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

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.

Novel functional role of GH/IGF-I in neonatal lung myofibroblasts and in rat lung growth after intrauterine growth restriction

“…Prior studies of our group showed reduced alveolar growth after IUGR followed by pulmonary catchup growth, perturbed matrix remodeling in adult rats, and dysfunction of lung fibroblast (4,6,7,66). Our previous findings coupled with the functional role of GH/IGF-I in fibrotic processes let us hypothesize that dysregulation of the pulmonary intrinsic GH/IGF-I signaling is linked to myofibroblast function and lung growth after IUGR with catchup growth.…”

“…Moreover, IUGR has been related to lower lung function and obstructive disease independent of BPD (43,58,65). These clinical findings in humans have been supported by experimental studies by our group showing that IUGR with catchup growth increased airway resistance and reduced lung compliance (4,7).…”

“…Adult Wistar rats were obtained from Charles River (Sulzfeld, Germany), housed in a humidity-and temperature-controlled room at 22 Ϯ 2°C, and exposed to a 12-h:12-h dark-light cycle. IUGR and postnatal catchup growth were induced as described previously (7,66). Briefly, time-mated rats received an isocaloric low-protein diet (8.0% casein, No.…”

“…Gene and protein expression analysis. Total RNA was isolated from frozen mouse lung tissue, and real-time RT-PCR was performed as described previously (7) using the 7500 Real-time PCR system (Applied Biosystems, Foster City, CA). Primer pairs and TaqMan probes used are listed in Table 2.…”

“…Various experimental studies showed impaired alveolarization after IUGR and altered expression of matrix components (6,24,48,49). For example, elastin synthesis (25,41) and increased deposition of collagen coupled with perturbed protease activity are structural features in lungs of former IUGR rats (7). Moreover, recent studies from our group demonstrated that IUGR inhibits alveolar formation early after birth; on the contrary, rapid postnatal weight gain after IUGR enables alveolar catchup in rats and activates myofibroblasts (66).…”