Comparison of inhaled nitric oxide with aerosolized prostacyclin or analogues for the postoperative management of pulmonary hypertension: a systematic review and meta-analysis

Abstract

Background: This study aims to compare the effectiveness of inhaled prostacyclin or its analoguesversus nitric oxide (NO) in treating pulmonary hypertension (PH) after cardiac or pulmonary surgery remains unclear.

Methods: PubMed, Cochrane, and Embase databases were searched for literature published prior to December 2019 using the following keywords: inhaled, nitric oxide, prostacyclin, iloprost, treprostinil, epoprostenol, Tyvaso, flolan, and pulmonary hypertension. Randomized controlled trials and multiple-armed prospective studies that evaluated inhaled NO versus prostacyclin (or analogues) in patients for perioperative and/or postoperative PH after either cardiac or pulmonary surgery were included. Retrospective studies, reviews, letters, comments, editorials, and case reports were excluded.

Results: Seven studies with a total of 195 patients were included. No difference in the improvement of mean pulmonary arterial pressure (pooled difference in mean change= ?0.10, 95% CI: ?3.98 to 3.78, p?=?.959) or pulmonary vascular resistance (pooled standardized difference in mean change= ?0.27, 95% CI: ?0.60 to 0.05, p?=?.099) were found between the two treatments. Similarly, no difference was found in other outcomes between the two treatments or subgroup analysis.

Conclusions: Inhaled prostacyclin (or analogues) was comparable to inhaled NO in treating PH after cardiac or pulmonary surgery.

• Key messages

• This study compared the efficacy of inhaled prostacyclin or its analogues versus inhaled NO to treat PH after surgery. The two types of agent exhibited similar efficacy in managing MPAP, PVR, heart rate, and cardiac output was observed.

• Inhaled prostacyclin may serve as an alternative treatment option for PH after cardiac or pulmonary surgery.

     

Use of gene chip technology for the characterisation of the regulation of renal transport processes and of nephrotoxicity in rats

Gene expression profiling using microarrays (rat-specific array RG-U34A, Affymetrix, U.S.A.) was employed for the investigation of: (1) hormonal regulation of renal function and (2) nephrotoxicity. For this purpose about 8,800 genes were analysed in kidney and, additionally, in liver tissue.

Ad 1.) Kidney functions develop during postnatal life. Thus, in vivo transport and accumulation of p-aminohippurate (PAH) was investigated on renal cortical slices (RCS) from 10- and 55-day-old rats. The animals were treated with dexamethasone (DEXA; 60 μg/100 g b.wt./day) for 3 days, which caused a significant reduction in the accumulation of PAH in 10-day-old rats (42 ± 5% whereas it was only slightly reduced in 55-day-old rats (70 ± 8%). To further clarify the regulation of renal function by DEXA, results were compared with those obtained previously after in vitro stimulation with DEXA. RCS were incubated for 24 hours in DEXA-containing medium (10⁻⁹ M). Under these conditions DEXA significantly increased the PAH uptake capacity in RCS obtained from 10- and 55-day-old rats up to 126 and 136%, respectively. Thus a stimulation of tubular transport capacity is possible in vitro. The effect of DEXA treatment on the gene expression of the kidney (in vivo) was moderate. Focussing especially on transporters, ion channels, ATPases, glucuronyltransferases, glutathione-S-transferase and cytochrome P450, the expression of only few genes were significantly changed (3 to 50-fold up- or down-regulation). Moreover, distinct age differences were found after in vivo administration of DEXA. The investigation of in vitro effects of DEXA is currently been performed.

Ad 2.) The kidney is threatened by nephrotoxins because of its ability to accumulate them. We used a single administration of uranyl nitrate (UN; 0.5 mg/100 g b.wt.) as a model for chronic renal failure (CRF). Clearance experiments were performed 10 weeks after UN administration (maximal symptoms of CRF) in adult female rats. As expected, UN induced interstitial cicatrices with reduced GFR and diminished PAH transport capacity. Despite the impressive morphological and functional changes in the kidney after exposure to UN, the gene expression profiles in the kidneys were only minimally affected: we found significantly changed expression levels for only 20 genes (5 genes were up-regulated [e.g. transgelin], 15 down-regulated [among these the Na-K-Cl-symporter, insulin-like growth factor, kallikrein, and ornithine decarboxylase). The lack of agreement between gene expression data and the nephrotoxic effects of UN can probably be explained by the long time interval between dosing and the assessment of the effect. The results confirm that primary genomic responses are likely to be strongest transiently after exposure and then decrease in intensity.     

