Upregulated tumor necrosis factor-alpha gene expression in the hypoplastic lung in patients with congenital diaphragmatic hernia.
Recent studies using animal models of congenital diaphragmatic hernia (CDH) have reported a reduction in both surfactant (SF) phospholipids and proteins in CDH lungs compared to controls, resulting in biophysical and physiologic impairment of SF function in the hypoplastic CDH lung. Furthermore, SF replacement has been shown to improve physiological function in CDH lungs. Tumor necrosis factor-alpha (TNF-alpha) is a polypeptide whose overproduction has been implicated in the pathogenesis of a number of pathological conditions, such as neonatal and adult respiratory distress syndrome. TNF-alpha has been shown to selectively inhibit the de-novo synthesis of SF phospholipid components in type II pneumocytes. It has been demonstrated that TNF-alpha is synthesized locally in lung and functions in an autocrine/paracrine mode. The aim of this study was to investigate TNF-alpha messenger RNA (mRNA) expression in hypoplastic CDH lung using in-situ hybridization histochemistry, to determine the molecular basis of the SF deficiency in the hypoplastic CDH lung. Lung-tissue samples were obtained at autopsy from 7 full-term newborns (age range: 1-21 days) with CDH and 4 stillborns with CDH. Normal lung tissue from eight infants with sudden infant death syndrome (age range: 5-30 days) acted as controls. In-situ hybridization was performed using TNF-alpha specific and digoxigenin-labeled oligonucleotide probe and visualized by nitroblue tetrazolium staining. In control lung tissue, mRNA expression of TNF-alpha was absent or weak in type II pneumocytes and alveolar macrophages. In contrast, mRNA expression of TNF-alpha was markedly increased in both type II pneumocytes and alveolar macrophages in hypoplastic CDH lung. Our findings of up-regulated TNF-alpha gene expression in CDH lung suggest that the SF deficiency observed in hypoplastic CDH lung may be the result of increased local production of TNF-alpha.
Ohshiro
K
K
Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin 12, Ireland.
Miyazaki
E
E
Taira
Y
Y
Puri
P
P
D016022:Case-Control Studies; D015870:Gene Expression; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D017403:In Situ Hybridization; D007231:Infant, Newborn; D008168:Lung / Q000002:abnormalities* / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000172:deficiency*; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha