EN
TÜRKÇE
Oral Presentation - 17
The Molecular Basis of Pathophysiology of Pulmonary Hypertension in Infants with Congenital Diaphragmatic Hernia
SMK Shehata*, W Mooi**, D Tibboel***
*Department of Pediatric Surgery, Tanta University Hospital, Tanta, Egypt
**Department of Pediatric Surgery, Sophia Children's Hospital
***Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
The most important factors determining survival in congenital diaphragmatic hernia (CDH) infants is the degree of pulmonary hypertension (PH). For improvement in the management and care of CDH patients, we need to understand in-detail the development of the pulmonary vasculature. Studies in human CDH and age matched controls are essential with regards to the pulmonary vasculature in the hypoplastic lungs to understand the pathology of PH in CDH.
Aim: In order to unravel some of these involved mechanisms with the evolution of molecular vascular biology techniques we conducted a group of investigations with the following aims:
- To evaluate the expression pattern of various angiogenic growth factors such as VEGF, PDGF-BB.
- To evaluate the expression pattern of nitric oxide synthase enzymes (NOS), which generate the vasodilator NO.?
- To evaluate some stress molecules at pulmonary vascular bed as heat shock proteins (HSPs: 27 and 70).
Materials:In our studies we used archival autopsy lung specimens of 33 term neonates who died of CDH. All cases belonged to the high-risk group and presented with respiratory insufficiency within the first 6 hours after birth and PH. Eleven age-matched neonates, who died from acute placental insufficiency that served as controls. Controls were subjected to similar ventilator therapy up to 16 hours. These controls showed no lung abnormalities or hypoplasia on histological examination and had no clinical features of PH as revealed by repeated cardiac ultrasounds.
Results:Significantly elevated levels of VEGF immunoreactivity were observed in CDH lungs as compared to the controls. Data on PDGF-BB expression revealed to be lower in CDH cases as compared to controls. No significant differences in eNOS immunolocalization were found. Endothelial expression of iNOS in small pulmonary arteries was reduced in CDH cases as compared to controls.There is enhanced expression of HSP-70 and HSP-27 inthe pulmonary vasculature as compared to controls.
Conclusions:We concluded that the role of PDGF-BB in the VEGF-stimulated angiogenesis pathway in human CDH cases is minimal, in contrast to the results observed in rat lung development.Our data of iNOS confer the observations of Hecker’s et al, supporting the notion of abnormal reactivity or non-responsiveness to the released NO without involvement of eNOS. This leads to altered pulmonary vascular response with development and/or persistence of PH in CDH cases.
We summarized that our studies regarding the molecular basis of pulmonary vasculature in CDH cases will provide some clues to the pathologic molecular mechanisms involved in the production of PH in human CDH. This understanding will have therapeutic implication by molecular alteration in the perinatal period.
The Molecular Basis of Pathophysiology of Pulmonary Hypertension in Infants with Congenital Diaphragmatic Hernia
SMK Shehata*, W Mooi**, D Tibboel***
*Department of Pediatric Surgery, Tanta University Hospital, Tanta, Egypt
**Department of Pediatric Surgery, Sophia Children's Hospital
***Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
The most important factors determining survival in congenital diaphragmatic hernia (CDH) infants is the degree of pulmonary hypertension (PH). For improvement in the management and care of CDH patients, we need to understand in-detail the development of the pulmonary vasculature. Studies in human CDH and age matched controls are essential with regards to the pulmonary vasculature in the hypoplastic lungs to understand the pathology of PH in CDH.
Aim: In order to unravel some of these involved mechanisms with the evolution of molecular vascular biology techniques we conducted a group of investigations with the following aims:
- To evaluate the expression pattern of various angiogenic growth factors such as VEGF, PDGF-BB.
- To evaluate the expression pattern of nitric oxide synthase enzymes (NOS), which generate the vasodilator NO.?
- To evaluate some stress molecules at pulmonary vascular bed as heat shock proteins (HSPs: 27 and 70).
Materials:In our studies we used archival autopsy lung specimens of 33 term neonates who died of CDH. All cases belonged to the high-risk group and presented with respiratory insufficiency within the first 6 hours after birth and PH. Eleven age-matched neonates, who died from acute placental insufficiency that served as controls. Controls were subjected to similar ventilator therapy up to 16 hours. These controls showed no lung abnormalities or hypoplasia on histological examination and had no clinical features of PH as revealed by repeated cardiac ultrasounds.
Results:Significantly elevated levels of VEGF immunoreactivity were observed in CDH lungs as compared to the controls. Data on PDGF-BB expression revealed to be lower in CDH cases as compared to controls. No significant differences in eNOS immunolocalization were found. Endothelial expression of iNOS in small pulmonary arteries was reduced in CDH cases as compared to controls.There is enhanced expression of HSP-70 and HSP-27 inthe pulmonary vasculature as compared to controls.
Conclusions:We concluded that the role of PDGF-BB in the VEGF-stimulated angiogenesis pathway in human CDH cases is minimal, in contrast to the results observed in rat lung development.Our data of iNOS confer the observations of Hecker’s et al, supporting the notion of abnormal reactivity or non-responsiveness to the released NO without involvement of eNOS. This leads to altered pulmonary vascular response with development and/or persistence of PH in CDH cases.
We summarized that our studies regarding the molecular basis of pulmonary vasculature in CDH cases will provide some clues to the pathologic molecular mechanisms involved in the production of PH in human CDH. This understanding will have therapeutic implication by molecular alteration in the perinatal period.