Developmental regulation of inflammatory cytokine-mediated Stat3 signaling: the missing link between intrauterine growth restriction and pulmonary dysfunction?

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2012-08, Vol.90 (8), p.945-957
• Main Authors: Alejandre Alcazar, Miguel Angel, Östreicher, Iris, Appel, Sarah, Rother, Eva, Vohlen, Christina, Plank, Christian, Dötsch, Jörg
• Format: Article
• Language: English
• Subjects: Adolescence; Animals; Animals, Newborn; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cytokines - genetics; Cytokines - metabolism; Diet, Protein-Restricted; Diseases of mother, fetus and pregnancy; Female; Fetal Growth Retardation - genetics; Fetal Growth Retardation - immunology; Fetal Growth Retardation - metabolism; General aspects; Gynecology. Andrology. Obstetrics; Human Genetics; Internal Medicine; Lung - immunology; Lung - metabolism; Lung - pathology; Medical sciences; Molecular Medicine; Original Article; Pregnancy; Pregnancy. Fetus. Placenta; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Signal Transduction - genetics; Signal Transduction - physiology; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-012-0860-9

Intrauterine growth restriction (IUGR) is a risk factor for impairment of lung function in adolescence and adulthood. Inflammatory and proliferative processes linking IUGR and perturbed extracellular matrix (ECM) as an underlying mechanism have not been addressed so far. Therefore, in this study, we aimed to investigate the developmental regulation of inflammatory and profibrotic processes in the lung subsequent to IUGR. IUGR was induced in rats by isocaloric protein restriction during gestation. Lung function was assessed with direct plethysmography at postnatal day (P) 28 and P70. Lungs were obtained at P1, P42, and P70 for assessment of mRNA, protein expression, immunohistochemistry, and gelatinolytic activity. Both respiratory system resistance and compliance were impaired subsequent to IUGR at P28 and this impairment was even more pronounced at P70. In line with these results, the expression of ECM components and metabolizing enzymes was deregulated. The deposition of collagen was increased at P70. In addition, the expression of inflammatory cytokines and both the activity and the expression of target genes of Stat3 signaling were dynamically regulated, with unaltered or decreased expression at P1 and significantly increased expression art P70. Taken together, these data give evidence for an age-dependent impairment of lung function as a result of a developmentally regulated increase in inflammatory and profibrotic processes subsequent to IUGR.