Experimental lung research
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CpG island methylation is an epigenetic modification of DNA associated with the silencing of gene transcription. The p16INK4a (p16) tumor suppressor gene is inactivated in human non-small cell lung cancers (NSCLCs) by either homozygous deletion or aberrant methylation. Inactivation of tumor suppressor genes by methylation has been linked in part to altered activity of the cytosine DNA-methyltransferase (DNA-MTase), the enzyme that catalyzes DNA methylation at CpG sites. ⋯ The results from these studies indicate that the modulation of DNA-MTase activity was cell specific, segregated with susceptibility, and occurred early in neoplastic evolution. Thus, the marked increase in enzyme activity detected in alveolar type II cells after carcinogen treatment could be a major factor contributing to the high susceptibility for chemical-induced neoplasia associated with the A/J mouse strain. The inactivation of the p16 gene in murine cancers induced by NNK most likely arises as a late event via homozygous deletion.
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Mucociliary transport is an important clearance mechanism of larger airways, but in the smallest ciliated airways (bronchioles) it may be less effective. The present study aimed at investigating whether clearance from the bronchioles in subjects with healthy airways was stimulated by an adrenergic agonist (terbutaline sulphate). Tracheobronchial clearance was studied twice in 10 healthy subjects after inhalation of 6-micron (aerodynamic diameter) monodisperse Teflon particles labeled with 111In. ⋯ This study shows that an adrenergic agonist does not significantly influence overall clearance from the bronchiolar region in healthy subjects. This suggests that mucociliary transport does not significantly contribute to clearance from the smallest ciliated airways. Other mechanisms may be more important for the transportation of mucus from these airways.
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The insulin-like growth factors (IGF-I and IGF-II) may play an important role in postpneumonectomy compensatory lung growth by translating hormonal inputs and mechanical forces into cellular proliferation signals. We examined the mRNA abundance of IGF-I, IGF-II, and IGF binding proteins (IGFBPs) in lungs of rats on postoperative days 1, 2, 3, 5, and 7 following left pneumonectomy (PNX) or shamoperation (SC) and in normal animals (CON). There was no difference in the abundance of lung IGF-I mRNA (measured by Northern analysis) or serum IGF-I (measured by radioimmunoassay (RIA)) between SC and PNX animals. ⋯ In contrast, all serum IGFBP bands were increased on postoperative day 1 following either sham or PNX surgery. In addition, serum IGFBP-4 was increased in PNX animals compared to the SC group on days 1 and 2 (increase of 38% and 78%, respectively, p < .05). We conclude that the changes observed in lung IGF and IGFBP expression following pneumonectomy do not represent major.
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The aim of the study was to extend existing evidence that intratracheal aerosolization of LPS may serve as a very relevant model to study ARDS. The authors investigated the sequence of pathogenic events reflected by changes in levels of tumor necrosis factor alpha (TNF alpha), surfactant-associated protein A (SP-A) in BAL fluid, in addition to cell count, edema formation, and respiratory function. Within 24 h following intratracheal aerosolization of LPS in the rat, ARDS could be diagnosed according to the lung injury score for patients. ⋯ In addition, other typical features of human ARDS appeared to be present in this model: (1) increased microvascular permeability reflected by edema, elevated levels of protein and of LDH, and increased numbers of PMNs in BAL fluid; (2) high levels of TNF alpha in BAL fluid preceding the appearance of PMNs; (3) changes in breathing pattern and a gradual development of respiratory failure with decreased compliance. SP-A levels in BAL fluid doubled within one hour after LPS administration, suggesting that this collectin may play a role in the immediate inflammatory response. Taken together, the findings presented here suggest that intratracheal LPS administration mimics the clinical development of ARDS very closely.
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Tracheobronchial clearance was studied twice in 16 patients with chronic obstructive bronchitis after inhalation of 6 microns (aerodynamic diameter) monodisperse Teflon particles labeled with 111In. At one exposure the particles were inhaled at an extremely slow flow, 0.05 L/s; at the other they were inhaled at a normal flow, 0.5 L/s. Theoretical calculations and experimental data in healthy subjects indicate particle deposition mainly in the smallest ciliated airways using 0.05 L/s, i.e., in the bronchiolar region, and an enhanced deposition in larger airways using 0.5 L/s. ⋯ There was, furthermore, an almost significant relationship between sputum volume and rate of tracheobronchial clearance between 0 and 24 h (in percentage of the total amount cleared during 72 h) at 0.05 L/s, r = .42 (p = .05). The results indicate that in patients with chronic bronchitis overall clearance of particles in small airways is incomplete, as compared to larger airways. An increased amount of mucus, however, seemed to improve clearance of peripherally deposited particles, possibly by making cough more effective in small airways.