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A7194 - Deficiency of TNFα Impairs Alveolar and Bronchial Development but Does Not Attenuate Asthma-Like Disease in Offspring of Obese Dams
Author Block: K. Dinger1, R. Schwind1, V. Jentgen1, J. Mohr1, D. V. Hirani1, C. Vohlen1, J. Dötsch2, M. Odenthal3, S. van Koningsbruggen-Rietschel4, M. Alejandre Alcazar5; 1Department of Pediatrics, Translational Experimental Pediatrics - Experimental Pulmonology, University Hospital Cologne, Cologne, Germany, 2Department of Pediatrics, University Hospital Cologne, Cologne, Germany, 3Department of Pathology, University Hospital Cologne, Cologne, Germany, 4Department of Pediatric Pulmonology, University Hospital Cologne, Cologne, Germany, 5Department of Pediatrics, Translational Experimental Pediatrics - Experimental Pulmonology, University of Cologne, Cologne, Germany.
Rationale: Maternal obesity and early childhood overweight are major risk factors for bronchial asthma. Tumor necrosis factor alpha (TNFα) is an adipocytokine and increases proportional to the degree of obesity. TNFα has also been shown to contribute to the pathogenesis of bronchial asthma and its inhibition has been discussed as a therapeutic strategy. The role of TNFα in lung development and in maternal obesity-induced asthma-like disease in the offspring, however, remains elusive. Therefore we hypothesized that TNFα regulates late lung development; and TNFα deficiency protects from early metabolic origin of asthma-like disease in mice. Methods: (1) To analyse the effect of TNFα on lung development offspring of wildtype (WT) and TNFα knockout (TNFα-/-) mice were used. (2) To investigate the role of TNFα in bronchial asthma due to maternal obesity female wildtype (WT) and TNFα knockout (TNFα-/-) mice were fed with high fat diet (HFD) or standard chow (SD) for 7 weeks prior mating then continued on their respective diets during pregnancy and lactation. Subsequently, offspring received standard diet until P70. Offspring was sacrificed at postnatal day (P) P21 and P70 and lungs were harvested. In addition, some mice underwent invasive lung function analysis at P70. Results: (1) Quantitative histomorphometric analysis revealed a 10% increase of the chord length in mice deficient of TNFalpha (TNFα-/- SD) at P21, indicating reduced alveolar formation. Simultaneously assessment of gene expression by qRT-PCR showed a significant increase of pulmonary PCNA mRNA in TNFα-/- SD. At P70, however, chord length in TNFα-/- SD was similar to WTSD and gene expression of Surfactant Protein C was increased, suggesting an alveolar catch-up growth with activation of type II alveolar epithelial cells. Moreover, comparison of TNFα-/- SD with WTSDshowed a 15% reduction of bronchial diameter in lungs by quantitative histomorphometric analysis coupled with a 2-fold increase of airway resistance at P70. (2) WT offspring of obese dams (WTHFD) exhibited a two-fold higher airway resistance than WTSD at P70; TNFα-/- deficiency, however, did not protect from maternal-obesity induced increased airway resistance. Conclusion Our study identifies TNFalpha as an important regulator of alveolar and bronchial development and highlights thereby the important functional role of adipocytokines in early origins of lung disease.