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Pulmonary hypertension in human newborns with congenital diaphragmatic hernia is associated with decreased vascular expression of nitric-oxide synthase

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Abstract

The molecular basis of the pathogenesis of pulmonary hypertension (PH) associated with congenital diaphragmatic hernia (CDH) is poorly understood. Variation in responses to therapeutic strategies such as nitric oxide (NO) inhalation and extracorporeal membrane oxygenation (ECMO) in patients with CDH remains a major problem in pediatric critical care. We investigated the expression pattern of NO-generating enzyme nitricoxide synthase (NOS) (both endothelial [eNOS] and inducible [iNOS] isoforms) in the lungs of CDH patients with PH and evaluated the influence of ECMO on the expression levels of these genes in an attempt to understand the underlying molecular mechanisms. Lung autopsy specimens from 23 cases of CDH not treated by ECMO and 10 ECMO-treated CDH cases were studied and compared with 11 age-matched controls. Expression of iNOS and eNOS was assessed by immunohistochemistry and video-image analysis. Expression of iNOS in the endothelium of small pulmonary arteries (external diameter≤200 μm) was significantly lower in CDH cases that had not received ECMO treatment (p=0.04). ECMO-treated CDH cases did not differ from controls in iNOS expression. Alveclar macrophages (CD68+ cells), of which the number also was increased, showed significantly enhanced staining for iNOS in CDH cases (p=0.03) compared with controls. The observed decrease in pulmonary expression of iNOS in patients with CDH suggests a potential role in the pathogenesis of pulmonary hypertension in newborns with CDH. ECMO treatment was correlated with induction of this enzyme, which may result in NO-mediated vasodilatation and thereby transiently reduce the pulmonary hypertension in CDH.

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Authors and Affiliations

  1. Department of Pharmacology Sophia Children's Hospital, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    Sherif M. K. Shehata & Hari S. Sharma

  2. Department of Pediatric Surgery, Sophia Children's Hospital, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    Sherif M. K. Shehata & Dick Tibboel

  3. Section of Pediatric Surgery, Tanta University Hospital, Tanta, Egypt

    Sherif M. K. Shehata

  4. Pathology, Free University Medical Center, Amsterdam, The Netherlands

    Wolter J. Mooi

Authors
  1. Sherif M. K. Shehata
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  2. Hari S. Sharma
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  3. Wolter J. Mooi
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  4. Dick Tibboel
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Correspondence to Dick Tibboel.

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Shehata, S.M.K., Sharma, H.S., Mooi, W.J. et al. Pulmonary hypertension in human newborns with congenital diaphragmatic hernia is associated with decreased vascular expression of nitric-oxide synthase. Cell Biochem Biophys 44, 147–155 (2006). https://doi.org/10.1385/CBB:44:1:147

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