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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhalation of silica in a number of occupational settings can result in debilitating and costly lung disease. It is thought that the pathological replacement of functional lung tissue with fibrotic lesions in silica-induced lung disease is the result of chronic inflammation mediated by products of the silica-exposed alveolar macrophage. In particular, inflammatory cytokines, growth factors and reactive oxygen species have been implicated in many acute and chronic inflammatory lung diseases. Pharmacological intervention to modify the production of these mediators has been shown to ameliorate several of these disease processes. Recent studies have demonstrated that the production of these inflammatory mediators is altered as a result of the activation of nuclear factor-kappaB (NF-kappaB). NF-kappaB is a pivotal transcription factor activated by silica in macrophages and other types of lung cells. The understanding of how silica induces NF-kappaB activation and what signaling pathways are involved in this silica-induced NF-kappaB activation is important and should provide valuable new information related to both the etiology and potential treatment of silica-related lung diseases. This review summarizes the molecular mechanisms involved in silica-induced NF-kappaB activation and discusses the importance of NF-kappaB as a critical transcription factor in mediating silica-induced lung diseases.
Mol Cell Biochem
PMID:NF-kappaB, a pivotal transcription factor in silica-induced diseases. 1216 30

Cytokines and other mediators whose induction in inflammatory lung disease is attenuated by glucocorticoids are potential targets for development of selective anti-inflammatory treatments. We refer to genes with these regulatory characteristics as glucocorticoid-attenuated response genes, or GARGs. Systematic identification of GARGs has not been attempted previously in vivo. Using an endotoxemia model in adrenalectomized mice, we constructed a subtracted lung library enriched in endotoxemia-induced genes and identified candidate GARGs by differential hybridization screening. Northern analysis confirmed induction in the lung during endotoxemia and attenuation by glucocorticoids of 36 genes of diverse types. The majority were genes of unknown function not previously implicated in the pulmonary response to inflammation, including a new member of a 2'-5'-oligoadenylate synthetase-like family and a novel lung inducible Neuralized-related C3HC4 RING protein. Our results suggest that a full understanding of glucocorticoid effects on lung inflammation will require elucidation of the roles of an extensive network of glucocorticoid-modulated genes.
Am J Physiol Lung Cell Mol Physiol 2002 Sep
PMID:Glucocorticoid-attenuated response genes induced in the lung during endotoxemia. 1216 84

Chronic obstructive pulmonary disease (COPD) is a common lung disease with cigarette smoking as the major etiological factor, but only 15% of smokers develop COPD. Destruction of lung elastin observed in COPD is mediated by many enzymes, including cysteine, serine, and matrix metalloproteinases (MMP). The contribution of these enzymes to the lung elastolytic load, released from alveolar macrophages collected from nonsmokers, healthy smokers, and COPD patients, was examined by radiolabeled elastin as substrate in the presence of specific enzyme inhibitors. The activity of MMP was further examined by zymography and Western blotting. COPD macrophages degraded more elastin than either of the other groups. Elastolysis was greatest in the initial 24 h. Through the 72-h culture period, the contribution to elastolysis of serine elastases decreased, MMP increased, and cysteine elastases remained constant. The increased release of elastolytic enzymes in COPD subjects may explain why some smokers develop COPD. This difference may be due to unknown susceptibility factors. Serine proteases play a significant role; however, other enzymes, particularly the MMP, deserve further investigation.
Am J Physiol Lung Cell Mol Physiol 2002 Oct
PMID:Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases. 1222 64

Accumulation of reactive iron in acute and chronic lung disease suggests that iron-driven free radical formation could contribute to tissue injury. Safe transport and sequestration of this metal is likely to be of importance in lung defense. We provide evidence for the expression and iron-induced upregulation of the metal transporter protein-1 (MTP1) genes in human and rodent lung cells at both the protein and mRNA levels. In human bronchial epithelial cells, a 3.8-fold increase in mRNA level and a 2.4-fold increase in protein level of MTP1 were observed after iron exposure. In freshly isolated human macrophages, as much as an 18-fold increase in the MTP1 protein level was detected after incubation with an iron compound. The elevation in expression of MTP1 gene was also demonstrated in iron-instilled rat lungs and in hypotransferrinemic mouse lungs. This is similar to our previous findings with divalent metal transporter-1 (DMT1), an iron transporter that is required for iron uptake and intracellular iron trafficking. These studies suggest the presence of iron mobilization and/or detoxification pathways in the lung that are crucial for iron homeostasis and lung defense.
Am J Physiol Lung Cell Mol Physiol 2002 Nov
PMID:Iron increases expression of iron-export protein MTP1 in lung cells. 1237 46

