American journal of respiratory cell and molecular biology
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Am. J. Respir. Cell Mol. Biol. · Jan 2014
Neutrophil-endothelial interactions mediate angiopoietin-2-associated pulmonary endothelial cell dysfunction in indirect acute lung injury in mice.
Unresolved inflammation in the lung is thought to elicit loss of endothelial cell (EC) barrier integrity and impaired lung function. We have shown, in a mouse model of shock/sepsis, that neutrophil interactions with resident pulmonary cells appear central to the pathogenesis of indirect acute lung injury (iALI). Normally, EC growth factors angiopoietin (Ang)-1 and Ang-2 maintain vascular homeostasis through tightly regulated interaction with the kinase receptor Tie2 expressed on ECs. ⋯ A murine model of hemorrhagic shock-induced priming for the development of iALI after subsequent septic challenge was used in this study. Our findings show that 1) Ang-2 is elevated in our experimental model for iALI, 2) direct EC/neutrophil interactions contribute significantly to EC Ang-2 release, and 3) suppression of Ang-2 significantly decreases inflammatory lung injury, neutrophil influx, and lung and plasma IL-6 and TNF-α. These findings support our hypothesis and suggest that Ang-2 plays a role in the loss of pulmonary EC barrier function in the development of iALI in mice resultant from the sequential insults of hemorrhagic shock and sepsis and that this is mediated by EC interaction with activated neutrophils.
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Am. J. Respir. Cell Mol. Biol. · Jan 2014
Pivotal role of the 5-lipoxygenase pathway in lung injury after experimental sepsis.
Postsepsis lung injury is a common clinical problem associated with significant morbidity and mortality. Leukotrienes (LTs) are important lipid mediators of infection and inflammation derived from the 5-lipoxygenase (5-LO) metabolism of arachidonate with the potential to contribute to lung damage after sepsis. ⋯ Selective antagonists for BLT1 or cys-LT1, the high-affinity receptors for LTB4 and cys-LTs, respectively, were insufficient to provide protection when used alone. These results point to an important role for 5-LO products in sepsis-induced lung injury and suggest that the use of 5-LO inhibitors may be of therapeutic benefit clinically.
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Am. J. Respir. Cell Mol. Biol. · Dec 2013
Sirtuin 3 deficiency does not augment hypoxia-induced pulmonary hypertension.
Alveolar hypoxia elicits increases in mitochondrial reactive oxygen species (ROS) signaling in pulmonary arterial (PA) smooth muscle cells (PASMCs), triggering hypoxic pulmonary vasoconstriction. Mice deficient in sirtuin (Sirt) 3, a nicotinamide adenine dinucleotide-dependent mitochondrial deacetylase, demonstrate enhanced left ventricular hypertrophy after aortic banding, whereas cells from these mice reportedly exhibit augmented hypoxia-induced ROS signaling and hypoxia-inducible factor (HIF)-1 activation. We therefore tested whether deletion of Sirt3 would augment hypoxia-induced ROS signaling in PASMCs, thereby exacerbating the development of pulmonary hypertension (PH) and right ventricular hypertrophy. ⋯ Sirt3(-/-) mice housed in chronic hypoxia (10% O2; 30 d) developed PH, PA wall remodeling, and right ventricular hypertrophy that was indistinguishable from Sirt3(+/+) littermates. Thus, Sirt3 deletion does not augment hypoxia-induced ROS signaling or its consequences in the cytosol of PASMCs, or the development of PH. These findings suggest that Sirt3 responses may be cell type specific, or restricted to certain genetic backgrounds.
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Am. J. Respir. Cell Mol. Biol. · Dec 2013
Foxa2 regulates leukotrienes to inhibit Th2-mediated pulmonary inflammation.
Foxa2 is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells of the developing and mature lung. Foxa2 is required for normal airway epithelial differentiation, and its deletion causes goblet-cell metaplasia and Th2-mediated pulmonary inflammation during postnatal development. Foxa2 expression is inhibited during aeroallergen sensitization and after stimulation with Th2 cytokines, when its loss is associated with goblet-cell metaplasia. ⋯ The inhibition of the cysteinyl LT (CysLT) signaling pathway by montelukast inhibited IL-4, IL-5, eotaxin-2, and regulated upon activation normal T cell expressed and presumably secreted expression in the developing lungs of Foxa2 gene-targeted mice. Montelukast inhibited the expression of genes regulating mucus metaplasia, including Spdef, Muc5ac, Foxa3, and Arg2. Foxa2 plays a cell-autonomous role in the respiratory epithelium, and is required for the suppression of Th2 immunity and mucus metaplasia in the developing lung in a process determined in part by its regulation of the CysLT pathway.
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Am. J. Respir. Cell Mol. Biol. · Dec 2013
Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension.
Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease via whole-lung transcriptome analysis. Wild-type mice were experimentally exposed to Schistosoma mansoni ova by intraperitoneal sensitization followed by tail-vein augmentation, and the phenotype was assessed by right ventricular catheterization and tissue histology, as well as RNA and protein analysis. ⋯ Whole-lung transcriptome analysis determined that the IL-6-STAT3-nuclear factor of activated T cells c2(NFATc2) pathway was up-regulated, as confirmed by PCR and the immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL-6 or treated with S3I-201 developed pulmonary hypertension, associated with significant intima remodeling after exposure to S. mansoni. Whole-lung transcriptome analysis identified the up-regulation of the IL-6-STAT3-NFATc2 pathway, and IL-6 signaling was found to be protective against Schistosoma-induced intimal remodeling.