Universität zu Köln

Nawabi, Jawed, Vohlen, Christina, Dinger, Katharina, Thangaratnarajah, Chansutha, Klaudt, Christian, Garcia, Eva Lopez, Hirani, Dharmesh V., Karakaya, Pinar Haznedar, Macheleidt, Iris, Odenthal, Margarete, Nuesken, Kai D., Doetsch, Joerg and Alcazar, Miguel A. Alejandre (2018). Novel functional role of GH/IGF-I in neonatal lung myofibroblasts and in rat lung growth after intrauterine growth restriction. Am. J. Physiol.-Lung Cell. Mol. Physiol., 315 (5). S. L623 - 15. BETHESDA: AMER PHYSIOLOGICAL SOC. ISSN 1522-1504

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Abstract

Intrauterine growth restriction (IUGR) is a risk factor for neonatal chronic lung disease (CLD) characterized by reduced alveoli and perturbed matrix remodeling. Previously, our group showed an activation of myofibroblasts and matrix remodeling in rat lungs after IUGR. Because growth hormone (GH) and insulin-like growth factor I (IGF-I) regulate development and growth, we queried 1) whether GH/IGF-I signaling is dysregulated in lungs after IUGR and 2) whether GH/IGF-I signaling is linked to neonatal lung myofibroblast function. IUGR was induced in Wistar rats by isocaloric low-protein diet during gestation. Lungs were obtained at embryonic day (E) 21, postnatal day (P) 3, P12, and P23. Murine embryonic fibroblasts (MEF) or primary neonatal myofibroblasts from rat lungs of control (pnF(Co)) and IUGR (pn(FIUGR)) were used for cell culture studies. In the intrauterine phase (E21), we found a reduction in GH receptor (GH-R), Stat5 signaling and IGF-I expression in lungs after IUGR. In the postnatal phase (P3-P23), catchup growth after IUGR was linked to increased GH mRNA, GH-R protein, activation of proliferative Stat5/Akt signaling, cyclin D1 and PCNA in rat lungs. On P23, a thickening of the alveolar septae was related to increased vimentin and matrix deposition, indicating fibrosis. In cell culture studies, nutrient deprivation blocked GH-R/IGF-IR signaling and proliferation in MEFs; this was reversed by IGF-I. Proliferation and Stat5 activation were increased in pn(FIUGR). IGF-I and GH induced proliferation and migration of pnF(Co); only IGF-I had these effects on pnFIUGR. Thus, we show a novel mechanism by which the GH/IGF-I axis in lung myofibroblasts could account for structural lung changes after IUGR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Nawabi, Jawed UNSPECIFIED UNSPECIFIED UNSPECIFIED Vohlen, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Dinger, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Thangaratnarajah, Chansutha UNSPECIFIED UNSPECIFIED UNSPECIFIED Klaudt, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Garcia, Eva Lopez UNSPECIFIED UNSPECIFIED UNSPECIFIED Hirani, Dharmesh V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Karakaya, Pinar Haznedar UNSPECIFIED UNSPECIFIED UNSPECIFIED Macheleidt, Iris UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuesken, Kai D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Doetsch, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Alcazar, Miguel A. Alejandre UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-166640
DOI:	10.1152/ajplung.00413.2017
Journal or Publication Title:	Am. J. Physiol.-Lung Cell. Mol. Physiol.
Volume:	315
Number:	5
Page Range:	S. L623 - 15
Date:	2018
Publisher:	AMER PHYSIOLOGICAL SOC
Place of Publication:	BETHESDA
ISSN:	1522-1504
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FACTOR RECEPTOR; SCHOOL-AGE; FETAL; HORMONE; COLLAGEN; MECHANISMS; EXPRESSION; BINDING; BIRTH; TERM Multiple languages Physiology; Respiratory System Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16664