Coordinated proliferation of lung cells is required for normal lung growth and differentiation. Chronic injury to developing lung may disrupt normal patterns of cell proliferation. To examine patterns of cell proliferation in injured developing lungs, we investigated premature baboons delivered at 125 days gestation (approximately 67% of term) and treated with oxygen and ventilation for 6, 14, or 21 days (PRN). Each PRN treatment group contained 3 or 4 animals. During normal in utero lung development, the proportion of proliferating lung cells declined as measured by the cell-cycle marker Ki67. In the PRN group, the proportion of proliferating lung cells was 2.5-8.5-fold greater than in corresponding gestational controls. By 14 days of treatment, the proportion of cells that expressed pro-surfactant protein B (proSP-B) was ~2.5-fold greater than in gestational controls. In the PRN group, 41% of proliferating cells expressed proSP-B compared with 5.8% in the gestational controls. By 21 days of treatment, proliferation of proSP-B-expressing epithelial cells declined substantially, but the proportion of proliferating non-proSP-B-expressing cells increased approximately sevenfold. These data show that the development of chronic lung disease is associated with major alterations in normal patterns of lung-cell proliferation.
Am J Physiol Lung Cell Mol Physiol 2002 Nov
PMID:Increased epithelial cell proliferation in very premature baboons with chronic lung disease. 1237 52

Increased airway smooth muscle (ASM) content is characteristic of infants with chronic lung disease of prematurity/bronchopulmonary dysplasia. Oxygen therapy, reactive oxygen species (ROS), and immature antioxidant defenses are major risk factors in chronic lung disease of prematurity/bronchopulmonary dysplasia, but their interrelationship is unclear. The direct effects of raised Po2 and modulation of ROS were examined on proliferation of cultured fetal human ASM cells. A bell-shaped relationship was found between Po2 and DNA synthesis induced by fetal bovine serum, platelet-derived growth factor, and basic fibroblastic growth factor, with peak responses occurring at 10-kPa Po2. Changes in DNA synthesis by Po2 did not occur in the absence of mitogen. ROS generation, estimated by dichlorodihydrofluorescein oxidation, was increased by mitogens but was unaffected by nonmitogens (bradykinin, histamine). There was an inverse relationship between ROS generation and Po2, and mitogen-induced ROS generation was substantially potentiated as the Po2 fell. H2O2 mimicked the effect of Po2 on fetal bovine serum-stimulated proliferation, whereas treatment with antioxidants (GSH, N-acetylcysteine) reduced it. These data demonstrate that increases in Po2 above levels found in utero modulate proliferation of fetal ASM cells but only in the presence of growth factors. They also strongly suggest that, under these conditions, proliferation is mediated in part by generation of ROS.
Am J Physiol Lung Cell Mol Physiol 2002 Dec
PMID:Oxygen regulates mitogen-stimulated proliferation of fetal human airway smooth muscle cells. 1238 46

Aberrant cell proliferation and differentiation after toxic injury to airway epithelium can lead to the development of various lung diseases including cancer. The activator protein-1 (AP-1) transcription factor, composed of mainly Jun-Jun and Jun-Fos protein dimers, acts as an environmental biosensor to various external toxic stimuli and regulates gene expression involved in various biological processes. Gene disruption studies indicate that the AP-1 family members c-jun, junB, and fra1 are essential for embryonic development, whereas junD, c-fos, and fosB are required for normal postnatal growth. However, broad or target-specific transgenic overexpression of the some of these proteins gives very distinct phenotype(s), including tumor formation. This implies that, although they are required for normal cellular processes, their abnormal activation after toxic injury can lead to the pathogenesis of the lung disease. Consistent with this view, various environmental toxicants and carcinogens differentially regulate Jun and Fos expression in cells of the lung both in vivo and in vitro. Moreover, Jun and Fos proteins distinctly bind to the promoter regions of a wide variety of genes to differentially regulate their expression in epithelial injury, repair, and differentiation. Importantly, lung tumors induced by various carcinogens display a sustained expression of certain AP-1 family members. Therefore a better understanding of the mechanisms of regulation and functional role(s), as well as identification of target genes of members of the AP-1 family in airway epithelial cells, will provide additional insight into toxicant-induced lung diseases. These studies might offer a unique opportunity to use AP-1 family members and transactivation as potential diagnostic markers or drug targets for early detection and/or prevention of various lung diseases.
Am J Physiol Lung Cell Mol Physiol 2002 Dec
PMID:Role and regulation of activator protein-1 in toxicant-induced responses of the lung. 1242 43

