Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high-altitude pulmonary edema

An exaggerated hypoxic pulmonary vasoconstriction is essential for development of high-altitude pulmonary edema (HAPE). We hypothesized that susceptibility to HAPE may be related to decreased production of nitric oxide (NO), an endogenous modulator of pulmonary vascular resistance, and that a decrease in exhaled NO could be detected during hypoxic exposure. Therefore, we investigated respiratory tract NO excretion by chemiluminescence and pulmonary artery systolic pressure (Ppa,s) by echocardiography in nine HAPE-susceptible mountaineers and nine HAPE-resistant control subjects during normoxia and acute hypoxia (fraction of inspired oxygen [FI(O2)] = 0.12). The subjects performed oral breathing. Nasally excreted NO was separated from respiratory gas by suction via a nasal mask. In HAPE-susceptible subjects, NO excretion in expired gas significantly decreased (p < 0.05) during hypoxia of 2 h in comparison with normoxia (28 +/- 4 versus 21 +/- 2 nl/min, mean +/- SEM). In contrast, the NO excretion rate of control subjects remained unchanged (31 +/- 6 versus 33 +/- 6 nl/ min, NS). Nasal NO excretion did not differ significantly between groups during normoxia (HAPE-susceptible group, 183 +/- 16 nl/ min; control subjects, 297 +/- 55 nl/min, NS) and was not influenced by hypoxia. The changes in Ppa,s with hypoxia correlated with the percent changes in lower respiratory tract NO excretion (R = -0.49, p = 0.04). Our data provide the first evidence of decreased pulmonary NO production in HAPE-susceptible subjects during acute hypoxia that may contribute among other factors to their enhanced hypoxic pulmonary vascular response.     

Role of nitric oxide and peroxynitrite anion in lung injury induced by intestinal ischemia－reperfusion in rats

AIM: To evaluate effects of nitric oxide (NO) and peroxynitrite anion (ONOO-) on lung injury following intestinal ischemia-reperfusion (IR) in rats. METHODS: A rat model of intestinal ischemia was made by clamping superior mesenteric artery and lung injury was resulted from reperfusion. The animals were randomly divided into 3 groups: sham operation (Sham), 2 h ischemia followed by 2 h reperfusion (IR) and IR pretreated with aminoguanidine (AG) - an inhibitor of inducible NO synthase (iNOS) 15 minutes before reperfusion (IR+AG). The lung malondialdehyde (MDA) and nitrate/nitrite (NO2/NO3)contents and morphological changes were examined.Western blot was used to detect the iNOS protein expression.Immunohistochemical staining was used to determine the change of nitrotyrosine (NT)- a specific "footprint" of ONOO-. RESULTS: The morphology revealed evidence for lung edema, hemorrhage and polymorphonuclear sequestration after intestinal IR. Compared with sham group, lung contents of MDA and NO2-/NO3- in IR group were significantly increased (12.00±2.18 vs23.44±1.25 and 76.39±6.08 vs140.40±4.34,P＜0.01) and the positive signals of iNOS and NT were also increased in the lung. Compared with IR group, the contents of MDA and NO2/NO3 in IR+AG group were significantly decreased (23.44±1.25 vs14.66±1.66 and 140.40±4.34 vs 80.00±8.56, P＜0.01) and NT staining was also decreased. CONCLUSION: Intestinal IR increases NO and ONOO production in the lung, which may be involved in intestinal IR-mediated lung injury.     

一氧化氮介导内毒素所致体外培养肝细胞凋亡

目的 研究一氧化氮（NO）介导内毒素（LPS）所致的肝细胞损伤的细胞死亡类型。方法 采用体外肝细胞／库普弗细胞混合培养,以光镜、电镜及抽提细胞DNA电泳观察受LPS刺激后NO产生增多所致肝细胞损伤的形态学及生物化学改变情况。结果 受LPS刺激后,培养基中NO产物水平显著升高,肝细胞变小、变圆。细胞表达出泡,核染色质致密、结块,结块,核膜皱折变形等,DNA电泳呈明显“云梯形式”。而同时加用诱导型一氧化氮合酶抑制基胍后,培养基中NO产物水平显著降低,,光镜、电镜及DNA电泳分析肝细胞均上述改变。结论 NO介导LPS所致的混合培养肝细胞损伤主要为肝细胞凋亡,提示LPS通过刺激NO大量产生而诱导肝细胞凋亡可能是其致肝损害机制之一。     

Mechanisms of pulmonary edema induced by tumor necrosis factor-alpha

We tested the hypothesis that human recombinant tumor necrosis factor-alpha (TNF) promotes pulmonary edema by neutrophil-dependent effects on the pulmonary vasculature. The isolated guinea pig lung was perfused with phosphate-buffered Ringer's solution with or without human neutrophils. The infusion of neutrophils (9 x 10(6) total) into lungs isolated after the in vivo administration of TNF (3.2 x 10(5) units/kg) resulted in weight gain (+1.951 +/- 0.311 g versus -0.053 +/- 0.053 g in control) and an increase in the lung (wet-dry)-to-dry weight ratio (8.3 +/- 0.5 versus 6.0 +/- 0.2 in control), indicating the formation of pulmonary edema. The neutrophil-dependent pulmonary edema induced by TNF was associated with a combination of increased capillary permeability (capillary filtration coefficient [Kf,c], 0.170 +/- 0.048 g/min/cm H2O/g at 30 minutes versus 0.118 +/- 0.008 g/min/cm H2O/g at baseline) and increased pulmonary capillary pressure (Ppc, 12.8 +/- 0.8 cm H2O at 60 minutes versus 6.0 +/- 0.3 cm H2O at baseline). The Ppc increase was mediated by thromboxane A2 (TXA2) because the TXA2 synthetase inhibitor Dazoxiben (0.5 mM) prevented the effect (Ppc, 6.7 +/- 0.6 cm H2O at 60 minutes with Dazoxiben), and thromboxane B2 (TXB2) levels were increased in the pulmonary venous effluent (5,244 +/- 599 pg/ml at 60 minutes versus 60 +/- 13 pg/ml at baseline). Studies using WEB-2086 (37 microM), a platelet activating factor (PAF) receptor antagonist, indicated that PAF mediated the increased vascular permeability (Kf,c, 0.107 +/- 0.014 g/min/cm H2O/g at 30 minutes using WEB-2086) and, in part, the increased Ppc (Ppc, 8.4 +/- 0.7 cm H2O at 60 minutes using WEB-2086). In addition, alterations of endothelial peripheral actin bands were noted after TNF administration. The data indicate that TNF induces neutrophil-dependent pulmonary edema associated with increased Ppc (mediated by TXA2 and PAF), increased Kf,c (mediated by PAF), and changes in endothelial peripheral actin bands.     

Pulmonary edema caused by inhaled nitric oxide therapy in two patients with pulmonary hypertension associated with the CREST syndrome

Pulmonary arterial hypertension (PAH) is commonly associated with the CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome. Inhaled nitric oxide (iNO) is often used to assess acute vasoresponsiveness in patients with PAH, and reports of adverse reactions have been infrequent. We describe two of nine patients with PAH and CREST syndrome who had pulmonary edema develop during acute iNO testing. This complication was not encountered in the 46 patients with other forms of PAH tested with iNO. We suggest that iNO should be used with caution, if at all, to test acute vasoreactivity in patients with CREST syndrome.     

Acute pulmonary edema induced by overdosage of phenothiazines.

Three schizophrenic adults with previous histories of using phenothiazine derivatives developed acute pulmonary edema after taking large amounts of these drugs. The clinical manifestations included coma (three), hypothermia (two), tachycardia (two), miosis (two) and hypotension (one). All three patients underwent gastric lavage and were treated supportively. The fulminant pulmonary edema in the three cases resolved within 18 to 40 h. The etiology of pulmonary edema following overdosage of phenothiazines remains unknown. The authors hypothesize that the most likely pathogenesis is a drug-induced neurogenic pulmonary edema resulting from a disturbance of hypothalamic function.     

