Endotoxin-induced nitric oxide production rescues airway growth and maturation in atrophic fetal rat lung explants.
Inflammation induces premature maturation of the fetal lung but the signals causing this effect remain unclear. We determined if nitric oxide (NO) synthesis, evoked by Escherichia coli lipopolysaccharide (LPS, 2 microg ml-1), participated in this process. Fetal rat lung airway surface complexity rose 2.5-fold over 96h in response to LPS and was associated with increased iNOS protein expression and activity. iNOS inhibition by N6-(1-iminoethyl)-L-lysine-2HCl (L-NIL) abolished this and induced airway atrophy similar to untreated explants. Surfactant protein-C (SP-C) expression was also induced by LPS and abolished by L-NIL. As TGFbeta suppresses iNOS activity, we determined if feedback regulation modulated NO-dependent maturation. LPS induced TGFbeta1 release and SMAD4 nuclear translocation 96 h after treatment. Treatment of explants with a blocking antibody against TGFbeta1 sustained NO production and airway morphogenesis whereas recombinant TGFbeta1 antagonized these effects. Feedback regulation of NO synthesis by TGFbeta may, thus, modulate airway branching and maturation of the fetal lung.
Rae
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Division of Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland, UK.
Cherry
J I
JI
Land
F M
FM
Land
S C
SC
D000818:Animals; D001284:Atrophy / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004731:Endotoxins / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D008168:Lung / Q000196:embryology*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D004731:Endotoxins; D008070:Lipopolysaccharides; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide