Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Supplemental oxygen therapy is frequently used in the treatment of pulmonary insufficiency, as is encountered in premature infants, and in patients with acute respiratory distress syndrome. However, hyperoxia causes lung damage in experimental animals and may do so in humans. Cytochrome P4501A enzymes have been implicated in hyperoxic lung injury. In this study, we investigated the mechanisms of CYP1A1 regulation by hyperoxia and tested the hypothesis that aryl hydrocarbon receptor (AHR)-dependent mechanisms contribute to induction of CYP1A1 and that modulation of CYP1A by hyperoxia may have implications for lung injury. Exposure of adult male Sprague-Dawley rats to hyperoxia for 24 to 48 h led to increased expression of pulmonary CYP1A1 enzyme, which was preceded by enhancement of the corresponding mRNA, followed by decline of induction at 60 h, when the animals displayed severe respiratory distress and lung inflammation. Similarly, hepatic CYP1A1/1A2 mRNAs were markedly induced between 24 and 48 h of hyperoxia, with induction declining by 60 h. Electrophoretic mobility shift assays (EMSA) and experiments with AHR (-/-) mice indicated that AHR-dependent mechanisms contributed to CYP1A induction. The AHR (-/-) mice were refractory to CYP1A1 induction by hyperoxia and were more sensitive to lung injury than wild-type mice. Lungs of hyperoxic rats showed increase in the expression of CYP1A1 in airway epithelial cells, type II pneumocytes, and endothelial cells. In conclusion, our results suggest that induction of CYP1A1 by hyperoxia is mediated by AHR-dependent mechanisms and that modulation of CYP1A enzymes by hyperoxia may have implications for hyperoxic lung injury.
Mol Pharmacol 2002 Mar
PMID:Regulation of pulmonary and hepatic cytochrome P4501A expression in the rat by hyperoxia: implications for hyperoxic lung injury. 1185 30

Intra-amniotic lipopolysaccharide (LPS) and cytokines may decrease respiratory distress syndrome (RDS) and increase chronic lung disease in the newborn. The aim was to identify the primary inflammatory mediators regulating the expression of surfactant proteins (SP) in explants from immature (22-day-old fetus) and mature (30-day term fetus and 2-day-old newborn) rabbits. In immature lung, interleukin (IL)-1alpha and IL-1beta upregulated the expression of SP-A and SP-B. These effects of IL-1 were diminished, and SP-C mRNA was suppressed additively in the presence of tumor necrosis factor (TNF)-alpha and either LPS or interferon (IFN)-gamma. LPS, TNF-alpha, or IFN-gamma had no effect alone. In explants from the term fetus and the newborn, LPS, IL-1alpha, and TNF-alpha additively suppressed the SPs. LPS acutely induced IL-1alpha in alveolar macrophages in mature lung but not in the immature lung. IFN-gamma that generally has low expression in intrauterine infection decreased the age dependence of the other agonists' effects on SPs. The present study serves to explain the variation of the pulmonary outcome after an inflammatory insult. We propose that IL-1 from extrapulmonary sources induces the SPs in premature lung and is responsible for the decreased risk of RDS in intra-amniotic infection.
Am J Physiol Lung Cell Mol Physiol 2002 Apr
PMID:Regulation of surfactant proteins by LPS and proinflammatory cytokines in fetal and newborn lung. 1188 Mar 7

Pulmonary surfactant protein D (SP-D) is expressed in alveolar type II and bronchiolar epithelial cells and is secreted into alveoli and conducting airways. However, SP-D has also been measured in serum and is increased in patients with acute respiratory distress syndrome, pulmonary fibrosis, and alveolar proteinosis. To demonstrate that SP-D can be measured in rat serum, we instilled rats with keratinocyte growth factor, which produces type II cell hyperplasia and an increase in SP-D in bronchoalveolar lavage fluid (BALF). To evaluate serum SP-D as a biomarker of lung injury, we examined several injury models. In rats treated with 1 unit of bleomycin, serum SP-D was elevated on days 3, 7, 14, and 28 after instillation, and SP-D mRNA was increased in focal areas as detected by in situ hybridization. However, there was no increase in whole lung SP-D mRNA when the expression was normalized to whole lung 18S rRNA. After instillation of 2 units of bleomycin, the serum levels of SP-D were higher, and SP-D was also increased in BALF and lung homogenates. In another model of subacute injury, serum SP-D was increased in rats treated with paraquat plus oxygen. Finally to evaluate acute lung injury, we instilled rats with HCl; SP-D was increased at 4 h after instillation. Our data indicate that serum SP-D may be a useful indicator of lung injury and type II cell hyperplasia in rats.
Am J Physiol Lung Cell Mol Physiol 2002 Apr
PMID:Serum SP-D is a marker of lung injury in rats. 1188 Mar 9