Role of inducible nitric oxide synthase in pulmonary microvascular protein leak in murine sepsis

The effects of nitric oxide (NO) from calcium-independent NO synthase (iNOS) on microvascular protein leak in acute lung injury (ALI) are uncertain, possibly because of disparate effects of iNOS-derived NO from different cells. We assessed the contribution of iNOS from inflammatory versus parenchymal cells to pulmonary protein leak in murine cecal ligation and perforation-induced ALI. We studied iNOS+/+, iNOS-/-, and two reciprocally bone marrow-transplanted iNOS chimeric mice groups: + to - (iNOS+/+ donor bone marrow-transplanted into iNOS-/- recipient mice) and - to +. Sepsis-induced ALI was characterized by pulmonary leukocyte infiltration, increased pulmonary iNOS activity, and increased pulmonary microvascular protein leak, as assessed by Evans blue (EB) dye. Despite equal neutrophil infiltration, sepsis-induced EB-protein leak was eliminated in iNOS-/- mice and in - to + iNOS chimeras (parenchymal cell-localized iNOS) but was preserved in + to - chimeric mice (inflammatory cell-localized iNOS). EB-protein leak was also prevented by pretreatment with allopurinol and superoxide dismutase. Microvascular protein leak in sepsis-induced ALI is uniquely dependent on iNOS in inflammatory cells with no obvious contribution of iNOS in pulmonary parenchymal cells. Pulmonary protein leak is also dependent on superoxide, suggesting an effect of peroxynitrite rather than NO itself.     

Role of nitric oxide in the progression of cardiovascular remodeling induced by carotid arterio-venous shunt in rabbits

Despite a variety of biological roles for nitric oxide (NO) in the cardiovascular system, little is known about whether NO is involved in cardiac hypertrophy. We hypothesized that NO production following a sustained increase in shear stress by volume-overload modifies the level of cardiac hypertrophy independent of hemodynamic changes. Volume-overload was induced by shunt formation between the left common carotid artery and the external jugular vein in 21 rabbits. These shunt rabbits were randomly assigned to 3 groups: shunt with no treatment (n = 8), shunt treated with a low dose of N(G)-nitro-L-arginine methyl ester (L-NAME. 0.5 g/L in drinking water, n=8), and shunt with a high dose of L-NAME (1.5 g/L, n = 5). Eight sham operated rabbits were used as controls. Treatments were started immediately after operation and were continued for 6 weeks. Chronic volume-overload by shunt formation caused left ventricular dilatation and arterial enlargement proximal to the fistula. The relative wall thickness of the left ventricle was decreased, indicating eccentric cardiac hypertrophy. L-NAME elevated mean arterial blood pressure (P < 0.01) and reduced the increment of cardiac output (P < 0.05). L-NAME attenuated ventricular weight (P < 0.01) ventricular cavity dilatation (P < 0.01). and arterial enlargement (P < 0.05). The re-capitulation of atrial natriuretic factor mRNA in the hypertrophied left ventricular myocardium by volume-overload was attenuated with L-NAME. In this model with chronic volume-overload, NO plays a pivotal role in the progression of cardiovascular remodeling by regulating the loading conditions of the heart.     

一氧化氮及一氧化氮合酶在低氧性肺动脉高压中的研究进展

一氧化氮可调节肺血管张力,维持肺血管正常结构和肺循环的低阻力状态,在低氧性肺动脉高压的发生机制中起重要作用.由于一氧化氮具有独特的理化性质和生物学活性,因此目前研究主要集中在对其合成的关键酶一氧化氮合酶.下面就一氧化氮、一氧化氮合酶在低氧性肺动脉高压发病中的作用机制及临床应用的研究作一简单综述.     