Pulmonary fibrosis (PF) is caused by a number of inhaled agents, as well as by some drugs and toxic particles. The elaboration of certain peptide growth factors is thought to be key to the development of this disease process. In addition, genetic susceptibility plays a role in the development of PF. For instance, we have previously shown that the 129J strain of mice is resistant, whereas the C57BL/6 strain is highly susceptible, to asbestos-induced fibrosis. To pursue this further, in one mouse model, we crossed the 129J strain to the C57BL/6 strain to produce an F1 generation and subsequently backcrossed the F1 mice to the inbred founders. This backcross to the 129 inbred strain produced reverse similar 25% of the offspring with a phenotype that was protected from the fibrogenic effects of inhaled asbestos fibers. In the second model, both strains of mice were treated intratracheally with an adenovirus vector (AdV), which transduces expression of active transforming growth factor (TGF)-beta(1) in the lungs, producing fibroproliferative lung disease. Compared with C57 mice, a significant number of 129 strain mice exhibited at least a 1-wk delay in the fibroproliferative response to TGF-beta(1) expression at three concentrations of virus. These findings suggest that certain sequences in a gene or a cluster of genes in the 129 mouse strain impart a phenotype in which there is a delay in, or protection from, the development of lung fibrogenesis.
Am J Respir Cell Mol Biol 2002 Dec
PMID:Susceptibility to asbestos-induced and transforming growth factor-beta1-induced fibroproliferative lung disease in two strains of mice. 1244 30

Alterations to pulmonary surfactant structure, composition, and function contribute to the severity of respiratory infections. Analysis of bronchoalveolar lavage fluid (BALF) from children undergoing diagnostic bronchoscopy for structural abnormalities (control group, n = 24), asthma (n = 18), lung infection (n = 30), and cystic fibrosis (CF, n = 15) showed that BALF phospholipid concentration decreased with age for the control group and was elevated in all disease groups. The fractional concentration of the major surface active component, dipalmitoyl phosphatidylcholine (PC16:0/16:0), correlated (r(2) = 0.608, P < 0.01) with airway resistance (FEV(1%) predicted), and decreased PC16:0/16:0 was accompanied by increased concentrations of phospholipid components characteristic of cell membranes (PC16:0/18:1 and PI18:0/20:4). Median minimal surface tension, measured by pulsating bubble surfactometer, was elevated (P < 0.01) in both infection (17.5 mN/m) and CF (17.1 mN/m) compared with the control group (1.5 mN/m). Centrifugation (60,000 x g, 40 min) of BALF indicated that infection was accompanied by accumulation of large aggregate forms of surfactant, in contrast to previous reports of increased conversion to inactive small aggregate surfactant particles in ventilated patients with respiratory failure. This accumulation of surface-inactive, large aggregate forms of surfactant, possibly due to mixing with membrane material from inflammatory cells, may contribute to severity of lung disease in children with respiratory infections.
Am J Respir Cell Mol Biol 2002 Dec
PMID:Altered phospholipid composition and aggregate structure of lung surfactant is associated with impaired lung function in young children with respiratory infections. 1244 31

Matrix metalloproteinases (MMPs) are a large family (>20) of cation-dependent proteinases believed to be important modulators of normal human lung development and potentially harmful mediators of lung damage. Little is known about MMP production and secretion by the lung during childhood or how alterations in MMP levels may be involved in lung damage. We examined endotracheal aspirates from children (<19 years) without lung disease for the presence of MMP activity. Only gelatinase activity was detectable, and inhibitor profiles suggest they represented one or more MMPs. Comparison of gelatinase activity, MMP expression, and MMP activity in children without pulmonary disease with children who required mechanical ventilation for respiratory failure show: 1) gelatinase activity was approximately five- to sixfold higher in respiratory failure; 2) MMP-7, MMP-8, and MMP-9 concentrations and MMP-8 and MMP-9 activities were markedly elevated in respiratory failure; and 3) MMP-7, MMP-8, and MMP-9 levels were significantly correlated in children with lung disease. These studies provide compelling evidence that specific MMPs are present in the diseased lung and may participate in the pathogenesis of pediatric respiratory failure.
Am J Physiol Lung Cell Mol Physiol 2003 Apr
PMID:Implications for matrix metalloproteinases as modulators of pediatric lung disease. 1245 87


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