American journal of physiology. Lung cellular and molecular physiology
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Nov 2008
Lubiprostone activates non-CFTR-dependent respiratory epithelial chloride secretion in cystic fibrosis mice.
Periciliary fluid balance is maintained by the coordination of sodium and chloride channels in the apical membranes of the airways. In the absence of the cystic fibrosis transmembrane regulator (CFTR), chloride secretion is diminished and sodium reabsorption exaggerated. ClC-2, a pH- and voltage-dependent chloride channel, is present on the apical membranes of airway epithelial cells. ⋯ In C57Bl/6 mice, inhibition of CFTR with topical application of CFTR inhibitor-172 did not abolish the lubiprostone response, thus confirming the response seen is independent of CFTR regulation. RT-PCR confirmed expression of ClC-2 mRNA in murine lung homogenate. The direct application of lubiprostone in the CF murine nasal airway restores nearly normal levels of chloride secretion in nasal epithelia.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Nov 2008
Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions.
Familial pulmonary arterial hypertension (PAH) is associated with mutations in bone morphogenetic protein type II receptor (BMPR2). Many of these mutations occur in the BMPR2 tail domain, leaving the SMAD functions intact. To determine the in vivo consequences of BMPR2 tail domain mutation, we created a smooth muscle-specific doxycycline-inducible BMPR2 mutation with an arginine to termination mutation at amino acid 899. ⋯ Gene array experiments show changes in stress response, muscle organization and function, proliferation, and apoptosis and developmental pathways before RVSP increases. Our results show that the primary phenotypic result of BMPR2 tail domain mutation in smooth muscle is pulmonary vascular pruning leading to elevated RVSP, associated with early dysregulation in multiple pathways with clear relevance to PAH. This model should be useful to the research community in examining early molecular and physical events in the development of PAH and as a platform to validate potential treatments.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Nov 2008
Effects of melatonin in an experimental model of ventilator-induced lung injury.
Melatonin is a free radical scavenger and a broad-spectrum antioxidant and has well-documented immunomodulatory effects. We studied the effects of this hormone on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Swiss mice (n = 48). Animals were randomized into three experimental groups: control (not ventilated); low-pressure ventilation [peak inspiratory pressure 15 cmH(2)O, positive end-expiratory pressure (PEEP) 2 cmH(2)O], and high-pressure ventilation (peak inspiratory pressure 25 cmH(2)O, PEEP 0 cmH(2)O). ⋯ Treatment with melatonin improved oxygenation and decreased histological lung injury but significantly increased oxidative stress quantified by malondialdehyde levels. There were no differences in TNF-alpha, IL-1beta, IL-6, or matrix metalloproteinases caused by melatonin treatment, but IL-10 levels were significantly higher in treated animals. These results suggest that melatonin decreases VILI by increasing the anti-inflammatory response despite an unexpected increase in oxidative stress.