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

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Abstract

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.

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Acknowledgments

The authors thank Ida Allabauer and Julia Dobner for expert technical assistance and Andrea Hartner (Department of Pediatric and Adolescent Medicine, University Hospital Erlangen, Germany) for access to microscopy facilities. The animal experiments were in part supported by a grant to Jörg Dötsch, Christian Plank, and Wolfgang Rascher by the Deutsche Forschungsgemeinschaft, Bonn, Germany; SFB 423, Collaborative Research Centre of the German Research Foundation: Kidney Injury: Pathogenesis and Regenerative Mechanisms, Project B13 and by a grant to Christian Plank and Miguel Angel Alejandre Alcázar by the Erlanger Leistungsbezogene Anschubfinanzierung und Nachwuchsförderung (ELAN) Erlangen, Köln Fortune, University of Cologne.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany

    Miguel Angel Alejandre Alcazar, Sarah Appel, Eva Rother, Christina Vohlen & Jörg Dötsch

  2. Department of Neonatology, Charité University Medical Center, Berlin, Germany

    Iris Östreicher

  3. Department of Pediatrics and Adolescent Medicine, University of Erlangen—Nuremberg, Nuremberg, Germany

    Christian Plank

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  1. Miguel Angel Alejandre Alcazar
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Correspondence to Miguel Angel Alejandre Alcazar.

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Alejandre Alcazar, M.A., Östreicher, I., Appel, S. et al. Developmental regulation of inflammatory cytokine-mediated Stat3 signaling: the missing link between intrauterine growth restriction and pulmonary dysfunction?. J Mol Med 90, 945–957 (2012). https://doi.org/10.1007/s00109-012-0860-9

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  • DOI: https://doi.org/10.1007/s00109-012-0860-9

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