Novel role of NPY in neuroimmune interaction and lung growth after intrauterine growth restriction

TY - JOUR

T1 - Novel role of NPY in neuroimmune interaction and lung growth after intrauterine growth restriction

AU - Thangaratnarajah, Chansutha

AU - Dinger, Katharina

AU - Vohlen, Christina

AU - Klaudt, Christian

AU - Nawabi, Jawed

AU - Lopez Garcia, Eva

AU - Kwapiszewska, Grazyna

AU - Dobner, Julia

AU - Nüsken, Kai D

AU - van Koningsbruggen-Rietschel, Silke

AU - von Hörsten, Stephan

AU - Dötsch, Jörg

AU - Alejandre Alcázar, Miguel A

N1 - Copyright © 2017 the American Physiological Society.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Individuals with intrauterine growth restriction (IUGR) are at risk for chronic lung disease. Using a rat model, we showed in our previous studies that altered lung structure is related to IL-6/STAT3 signaling. As neuropeptide Y (NPY), a coneurotransmitter of the sympathetic nervous 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 lung 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 was decreased, and AKT/PKC and STAT3/AMPKα signaling was reduced. 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 with 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 regulates1) IL-6 and lung STAT3/AMPKα signaling, and2) proliferation and migration of myofibroblasts. These new insights in pulmonary neuroimmune interaction offer potential strategies to enable lung growth.

AB - Individuals with intrauterine growth restriction (IUGR) are at risk for chronic lung disease. Using a rat model, we showed in our previous studies that altered lung structure is related to IL-6/STAT3 signaling. As neuropeptide Y (NPY), a coneurotransmitter of the sympathetic nervous 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 lung 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 was decreased, and AKT/PKC and STAT3/AMPKα signaling was reduced. 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 with 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 regulates1) IL-6 and lung STAT3/AMPKα signaling, and2) proliferation and migration of myofibroblasts. These new insights in pulmonary neuroimmune interaction offer potential strategies to enable lung growth.

KW - Adenylate Kinase

KW - Animals

KW - Animals, Newborn

KW - Apoptosis

KW - Biomarkers

KW - Cell Movement

KW - Cell Proliferation

KW - Cell Survival

KW - Diet

KW - Fetal Growth Retardation

KW - Gene Expression Regulation

KW - Interleukin-6

KW - Lung

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Models, Biological

KW - Myofibroblasts

KW - Neuropeptide Y

KW - Neurotransmitter Agents

KW - Protein Kinase C

KW - Rats, Wistar

KW - Receptors, Neuropeptide Y

KW - STAT3 Transcription Factor

KW - Signal Transduction

KW - Suppressor of Cytokine Signaling 3 Protein

KW - Sympathetic Nervous System

KW - Weight Gain

KW - Journal Article

U2 - 10.1152/ajplung.00432.2016

DO - 10.1152/ajplung.00432.2016

M3 - SCORING: Journal article

C2 - 28572154

VL - 313

SP - L491-L506

IS - 3

ER -