American journal of respiratory cell and molecular biology
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Am. J. Respir. Cell Mol. Biol. · Oct 2003
Neutrophil adhesion molecule expression in the developing neonatal rat exposed to hyperoxia.
Neonatal rats have an increased tolerance to hyperoxia, which is associated with a diminished pulmonary inflammatory response compared with adults. To investigate this differing response, expression of the neutrophil adhesion molecules, L-selectin and CD18, and levels of soluble L-selectin, were examined using flow cytometry and sandwich enzyme-linked immunosorbent assay on air-exposed neonatal rat neutrophils at 0-24 and 72 h and 7, 10, 14, and 21 d of age compared with the adult and after exposure to hyperoxia (>/= 98% O2) for 56 h in adults and for 72 h and 7 d in neonates. Expression of L-selectin in 0-24-h neonates was similar to adults, but was significantly lower than adults at 72 h and 7 d (P = 0.011). ⋯ CD18 expression in unstimulated and activated neutrophils of neonatal rats was higher at 0-24 h than in the adult (P < 0.001), but thereafter did not differ from adults. After hyperoxic exposure, L-selectin did not differ between the exposure groups but soluble L-selectin tended to increase in neonates after 7 d of O2 exposure Finally, CD18 was significantly higher after hyperoxic exposure of the adult (P = 0.008), but did not change with oxygen exposure in the neonate. Based on these findings, we speculate that differences between neonatal and adult rats in expression of L-selectin may contribute to delayed oxygen toxicity in neonatal rats.
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Am. J. Respir. Cell Mol. Biol. · Sep 2003
Alpha 1-antitrypsin deficiency alleles in cystic fibrosis lung disease.
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) genotype does not explain the heterogeneity observed in CF pulmonary disease severity. Modifier genes are implicated for this heterogeneity. alpha1-antitrypsin (alpha1-AT) is one of the few antiproteases capable of inactivating neutrophil elastase. We investigated whether alpha1-AT alleles (Z, S deficiency alleles and the 3' G1237-->A mutation) were associated with increased disease severity and the alpha1-AT acute phase response during pulmonary exacerbations. ⋯ There were 69, 13, and 18 patients with CF who were MS, SS, and MZ, respectively. There were 95 and 7 patients with CF heterozygous or homozygous for the A1237 allele, respectively. alpha1-AT genotype did not predict pulmonary disease severity, and was not associated with more severe clinical outcome (death or lung transplantation) or age of onset of Pseudomonas aeruginosa infection. Body mass index was a significant predictor of alpha1-AT levels during exacerbations. alpha1-AT genotype is not a major contributor to the variability of pulmonary disease severity in CF.
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Am. J. Respir. Cell Mol. Biol. · Sep 2003
Airway obstruction in sheep with burn and smoke inhalation injuries.
The goals of this study were (i) to compare the degree and (ii) temporal changes in airway obstruction in sheep with pulmonary injury induced by smoke inhalation and/or burn; (iii) to qualitatively assess the cellular and mucous content of obstructive material; and (iv) to statistically assess a possible relationship between the degree of airway obstruction and pulmonary dysfunction. Using masked histologic slides, we estimated the degree of luminal obstruction in all cross-sectioned airways. The mean degree of bronchial, bronchiolar, and terminal bronchiolar obstruction was significantly greater in animals with smoke injury alone or combined smoke inhalation and burn (S+B) injury, compared with animals with burn injury alone or uninjured animals (P < 0.05). ⋯ Localization of specific mucin subtypes in S+B tissues suggests that increasing bronchiolar obstruction is derived, in part, from upper airway material. Multiple linear regression analysis of airway obstruction scores compared with PaO2/FIO2 values showed a correlation coefficient of r = 0.76, with bronchial and bronchiolar scores predictive of PaO2/FIO2, (P < 0.05). These results suggest that strategies to remove or decrease formation of upper airway obstructive material may reduce its deposition into small airways and parenchyma and may improve respiratory function in victims of smoke inhalation injury.
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Am. J. Respir. Cell Mol. Biol. · Aug 2003
Bone marrow origin of myofibroblasts in irradiation pulmonary fibrosis.
There is a rapid onset of organizing alveolitis/fibrosis at 120-140 d after whole lung irradiation of C57BL/6J mice. To test the hypothesis that circulating cells of bone marrow origin contribute to irradiation fibrosis, irradiated chimeric green fluorescent protein (GFP)+ C57BL/6J mice were followed for GFP+ cells in areas of lung fibrosis. In a second experimental model, C57BL/6J female mice received 20 Gy total lung irradiation, and after 60 or 80 d were intravenously injected with cells from a clonal GFP+ male bone marrow stromal cell line or male GFP+ whole bone marrow, respectively. ⋯ Immunohistochemistry demonstrated that these cells were macrophages and fibroblasts, not endothelial cells. Mice that received manganese superoxide dismutase-plasmid/liposome intratracheal injection 24 h before total lung irradiation demonstrated a decrease in GFP+ fibroblastic cells in the lung. Thus, pulmonary irradiation fibrosis contains proliferating cells of bone marrow origin, and gene therapy prevention of this condition acts in part by decreasing the migration and proliferation of marrow origin cells.
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Am. J. Respir. Cell Mol. Biol. · Jul 2003
Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-[kappa]B activation.
Although permissive hypercapnia improves the prognosis of patients with acute respiratory distress syndrome, it has not been conclusively determined whether hypercapnic acidosis (HA) is harmful or beneficial to sustained inflammation of the lung. The present study was designed to explore the molecular mechanism of HA in modifying lipopolysaccharide (LPS)-associated signals in pulmonary endothelial cells. LPS elicited degradation of inhibitory protein kappaB (IkappaB)-alpha, but not IkappaB-beta, resulting in activation of nuclear factor (NF)-kappaB in human pulmonary artery endothelial cells. ⋯ Following the reduced NF-kappaB activation, HA suppressed the mRNA and protein levels of intercellular adhesion molecule-1 and interleukin-8, resulting in a decrease in both lactate dehydrogenase release into the medium and neutrophil adherence to LPS-activated human pulmonary artery endothelial cells. In contrast, HA did not inhibit LPS-enhanced neutrophil expression of integrin, Mac-1. Based on these findings, we concluded that hypercapnic acidosis would have anti-inflammatory effects essentially through a mechanism inhibiting NF-kappaB activation, leading to downregulation of intercellular adhesion molecule-1 and interleukin-8, which in turn inhibits neutrophil adherence to pulmonary endothelial cells.