Novel role of NPY in neuro-immune interaction and lung growth after intrauterine growth restriction

Individuals with intrauterine growth restriction (IUGR) are at risk for chronic lung disease. Using a rat model, our previous studies showed that altered lung structure is related to IL-6/STAT3 signaling. As Neuropeptide Y (NPY), a co-neurotransmitter of the sympathetic nerve system, regulates proliferation and immune response, we hypothesized that dysregulated NPY after IUGR is linked to IL-6, impaired myofibroblast function, and alveolar growth. IUGR was induced in rats by isocaloric low-protein diet; lungs were analyzed on embryonic day (E) 21, postnatal day (P) 3, P12 and P23. Finally, primary neonatal myofibroblasts (pnF) and murine embryonic fibroblasts (MEF) were used to assess proliferation, apoptosis, migration, and IL-6 expression. At E21, NPY and IL-6 expression were decreased and AKT/PKC and STAT3/AMPKα signaling reduced, respectively. Early reduction of NPY/IL-6 was associated with increased chord length in lungs after IUGR at P3, indicating reduced alveolar formation. At P23, however, IUGR-rats exhibited a catch-up of body weight and alveolar growth coupled with more proliferating myofibroblasts. These structural findings after IUGR were linked to activated NPY/PKC, IL-6/AMPKα signaling. Complementary, IUGR-pnF showed increased survival, impaired migration and reduced IL-6 compared to control-pnF (Co-pnF). In contrast, NPY induced proliferation, migration and increased IL-6 synthesis in fibroblasts. Additionally, NPY(-/-) mice showed reduced IL-6 signaling and less proliferation of lung fibroblasts. Our study presents a novel role of NPY during alveolarization: NPY regulates (1) IL-6 and lung STAT3/AMPKα signaling, and (2) proliferation and migration of myofibroblasts. These new insights in pulmonary neuro-immune interaction offer potential strategies to enable lung growth.

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