American journal of physiology. Lung cellular and molecular physiology
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Am. J. Physiol. Lung Cell Mol. Physiol. · Feb 2011
Cigarette smoke-induced lung emphysema in mice is associated with prolyl endopeptidase, an enzyme involved in collagen breakdown.
There is increasing evidence that the neutrophil chemoattractant proline-glycine-proline (PGP), derived from the breakdown of the extracellular matrix, plays an important role in neutrophil recruitment to the lung. PGP formation is a multistep process involving neutrophils, metalloproteinases (MMPs), and prolyl endopeptidase (PE). This cascade of events is now investigated in the development of lung emphysema. ⋯ Moreover, RTR inhibited the smoke-induced neutrophil influx in the lung after 5 days' smoke exposure. In the present murine model of cigarette smoke-induced lung emphysema, it is demonstrated for the first time that all relevant components (neutrophils, MMP-8, MMP-9, PE) involved in PGP formation from collagen are upregulated in the airways. Together with MMPs, PE may play an important role in the formation of PGP and thus in the pathophysiology of lung emphysema.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Feb 2011
TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness.
Doxorubicin, a common chemotherapeutic agent, causes respiratory muscle weakness in both patients and rodents. Tumor necrosis factor-α (TNF), a proinflammatory cytokine that depresses diaphragm force, is elevated following doxorubicin chemotherapy. TNF-induced diaphragm weakness is mediated through TNF type 1 receptor (TNFR1). ⋯ Etanercept, a soluble TNF receptor, and TNFR1 deficiency protected against the depression in diaphragm-specific force caused by doxorubicin. Doxorubicin stimulated an increase in TNFR1 mRNA and protein (P < 0.05) in the diaphragm, along with colocalization of TNFR1 to the plasma membrane. These results suggest that doxorubicin increases diaphragm sensitivity to TNF by upregulating TNFR1, thereby causing respiratory muscle weakness.
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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. · Feb 2011
Increased deposition of chondroitin/dermatan sulfate glycosaminoglycan and upregulation of β1,3-glucuronosyltransferase I in pulmonary fibrosis.
Pulmonary fibrosis (PF) is characterized by increased deposition of proteoglycans (PGs), in particular core proteins. Glycosaminoglycans (GAGs) are key players in tissue repair and fibrosis, and we investigated whether PF is associated with changes in the expression and structure of GAGs as well as in the expression of β1,3-glucuronosyltransferase I (GlcAT-I), a rate-limiting enzyme in GAG synthesis. Lung biopsies from idiopathic pulmonary fibrosis (IPF) patients and lung tissue from a rat model of bleomycin (BLM)-induced PF were immunostained for chondroitin sulfated-GAGs and GlcAT-I expression. ⋯ TGF-β(1) upregulated GlcAT-I and versican expression in lung fibroblasts, and signaling through TGF-β type I receptor/p38 MAPK was required for TGF-β(1)-mediated GlcAT-I and CS-GAG expression in fibroblasts. Our data show for the first time increased expression of CS-GAGs and GlcAT-I in IPF, fibrotic rat lungs, and fibrotic lung fibroblasts. These data suggest that alterations of sulfation isomers of CS/DS and upregulation of GlcAT-I contribute to the pathological PG-GAG accumulation in PF.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Feb 2011
ReviewTitin-based mechanosensing and signaling: role in diaphragm atrophy during unloading?
The diaphragm, the main muscle of inspiration, is constantly subjected to mechanical loading. One of the very few occasions during which diaphragm loading is arrested is during controlled mechanical ventilation in the intensive care unit. Recent animal studies indicate that the diaphragm is extremely sensitive to unloading, causing rapid muscle fiber atrophy: unloading-induced diaphragm atrophy and the concomitant diaphragm weakness has been suggested to contribute to the difficulties in weaning patients from ventilatory support. ⋯ Titin is the largest protein known to date and acts as a mechanosensor that regulates muscle protein expression in a sarcomere strain-dependent fashion. Thus, titin is an attractive candidate for sensing the sudden mechanical arrest of the diaphragm when patients are mechanically ventilated, leading to changes in muscle protein expression. Here, we provide a novel perspective on how titin, and its biomechanical sensing and signaling, might be involved in the development of mechanical unloading-induced diaphragm weakness.