American journal of physiology. Lung cellular and molecular physiology
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Am. J. Physiol. Lung Cell Mol. Physiol. · Apr 2015
Sirt1 restrains lung inflammasome activation in a murine model of sepsis.
Excessive inflammation is a major cause of organ damage during sepsis. The elderly are highly susceptible to sepsis-induced organ injury. Sirt1 expression is reduced during aging. ⋯ Furthermore, inflammasome activity was increased in Sirt1(-/-) mice after CLP, as demonstrated by increased IL-1β and caspase-7 cleavage and activation. Aggravated inflammasome activation in Sirt1(-/-) mice was associated with the increased production of lung proinflammatory mediators, including ICAM-1 and high-mobility group box 1, and further disruption of tight junctions and adherens junctions, as demonstrated by dramatic reduction of lung claudin-1 and vascular endothelial-cadherin expression, which was associated with the upregulation of matrix metallopeptidase 9 expression. In summary, our results suggest that Sirt1 suppresses acute lung inflammation during sepsis by controlling inflammasome activation pathway.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Apr 2015
Genetic variation associates with susceptibility for cigarette smoke-induced neutrophilia in mice.
Neutrophilic airway inflammation is one of the major hallmarks of chronic obstructive pulmonary disease and is also seen in steroid resistant asthma. Neutrophilic airway inflammation can be induced by different stimuli including cigarette smoke (CS). Short-term exposure to CS induces neutrophilic airway inflammation in both mice and humans. ⋯ Analysis of the expression levels of the susceptibility genes by quantitative RT-PCR revealed that three of the four genes associated with CS-induced tissue MPO levels had CS-induced changes in gene expression levels that correlate with CS-induced airway inflammation. Most notably, CS exposure induces an increased expression of the coiled-coil domain containing gene, Ccdc93, in mouse strains susceptible for CS-induced airway inflammation whereas Ccdc93 expression was decreased upon CS exposure in nonsusceptible mouse strains. In conclusion, this study shows that CS-induced neutrophilic airway inflammation has a genetic component and that several genes contribute to the susceptibility for this response.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Mar 2015
Cecal ligation and puncture accelerates development of ventilator-induced lung injury.
Sepsis is a leading cause of respiratory failure requiring mechanical ventilation, but the interaction between sepsis and ventilation is unclear. While prior studies demonstrated a priming role with endotoxin, actual septic animal models have yielded conflicting results regarding the role of preceding sepsis on development of subsequent ventilator-induced lung injury (VILI). Using a rat cecal ligation and puncture (CLP) model of sepsis and subsequent injurious ventilation, we sought to determine if sepsis affects development of VILI. ⋯ CLP rats had an accelerated and worse loss of end-expiratory lung volume relative to sham, and consistently higher levels of alveolar interleukin-1β. Loss of aeration and progression of edema was more pronounced in dependent lung regions. We conclude that CLP initiated pulmonary inflammation in rats, and accelerated the development of subsequent VILI.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Feb 2015
Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia.
Endothelin-1 (ET-1) increases pulmonary vascular tone through direct effects on pulmonary artery smooth muscle cells (PASMC) via membrane-bound ET-1 receptors. Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. ⋯ SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Feb 2015
Editorial Historical ArticleEbola: history, treatment, and lessons from a new emerging pathogen.