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 mu g ml(-1)), participated in this process. Fetal rat lung airway surface complexity rose 2.5-fold over 96 h 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 TGF beta suppresses iNOS activity, we determined if feedback regulation modulated NO-dependent maturation. LPS induced TGF beta 1 release and SMAD4 nuclear translocation 96 h after treatment. Treatment of explants with a blocking antibody against TGF beta 1 sustained NO production and airway morphogenesis whereas recombinant TGF beta 1 antagonized these effects. Feedback regulation of NO synthesis by TGF beta may, thus, modulate airway branching and maturation of the fetal lung. (c) 2006 Elsevier Inc. All rights reserved.