05) counteracted by quercetin pretreatment. Additionally, quercetin significantly (p < 0.05) suppressed the malondialdehyde level and increased the activities of superoxide dismutase, catalase, and glutathione peroxidase in the lung of LPS-treated rats.

Conclusions

Quercetin pretreatment effectively ameliorates LPS-induced ALI, largely through suppression of inflammation and oxidative stress, and may thus have therapeutic potential in the prevention of this disease.     

Effects of tacrolimus (FK506) and mycophenolate mofetil (MMF) on regulatory T cells and co-inhibitory receptors in the peripheral blood of human liver allograft patients

Context: Recent studies have shown that a combination treatment of mycophenolate mofetil (MMF) and tacrolimus (FK506) may be an option for organ transplantation patients.

Objective: In this study, we detected the effects of FK506 and MMF on the expressions of regulatory T cells (Tregs) and co-inhibitory receptors on Tregs in peripheral blood mononuclear cells (PBMC) of patients with stable phase after liver transplantation.

Materials and methods: A total of 35 patients with stable stage after 6?months of liver transplantation were divided into two groups including 20 patients were treated with FK506 monotherapy (FK506 group), and 15 patients with FK506 and MMF combination (FK506?+?MMF group). 15 healthy subjects were served as the control.

Results: It is found that percentages of CD3⁺, CD3⁺CD4⁺ and CD3⁺CD8⁺ T cells in FK506 group are lowered compared to the control group but they are elevated in FK506?+?MMF group. Amount of CD4⁺CD25⁺CD127low/-Treg cells in CD3⁺ CD4⁺T cells in FK506?+?MMF group was higher than that in FK506 group and control group. The expressions of co-inhibitory receptors (CTLA-4, PD-1, Tim-3, LAG-3 and TIGIT) on Tregs in FK506?+?MMF group were significant higher than those in the FK506 group and control group. The levels of the relative cytokines (TGF-β and IL-10) in FK506 group are down-regulated compared to the control group.

Conclusion: The application of FK506 combined with MMF may be superior to FK506 monotherapy for the patients to further induce the immune tolerance after liver transplantation.     

长春西汀注射液减轻脂多糖诱导的大鼠急性肺损伤

目的:观察长春西汀注射液对脂多糖(lipopolysaccharide,LPS)诱导大鼠急性肺损伤(acute lung injury,ALI)的作用,并研究初步的作用机制。方法:雄性Wistar大鼠50只,随机分为正常对照组(control)、模型组(ALI组)以及长春西汀低剂量组、中剂量组和高剂量组,每组10只。正常对照组股静脉注射0.9%氯化钠注射液(5 m L/kg);模型组股静脉注射LPS 10 mg/kg;长春西汀低、中和高剂量组股静脉注射LPS 10 mg/kg,30 min后分别腹腔注射长春西汀注射液0.2 mg/kg、0.7 mg/kg和1.2 mg/kg。伊红染色观察肺部组织病理学切片,TUNEL法检测肺组织的细胞凋亡,分光光度法检测并计算肺组织髓过氧化物酶(MPO)活性,Western blot法检测肺组织中NF-κB、ICAM-1、VCAM-1、Bax与Bcl-2的蛋白水平。结果:与模型组相比,采用长春西汀给药后,明显减轻急性肺损伤的肺组织结构损伤与炎性细胞浸润,降低肺组织凋亡的细胞数与MPO活性,下调细胞中NF-κB、ICAM-1、VCAM-1与Bax的蛋白表达水平,上调Bcl-2的蛋白表达水平。结论:长春西汀注射液对急性肺损伤大鼠的肺组织具有保护作用,可能与降低肺组织中MPO活性,以及调控NF-κB、ICAM-1、VCAM-1、Bax与Bcl-2蛋白表达水平有关。     

他克莫司后处理诱导缺血脊髓对再灌注损伤的耐受*

目的探讨他克莫司后处理能否诱导大鼠缺血脊髓对再灌注损伤的耐受。方法成年雄性SD大鼠30只,随机分为假手术（s0）组、缺血再灌注（IR）组和他克莫司后处理（TP）组,每组10只大鼠,采用经股动脉置管球囊扩张制备脊髓缺血模型,SO组仅行置管,IR组在脊髓缺血20分钟后行再灌注,TP组在脊髓缺血20分钟后再灌注,即刻经左颈总动脉一次性注射他克莫司0．5mg／kg。再灌注后7、14天采用Tarlov评分法检测大鼠后肢运动功能,脊髓组织切片HE染色观察病理学改变。结果SO组大鼠各时间点后肢Tarlov评分均为5分,形态学检测显示脊髓组织结构正常;IR组大鼠Tarlov评分明显降低,脊髓组织呈现出坏死、水肿、空腔形成等缺血再灌注损伤表现;TP组大鼠Tarlov评分结果显著优于IR组,脊髓组织病理变化较IR组为轻。结论建立大鼠脊髓缺血再灌注损伤模型,并初步证实他克莫司后处理能诱导缺血脊髓对再灌注损伤的耐受。     

