View Abstract

A7193 - Adipose-Tissue Secretome Induces Bronchial Smooth Muscle Cell Proliferation Via an IL-6/FoxO1 Dependent Mechanism in Offspring of Obese Mice
Author Block: K. Dinger1, J. Mohr2, V. Jentgen1, D. V. Hirani2, C. Vohlen1, S. S. Pullamsetti3, J. Dötsch4, M. Odenthal5, M. Alejandre Alcazar6; 1Translational Experimental Pediatrics - Experimental Pulmonology, University Hospital Cologne, Cologne, Germany, 2Department of Pediatrics, Translational Experimental Pediatrics - Experimental Pulmonology, University Hospital Cologne, Cologne, Germany, 3Max Planck Institute For Heart and Lung Research, Bad Nauheim Hessen 61231, Germany, 4Department of Pediatrics, University Hospital Cologne, Cologne, Germany, 5Department of Pathology, University Hospital Cologne, Cologne, Germany, 6Department of Pediatrics, Translational Experimental Pediatrics - Experimental Pulmonology, University of Cologne, Cologne, Germany.
Rationale: Maternal obesity is linked to early-onset obesity and asthma-like phenotype in the offspring. We have previously shown that obesity-associated bronchial smooth muscle cell (bSMC) hyperplasia and increased airway resistance are mediated by Interleukin-6 (IL-6). The transcription factor FoxO1 is a key regulator of SMC proliferation and a target of cytokine signaling. Since the secretome of white adipose tissue (WAT) comprises various inflammatory adipocytokines, notable amongst those IL-6, we hypothesized that the WAT secretome regulates bSMC proliferation via a FoxO1 dependent mechanism, and could thereby contribute to early metabolic origins of bronchial asthma. Methods: (1) Female wildtype (WT) and IL-6-/- mice were fed with high-fat diet (HFD) or standard chow (Co) for 7 weeks prior mating then continued on their respective diets during pregnancy and lactation. After weaning offspring received standard chow. At postnatal day (P) 21 and P70 lungs were harvested for histomorphometrical analysis. At P70 some mice underwent lung function analysis. (2) At P21 WAT and primary bSMCs were isolated. bSMCWT were stimulated with conditioned media of WAT (CMWAT), IL-6/sIL-6R, and Paclitaxel (FoxO1 activator), followed by cellular localization of Foxo1 (immunocytochemistry) and analysis of proliferation (BrdU, MTT). (3) Lungs of mice with a specific ablation of FoxO1 (FoxO1sm22) were analysed by lung function test and immunohistochemistry. Primary bSMCFoxO1/sm22 were isolated. Results: (1) WTHFD compared to WTCo exhibited thickening of the bSMC layer by 30%, decreased nuclear FoxO1 expression in bSMC and a ~2-fold increase of airway resistance. IL-6 deficiency protected from structural and functional changes induced in WTHFD. Moreover, analysis of nuclear FoxO1 showed no differences between IL-6-/- HFD and IL-6 -/- SD. (2) Additionally primary IL-6-/- bSMC were less proliferative than those of WT mice. Stimulation of primary bSMCWT with IL-6/sIL-6R and CMWAT induced significantly proliferation, while nuclear FoxO1 abundancy was reduced. Paclitaxel treatment, however, increased nuclear FoxO1 and reversed anti-proliferative effect of IL-6 and CMWAT in bSMCWT. (3) Primary bSMCFoxO1/sm22 showed more than a 2-fold increased proliferation compared to bSMCWT. Moreover, quantitative morphometric analysis revealed a three-fold thicker bSMC layer and a two-fold higher airway resistance in FoxO1sm22 when compared to WT. Conclusion: Here we identify a novel WAT-lung axis during development, which could mediate bronchial SMC hyperplasia and increased airway resistance via a FoxO1-dependent mechanism. Activation of FoxO1 protects from proliferative effect of WAT secretome on bSMC and could thereby potentially offer a novel innovative target for early metabolic origins of bronchial asthma.