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Intrauterine Malnutrition Reduced Long Leptin Receptor Isoform Expression and Proinflammatory Cytokine Production in Male Rat Pulmonary Endothelial Cells Stimulated by Lipopolysaccharide.
Balbino AM
,
Silva MM
,
Azevedo GA
,
Gil NL
,
Ferreira RR
,
Dos Santos LA
,
Gasparin RM
,
Fernandes L
,
Landgraf MA
,
Landgraf RG
.
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Background/Aims: We have previously shown that low birth weight (LBW) rats exposed to intrauterine malnutrition have an impaired lung inflammatory response and reduced levels of inflammatory mediators; however, circulating leptin levels were not increased. We evaluated long leptin receptor isoform (ObRb) expression in lung endothelial cells from low birth weight rats and examined its role in the production of lipid mediators and cytokines.
Methods: Lung endothelial cells were obtained from normal birth weight (NBW) rats or LBW rats subjected to intrauterine malnutrition. These cells were stimulated with leptin (10 ng/mL), LPS (lipopolysaccharide, 1 μg/mL), or leptin plus LPS. Six hours after stimulation, the production of inflammatory mediators (PGE2, LTB4, IL-1β, and IL-6) was evaluated using commercial ELISA kits, and Western blotting was performed to investigate p38MAPK, NF-κB, and ObRb expression.
Results: Leptin increased IL-1β levels in only cells from the NBW group, whereas LPS increased PGE2 and LTB4 levels in cells from both groups; leptin addition potentiated lipid mediator production induced by LPS in the NBW group. LPS enhanced the production of IL-1β and IL-6 in only endothelial cells from NBW rats. Leptin receptor expression was decreased (63%) in endothelial cells from LBW rats. None of the stimuli increased NF-κB or p38 signaling pathway expression in cells from LBW rats.
Conclusion: These results suggest that intrauterine malnutrition compromises leptin receptor expression and cytokine production in pulmonary endothelial cells stimulated by LPS; these effects seem to involve the NF-κB and p38MAPK signaling pathways.
Figure 2. Immunostaining of specific endothelial cell markers. Staining for (a) Ulex europeaus lectin agglutinin I (UEA-1), green, and (b) von Willebrand factor (vWF), red. The nuclei were counterstained with DAPI solution for cellular localization. 400-fold increase.
Figure 6. Effect of leptin on LPS-induced Ob-R expression in pulmonary endothelial cells. Endothelial cells were harvested 6 h after stimulus with LPS and/or leptin to quantify the expression levels of Ob-R using Western blotting. The graphs represent the band intensities determined by densitometric analyses and normalized to the total amount of β-actin present in each lane. Cells were obtained from 8 male Wistar rats selected randomly from 6 different litters per group. The results are presented as the means ± SEM, ∗P < 0.05.
Figure 7. Involvement of the p38 kinase and NF-κB pathways in the regulation of Ob-R expression on LPS-induced Ob-R expression in pulmonary endothelial cells. Endothelial cells were harvested 6 h after stimulus with LPS and/or leptin to quantify the activation of the p38 MAPK and NF-κB pathways using Western blotting. The graphs represent the band intensities determined by densitometric analyses and normalized to the total amount of β-actin (NF-κB) and β-actinin (pp38) present in each lane. Cells were obtained from 8 male Wistar rats selected randomly from 5 different litters per group. The results are presented as the means ± SEM, ∗P < 0.05.
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