Polydatin attenuates ipopolysaccharide-induced acute lung injury in rats

Anti-inflammatory and anti-apoptotic effects of polydatin (PD) have been demonstrated in our previous studies. Recently, we have found that PD treatment can ameliorate burn-induced acute lung injury (ALI). In the present study, we hypothesized that PD may provide protective effect against LPS-induced ALI through reducing inflammation and apoptosis. Rats were respectively pretreated with PD at doses of 15, 30 and 45 mg/kg weight, followed by intratracheal administration of lipopolysaccharide (LPS). LPS-challenged rats exhibited significant lung injury characterized by the deterioration of histopathology, pulmonary microvascular hyperpermeability, wet-to-dry weight ratio, and oxygenation index, which was attenuated by PD (30 and 45 mg/kg) treatment. Moreover, PD (30 and 45 mg/kg) treatment inhibited LPS-induced inflammatory response, as evidenced by the downregulation of lung myeloperoxidase activity, total cells and PMNs in bronchoalveolar lavage fluid, and the systemic levels of the pro-inflammatory cytokines. Furthermore, PD (30 and 45 mg/kg) treatment remarkably improved LPS-induced increase in TUNEL (deoxynucleotidyl transferase dUTP nick end labeling) staining-positive cells, caspase 3 activity, Bax over-expression and Bcl-2 down-expression. In conclusion, these results demonstrate that PD (30 and 45 mg/kg) treatment attenuates LPS-induced ALI through reducing lung inflammation and apoptosis.     

细胞自噬在急性肺损伤发展进程中的双刃剑作用

<正>急性肺损伤(acute lung injury,ALI)是急危重症患者常见的一种器官损伤,肺实质细胞死亡是ALI的基础,明确细胞死亡的发生机制将为防治ALI提供重要的理论支撑^[1]。细胞自噬(autophagy)是细胞代谢过程中的衰老细胞器和异常蛋白质等成分降解的过程,受多条信号通路与多种信号分子的调节,有利于维持细胞稳态;病理状态下,自噬被激活或抑     

一氧化氮吸入对急性高浓度氧肺损伤新生大鼠肺水通道蛋白1和5表达的影响

目的：观察一氧化氮(NO)吸入对急性高浓度氧肺损伤新生大鼠肺上皮水转运体系的影响。方法：32只新生SD大鼠，随机分为：(1)空气组(C)：予空气48 h；（2）高浓度氧组(O)：予高浓度氧持续吸入48 h，维持FiO₂＞0.95；(3)高浓度氧+NO组(ONO)：予高浓度氧持续吸入48 h，维持FiO₂＞0．95，前24 h同时予1×10-5NO吸入；（4）空气 + NO组(CN)： 予空气48 h，前24 h同时予1×10^-5NO吸入。各组分别测肺组织湿重/干重比值(Q_W/Q_D)，行肺组织病理学检查，用RT-PCR方法测定肺组织AQP1、AQP5、α₁-NKA和α-ENaC mRNA含量。结果： 高浓度氧组肺湿重/干重比值明显高于正常对照组(5.81±1.01 vs 4.33±0.94，P<0.01)；而肺组织AQP1 mRNA含量明显低于正常对照组(0.68±0.38 vs 1.81±0.76， P<0.01)，AQP5mRNA含量无明显变化。1×10^-5 NO+高浓度氧组肺组织湿重/干重比值明显高于高浓度氧组(4.89±0.68 vs 5.81±1.01， P<0.05)；而肺组织AQP1 mRNA含量明显高于高浓度氧组(1.27±0.54 vs 0.68±0.38，P<0.05)，AQP5mRNA含量无明显变化。结论：1×10^-5NO吸入24 h能减轻急性高浓度氧肺损伤新生大鼠的肺水肿，提高肺内水通道蛋白1mRNA含量，水通道蛋白5的mRNA含量无明显改变，提示1×10^-5NO的吸入可能对急性高浓度氧肺损伤新生大鼠肺内水通道蛋白1有一定的保护作用。