Time-dependent changes in orally exhaled nitric oxide and pulmonary functions induced by inhaled corticosteroids in childhood asthma.

Exhaled nitric oxide levels are elevated in asthmatic children and decrease after inhaled steroid treatment. We evaluated the time-dependent changes in fractional exhaled nitric oxide concentration (FENO) and pulmonary function parameters following inhaled steroid therapy. Thirty-nine steroid-naive atopic patients (age 11.92+/-0.48 years) with mild intermittent asthma and 22 age-matched healthy controls were enrolled in the study; pulmonary functions and FE(NO) levels were measured. Low doses of inhaled steroids were prescribed to all asthmatic patients who were reevaluated in a second visit (between 10 and 40 days after the beginning of the treatment). At the enrolment, asthmatic patients had similar forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) values (p > 0.05) but reduced forced expiratory flows at 25-75% of the vital capacity (FEF(25-75%)) values, as compared to controls (p < 0.05). In addition, FE(NO) levels were significantly higher in asthmatics with respect to control subjects (30.8+/-3.0 and 4.0+/-0.5 ppb, respectively; p < 0.01). All asthmatics had FE(NO) levels higher than 8.8 ppb (i.e., > 2 standard deviations of the mean in controls). After steroid treatment, patients showed significant improvement of FEV1, FVC, and FEF(25-75%) (p = 0.0001; each comparison) and a reduction of FE(NO) levels (p = 0.0001). A weak significant correlation was found between percent decrease in FE(NO) levels and percent increase in FEV1 (r = 0.33, p = 0.04) or in FEF(25-75%) (r = 0.4, p = 0.01) after treatment. When changes in FE(NO) levels and in pulmonary function parameters were corrected for days of treatment, significant correlations were still present between percent decrease in FE(NO) levels and percent increase in FEV1 (r = 0.57, p = 0.0004) or percent increase in FEF(25-75%) (r = 0.45, p = 0.006). Sixteen of the 39 asthmatic patients were evaluated on two occasions after the beginning of treatment, at days 10 and 40. The significant reduction in FE(NO) levels (p < 0.01) and the significant increase in FEV1 and FEF(25-75%) values observed (p < 0.05) after 10 days did not further improve at day 40. These data show that it is possible to demonstrate early effects of low-dose inhaled steroids in asthmatic children using objective measurements of airway caliber and inflammation.     

肺源性一氧化氮过度表达在急性坏死性胰腺炎肺损伤中的作用

目的 探讨肺源性一氧化氮（NO）过度表达对急性坏死性胰腺炎（ANP）肺损伤的影响。方法 将72只成年SD大鼠随机分为三组各24只。ANP组、ANP预处理组（预处理组）逆行性胰胆管注射5％牛磺酸钠建立ANP大鼠模型，对照组注射等量生理盐水。造模前30min，预处理组腹腔注射N-硝基-L-精氨酸甲酯（L-NAME）10mg／kg。造模后1、3、6、12h分别处死大鼠各6只，取肺泡巨噬细胞（AM）检测NO水平及诱导型一氧化氮合成酶（iNOS）mRNA表达情况及TNF-a水平，并行肺组织病理学检查。结果 ANP组肺损伤随时间延长而逐渐加重；AM分泌TNF-a，NO水平逐渐升高，至6h达到高峰，12h回落。AMiNOS mRNA的表达情况与NO的变化趋势相似。预处理组各指标变化趋势与ANP组相似，但各指标均低于ANP组（P均〈0．05）；肺组织髓过氧化物酶（MPO）、支气管肺泡灌洗液（BALF）蛋白含量、肺组织湿／干重值逐渐升高，12h达最高值．动脉血氧分压值逐渐降低。结论 ANP发生后肺泡AM的iNOS表达增强，肺源性NO过量表达，并促进TNF-a大量分泌，加重肺损伤，应用iNOS抑制剂则能减轻肺损伤。