American journal of physiology. Lung cellular and molecular physiology
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Am. J. Physiol. Lung Cell Mol. Physiol. · Feb 2011
Chronic intermittent hypoxia induces lung growth in adult mice.
Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality, which have been attributed to intermittent hypoxia (IH). The effects of IH on lung structure and function are unknown. We used a mouse model of chronic IH, which mimics the O(2) profile in patients with OSA. ⋯ There was no increase in apoptosis. IH upregulated pathways of cellular movement and cellular growth and development, including key developmental genes vascular endothelial growth factor A and platelet-derived growth factor B. We conclude that IH increases alveolar surface area by stimulating lung growth in adult mice.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Jan 2011
Linking lung function and inflammatory responses in ventilator-induced lung injury.
Despite decades of research, the mechanisms of ventilator-induced lung injury are poorly understood. We used strain-dependent responses to mechanical ventilation in mice to identify associations between mechanical and inflammatory responses in the lung. BALB/c, C57BL/6, and 129/Sv mice were ventilated using a protective [low tidal volume and moderate positive end-expiratory pressure (PEEP) and recruitment maneuvers] or injurious (high tidal volume and zero PEEP) ventilation strategy. ⋯ Three factors were identified linking 1) pulmonary edema, protein leak, and macrophages, 2) atelectasis, IL-6, and TNF-α, and 3) IL-1β and neutrophils, which were independent of responses in lung mechanics. This approach has allowed us to identify specific inflammatory responses that are independently associated with overstretch of the lung parenchyma and loss of lung volume. These data provide critical insight into the mechanical responses in the lung that drive local inflammation in ventilator-induced lung injury and the basis for future mechanistic studies in this field.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Dec 2010
Inflammation in fetal sheep from intra-amniotic injection of Ureaplasma parvum.
Bronchopulmonary dysplasia is associated with chorioamnionitis and fetal lung inflammation. Ureaplasma species are the bacteria most frequently isolated from chorioamnionitis. Very chronic ureaplasma colonization of amniotic fluid causes low-grade lung inflammation and functional lung maturation in fetal sheep. ⋯ CD3-positive cells in the posterior mediastinal lymph node increased in ureaplasma-exposed animals at 3, 7, and 14 days (P = 0.002). Focal elastin depositions decreased in alveolar septa at 14 days (P = 0.002), whereas α-SMA increased in arteries and bronchioli. U. parvum induced a mild acute inflammatory response and changed elastin and α-SMA deposition in the lung, which may affect lung structure and subsequent development.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Dec 2010
MicroRNA-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration.
Hypoxia stimulates pulmonary artery smooth muscle cell (PASMC) proliferation. Recent studies have implicated an important role for microRNAs (miRNAs) in hypoxia-mediated responses in various cellular processes, including cell proliferation. In this study, we investigated the role of microRNA-21 (miR-21) in hypoxia-induced PASMC proliferation and migration. ⋯ Protein expression of miR-21 target genes, specifically programmed cell death protein 4 (PDCD4), Sprouty 2 (SPRY2), and peroxisome proliferator-activated receptor-α (PPARα), was decreased in hypoxia and in PASMC overexpressing miR-21 in normoxia and increased in hypoxic cells in which miR-21 was knocked down. In addition, PPARα 3'-untranslated region (UTR) luciferase-based reporter gene assays demonstrated that PPARα is a direct target of miR-21. Taken together, our findings indicate that miR-21 plays a significant role in hypoxia-induced pulmonary vascular smooth muscle cell proliferation and migration by regulating multiple gene targets.