The formation of alpha(2)-macroglobulin (alpha(2)-M)/interleukin-8 (IL-8) complexes may influence the biological activity of IL-8 and the quantitative assessment of IL-8 activity. Therefore, in this study, concentrations of free IL-8 and IL-8 complexes with alpha(2)-M were measured in pulmonary edema fluid samples from patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and compared with control patients with hydrostatic pulmonary edema. Patients with ALI/ARDS had significantly higher concentrations of alpha(2)-M (P < 0.01) as well as alpha(2)-M/IL-8 complexes (P < 0.05). Because a substantial amount of IL-8 is complexed to alpha(2)-M, standard assays of free IL-8 may significantly underestimate the concentration of biologically active IL-8 in the distal air spaces of patients with ALI/ARDS. Furthermore, IL-8 bound to alpha(2)-M retained its biological activity, and this fraction of IL-8 was protected from proteolytic degradation. Thus complex formation may modulate the acute inflammatory process in the lung.
Am J Physiol Lung Cell Mol Physiol 2002 May
PMID:Activity of pulmonary edema fluid interleukin-8 bound to alpha(2)-macroglobulin in patients with acute lung injury. 1194 75

High oxygen concentrations are used in the treatment of acute respiratory distress syndrome and hyaline membrane disease. Hyperoxia, however, can damage alveolar epithelial cells through the release of free oxygen radicals. Supplemental glutamine (Gln) has recently been shown to increase survival of A549 cells, a distal epithelial cell line, during hyperoxia (). We found that supplemental Gln (Gln+) is essential for cell growth in A549 cells. In room air, cells without supplemental Gln (Gln-) survived with BCL-2 levels similar to those of Gln+ cells, but cell growth was minimal. We also evaluated the role of glutamine synthetase (GS) in A549 cells during hyperoxia. L-methionine sulfoximine (MSO), an irreversible inhibitor of GS, was added to Gln+ and Gln- cells. In hyperoxia, Gln- cells had greater survival then Gln- cells treated with MSO. Supplemental Gln could rescue cells in hyperoxia from the effect of MSO, suggesting that GS, through the endogenous synthesis of Gln, could attenuate hyperoxic cell injury. In hyperoxia, cells treated with 10-mM concentrations of Gln had increased survival compared with cells receiving 2-mM concentrations. The higher concentration of Gln, however, did not decrease the percentage of cells undergoing necrosis.
Am J Respir Cell Mol Biol 2002 Jul
PMID:Inhibition of glutamine synthetase in a549 cells during hyperoxia. 1209 Dec 52

Recently, many findings indicate that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the pathogenesis of acute and chronic lung diseases. In the present paper, the production of this cytokine in human pulmonary microvascular endothelial cells (HPMEC) is investigated. In an in vitro study, quiescent HPMEC did not express GM-CSF, either at the transcriptional or at the protein level. After activation for 4 h with tumor necrosis factor (TNF)-alpha (30/300 U/ml), lipopolysaccharide (LPS; 0.1/1 microg/ml), or interleukin (IL)-1 beta (100 U/ml), a significant release of GM-CSF was measured by enzyme-linked immunosorbent assay, with a time-dependent increase over 72 h. IL-8 (4, 16, or 64 ng/ml) or IL-1 beta at a concentration of 10 U/ml did not induce the release of GM-CSF. Human umbilical vein endothelial cells (HUVEC) and the angiosarcoma cell line HAEND served as reference cell lines. GM-CSF release in HPMEC was significantly (P < 0.025-0.05) less inducible by IL-1 beta than in HUVEC. A constitutive expression of GM-CSF by HAEND was observed. Additionally, GM-CSF expression in vivo by the lung microvasculature was confirmed by immunohistochemistry in lung tissue. To our knowledge, this is the first report of the ability of human pulmonary endothelial cells to synthesize and release GM-CSF. These results support the hypothesis that the lung microvasculature via the production of GM-CSF is a potential contributor to the cytokine network in lung diseases. This could be of particular importance in the pathogenesis of the acute respiratory distress syndrome in which endothelial dysfunction plays a central pathogenetic role.
Am J Physiol Lung Cell Mol Physiol 2002 Aug
PMID:GM-CSF expression by human lung microvascular endothelial cells: in vitro and in vivo findings. 1211 9