Comparison of epidermal keratinocytes and dermal fibroblasts as potential target cells for somatic gene therapy of phenylketonuria

Phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase (PAH) and increased levels of phenylalanine. PAH requires the cofactor BH(4) to function and the rate-limiting step in the synthesis of BH(4) is GTP cyclohydrolase I (GTP-CH). The skin is a potential target tissue for PKU gene therapy. We have previously shown that overexpression of PAH and GTP-CH in primary human keratinocytes leads to high levels of phenylalanine clearance without BH(4) supplementation [Gene Ther. 7 (2000) 1971]. Here, we investigate the capacity of fibroblasts, another cell type from the skin, to metabolize phenylalanine. After retroviral gene transfer of PAH and GTP-CH both normal and PKU patient fibroblasts were able to metabolize phenylalanine, however, in lower amounts compared to genetically modified keratinocytes. Further comparative analyses between keratinocytes and fibroblasts revealed a higher copy number of transgenes in keratinocytes and also a higher metabolic capacity.     

Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.

Mutations in the human phenylalanine hydroxylase gene producing phenylketonuria or hyperphenylalaninemia have now been identified in many patients from various ethnic groups. These mutations all exhibit a high degree of association with specific restriction fragment-length polymorphism haplotypes at the PAH locus. About 50 of these mutations are single-base substitutions, including six nonsense mutations and eight splicing mutations, with the remainder being missense mutations. One splicing mutation results in a 3 amino acid in-frame insertion. Two or 3 large deletions, 2 single codon deletions, and 2 single base deletions have been found. Twelve of the missense mutations apparently result from the methylation and subsequent deamination of highly mutagenic CpG dinucleotides. Recurrent mutation has been observed at several of these sites, producing associations with different haplotypes in different populations. About half of all missense mutations have been examined by in vitro expression analysis, and a significant correlation has been observed between residual PAH activity and disease phenotype. Since continuing advances in molecular methodologies have dramatically accelerated the rate in which new mutations are being identified and characterized, this register of mutations will be updated periodically.     

慢阻肺合并肺动脉高压患者机体炎性反应与肺阻力的相关性

目的:观察慢阻肺合并肺动脉高压患者机体炎性反应指标及与肺阻力相关指标表达,分析患者炎性反应与肺阻力的相关性。方法:回顾性选取医院收治的116例慢阻肺患者病历资料,根据患者是否合并肺动脉高压将其分为非肺动脉高压组(59例)和肺动脉高压组(57例)。抽取两组患者清晨空腹静脉血,检测炎性反应指标中的C反应蛋白(CRP)、白细胞计数(WBC)、降钙素原(PCT)、白细胞介素-6(IL-6)以及血沉(ESR),并进行对比;检测两组患者肺阻力指标振荡频率5 Hz下的气道粘性阻力实测值占预计值的百分比[R_5占预计值(%)]、振荡频率5 Hz与共振频率(Fres)之间电抗X曲线下面积(AX),振荡频率在5 Hz的肺弹性阻力(X₅),并进行对比。分析炎性反应相关指标与肺阻力指标的相关性。结果:肺动脉高压组CRP、WBC、PCT及IL-6水平均高于非肺动脉高压组,ESR低于非肺动脉高压组,差异有统计学意义(t=16.243,t=12.413,t=6.726,t=32.670,t=10.102;P<0.05);肺动脉高压组R5占预计值(%)、AX及X₅均高于非肺动脉高压组,差异有统计学意义(t=19.770,t=8.230,t=19.685;P<0.05);相关检验结果显示,慢阻肺合并肺动脉高压患者CRP、WBC、PCT及IL-6水平与R_5占预计值%、AX及X₅值呈正相关,ESR水平与R_5占预计值%、AX及X₅值呈负相关。结论:慢阻肺合并肺动脉高压患者常伴不同程度的炎性反应与肺阻力,且炎性反应程度与患者肺阻力间呈明显相关性,炎性因子检测可能对评估慢阻肺合并肺动脉高压患者的肺阻力情况有一定价值,可指导临床诊治。     

Breast cancer among Danish women occupationally exposed to diesel exhaust and polycyclic aromatic hydrocarbons, 1964–2016

Objective:The aim of this study was to explore the association between occupational exposure to diesel exhaust and polycyclic aromatic hydrocarbons (PAH), respectively, and breast cancer subtypes.Methods:The study included 38 375 women <70 years with incident breast cancer, identified in the Danish Cancer Registry, and 5 breast cancer-free controls per case who were randomly selected from the Danish Civil Registration System and matched on year of birth. Full employment history was obtained for all study subjects from a nationwide pension fund, and exposure to diesel exhaust and PAH was assessed using a job exposure matrix. Conditional logistic regression was used for estimation of odds ratios (OR) with adjustment for reproductive factors and socioeconomic status.Results:No noteworthy associations were observed for overall breast cancer in women exposed to diesel exhaust. However, diesel exhaust modestly elevated the risk of estrogen receptor negative breast tumors before age 50 [OR 1.26, 95% confidence interval (CI) 1.09–1.46]. Duration– and dose–response relationships were further observed for this subtype in this age group. No notable risk patterns were generally observed for PAH exposure.Conclusion:Occupational exposure to diesel exhaust may increase the risk of early-onset estrogen receptor negative breast tumors in women. Future studies exploring this association are warranted.     

Assessment of polynuclear aromatic hydrocarbons ecotoxicity threshold in marine sediments through in situ input/decay measurements

The ability of decomposers to process variable amounts of xenobiotics in the marine sediment is a useful aggregate indicator of their capacity to prevent their accumulation and eventual ecotoxic effects. Since decomposition processes depend on environmental factors at the sediment which are difficult to mimic in laboratory systems, in situ evaluations in undisturbed sediments are of great interest. A method and its results are presented to evaluate the decomposition rates of PAHs (polynuclear aromatic hydrocarbons) in coastal undisturbed marine sediments at different levels of pollution input. The method is based on the application of pulse chromatography concepts to interpret trap and bed sediment monitoring data obtained at regular time intervals, using models of the water column as an anisotropic carrying medium. The results are for a 14 month data series from moderately polluted sediments near an urban site and at a more distant nearly pristine site on the south Atlantic coast. QSAR (quantitative structure activity relations) indicate that decay rates increase with higher UV absorption and lipidic solubility. At low levels of total PAH input to the sediments (<0.05 g day^–1 g^–1), decomposition mechanisms effectively process these compounds within a few days. At higher input levels (up to 0.12 g day^–1 g^–1), decomposition lags behind the inputs by approximately 25% and PAHs accumulate in the sediment. In situ estimates of the PAH input/decay ratios provide reliable ecosystem indicators of a safe threshold for anthropogenic inputs of PAHs to the marine environment and a basis for receptor-based standards aimed at their regulation.     

7,12-Dimethylbenz[a]anthracene-induced bone marrow toxicity is p53-dependent.

Polycyclic aromatic hydrocarbons (PAHs) are known immunotoxins and carcinogens. Our laboratory and others have demonstrated that metabolism of these compounds by CYP1B1 is required for carcinogenicity and immunotoxicity to occur. Previously, our laboratory reported significantly decreased bone marrow cellularity in mice following 7,12-dimethlybenz[a]anthracene (DMBA) administration. In addition, we have observed that DMBA causes apoptosis via activation of both caspase-8 and -9 in pre-B cells co-cultured with bone marrow stromal cells in vitro. In this study, we investigated the importance of the p53 protein in the bone marrow response to DMBA. Through the use of p53 gene knockout mice, we demonstrated that the effect of DMBA on bone marrow cellularity is p53-dependent. In addition, apoptosis of primary cultures of progenitor B cells cultured with bone marrow stromal cells and DMBA is also p53-dependent. The results of this study provide evidence for the importance of p53 in the signaling pathways by which PAHs cause immunotoxicity.