Severe pancreatitis is frequently associated with acute lung injury (ALI) and the respiratory distress syndrome. The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mediating the ALI associated with secretagogue-induced experimental pancreatitis was evaluated with GM-CSF knockout mice (GM-CSF -/-). Pancreatitis was induced by hourly (12x) intraperitoneal injection of a supramaximally stimulating dose of the cholecystokinin analog caerulein. The resulting pancreatitis was similar in GM-CSF-sufficient (GM-CSF +/+) control animals and GM-CSF -/- mice. Lung injury, quantitated by measuring lung myeloperoxidase activity (an indicator of neutrophil sequestration), alveolar-capillary permeability, and alveolar membrane thickness was less severe in GM-CSF -/- than in GM-CSF +/+ mice. In GM-CSF +/+ mice, pancreas, lung and serum GM-CSF levels increase during pancreatitis. Lung levels of macrophage inflammatory protein (MIP)-2 are also increased during pancreatitis, but, in this case, the rise is less profound in GM-CSF -/- mice than in GM-CSF +/+ controls. Administration of anti-MIP-2 antibodies was found to reduce the severity of pancreatitis-associated ALI. Our findings indicate that GM-CSF plays a critical role in coupling pancreatitis to ALI and suggest that GM-CSF may act indirectly by regulating the release of other proinflammatory factors including MIP-2.
Am J Physiol Lung Cell Mol Physiol 2002 Sep
PMID:In vivo evidence for the role of GM-CSF as a mediator in acute pancreatitis-associated lung injury. 1216 73

The acute respiratory distress syndrome (ARDS) is a major cause of morbidity after injury. We hypothesized that alveolar macrophage (AMPhi) chemokine and cytokine release after hemorrhage and sepsis is regulated by NF-kappaB and MAPK. Adult male rats underwent soft tissue trauma and hemorrhagic shock (~90 min) followed by crystalloid resuscitation. Sepsis was induced by cecal ligation and puncture (CLP) 20 h after resuscitation. AMPhi were harvested, and TNF-alpha, IL-6, and macrophage inflammatory protein (MIP)-2 release and serum IL-6 and TNF-alpha levels were measured at 5 h after HCLP. Lung tissues were analyzed for activation of NF-kappaB, myeloperoxidase activity, and wet/dry weight ratio. In control animals, AMPhi were stimulated with LPS with or without inhibitors of NF-kappaB and MAPK. Serum TNF-alpha and IL-6 levels and spontaneous AMPhi TNF-alpha and MIP-2 release were elevated (P < 0.05) after HCLP, concomitantly with the development of lung edema and leukocyte activation. Activation of NF-kappaB increased in lungs from the hemorrhage and CLP group compared with shams. Inhibition of NF-kappaB or the upstream MAPK significantly decreased LPS-stimulated AMPhi activation. Because enhanced release of inflammatory mediators by AMPhi may contribute to ARDS after severe trauma, inhibition of intracellular signaling pathways represents a target to attenuate organ injury under those conditions.
Am J Physiol Lung Cell Mol Physiol 2002 Oct
PMID:Alveolar macrophage activation after trauma-hemorrhage and sepsis is dependent on NF-kappaB and MAPK/ERK mechanisms. 1222 57

Mature alveolar type II cells that produce pulmonary surfactant are essential for adaptation to extrauterine life and prevention of infant respiratory distress syndrome. We have developed a new in vitro model to further investigate regulation of type II cell differentiation. Epithelial cells isolated from human fetal lung were cultured in serum-free medium on plastic. Cells treated with dexamethasone + cAMP analog and isobutylmethylxanthine for 4 days exhibited increased phosphatidylcholine synthesis and content of disaturated phosphatidylcholine species, manyfold increases in all surfactant proteins with processing to mature forms, and abundant lamellar bodies. DNA microarray analysis identified approximately 3,100 expressed genes, including subsets of genes induced 2- to >100-fold (approximately 2.5%) or repressed 2- to 18-fold (approximately 1.2%) by hormone treatment. Of the highly regulated genes, most were coregulated in an additive or synergistic manner by dexamethasone and cAMP agents. Approximately 90% of the regulated genes identified by this initial microarray analysis have not been previously recognized as hormone responsive. One newly identified hormone-induced gene is Nkx2.1 (thyroid transcription factor-1), which has a critical role in surfactant protein gene expression. Our findings indicate that glucocorticoid + cAMP is sufficient and necessary for precocious induction of functional type II cells in this in vitro system and that these hormones act primarily in combination to regulate expression of a subset of specific genes.
Am J Physiol Lung Cell Mol Physiol 2002 Nov
PMID:Differentiation of human pulmonary type II cells in vitro by glucocorticoid plus cAMP. 1237 47

An 8-month-old girl with respiratory distress and stridor was admitted to the authors' hospital. Two days later, she died of respiratory insufficiency due to pneumonia. Autopsy confirmed the presence of follicular bronchiolitis (FBB) in both lungs. After considering her clinical course, the authors focused on three pathogens: Legionella pneumophilia, Pneumocystis carinii, and Mycobacterium tuberculosis. Only Legionella pneumophilia was detected by both immunohistochemistry and PCR.
Pediatr Pathol Mol Med
PMID:Follicular bronchiolitis (FBB) associated with Legionella pneumophilia infection. 1253 68


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