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

Increased oxidative stress is associated with perinatal asphyxia and respiratory distress in the newborn period. Induction of nuclear factor erythroid 2 p45-related factor (Nrf2) has been shown to decrease oxidative stress through the regulation of specific gene pathways. We hypothesized that Nrf2 attenuates mortality and alveolar growth inhibition in newborn mice exposed to hyperoxia. Nrf2(+/+) and Nrf2(-/-) newborn mice were exposed to hyperoxia at 24 h. Survival was significantly less in Nrf2(-/-) mice exposed to 72 h of hyperoxia and returned to room air (P < 0.0001) and in Nrf2(-/-) mice exposed to hyperoxia for 8 continuous days (P < 0.005). To determine the response of Nrf2 target genes to hyperoxia, glutathione peroxidase 2 (Gpx2) and NAD(P)H:quinone oxidoreductase (NQO1) expression was measured from lung of newborn mice using real-time PCR. In the Nrf2(+/+) mice, significant induction of lung Gpx2 and NQO1 above room air controls was found with hyperoxia. In contrast, Nrf2(-/-) mice had minimal induction of lung Gpx2 and NQO1 with hyperoxia. Expression of p21 and IL-6, genes not regulated by Nrf2, were also measured. IL-6 expression in Nrf2(-/-) lung was markedly induced by 72 h of hyperoxia in contrast to the Nrf2(+/+) mice. p21 was induced in both Nrf2(+/+) and Nrf2(-/-) lung by hyperoxia. Mean linear intercept (MLI) and mean chord length (MCL) were significantly increased in 14-day-old Nrf2(-/-) mice previously exposed to hyperoxia compared with Nrf2(+/+) mice. The percentage of surfactant protein C (Sp-c(+)) type 2 alveolar cells in 14-day-old Nrf2(-/-) mice exposed to neonatal hyperoxia was also significantly less than Nrf2(+/+) mice (P < 0.02). In summary, these findings indicate that Nrf2 increases survival in newborn mice exposed to hyperoxia and that Nrf2 may help attenuate alveolar growth inhibition caused by hyperoxia exposure.
Am J Physiol Lung Cell Mol Physiol 2009 Apr
PMID:Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia. 1915 Nov 8

Patients with mutations in the pulmonary surfactant protein C (SP-C) gene develop interstitial lung disease and pulmonary exacerbations associated with viral infections including respiratory syncytial virus (RSV). Pulmonary infection with RSV caused more severe interstitial thickening, air space consolidation, and goblet cell hyperplasia in SP-C-deficient (Sftpc(-/-)) mice compared with SP-C replete mice. The RSV-induced pathology resolved more slowly in Sftpc(-/-) mice with lung inflammation persistent up to 30 days postinfection. Polymorphonuclear leukocyte and macrophage counts were increased in the bronchoalveolar lavage (BAL) fluid of Sftpc(-/-) mice. Viral titers and viral F and G protein mRNA were significantly increased in both Sftpc(-/-) and heterozygous Sftpc(+/-) mice compared with controls. Expression of Toll-like receptor 3 (TLR3) mRNA was increased in the lungs of Sftpc(-/-) mice relative to Sftpc(+/+) mice before and after RSV infection. Consistent with the increased TLR3 expression, BAL inflammatory cells were increased in the Sftpc(-/-) mice after exposure to a TLR3-specific ligand, poly(I:C). Preparations of purified SP-C and synthetic phospholipids blocked poly(I:C)-induced TLR3 signaling in vitro. SP-C deficiency increases the severity of RSV-induced pulmonary inflammation through regulation of TLR3 signaling.
Am J Physiol Lung Cell Mol Physiol 2009 Jul
PMID:Surfactant protein C-deficient mice are susceptible to respiratory syncytial virus infection. 1930 6

We investigated the influence of extracellular matrix on transport properties of mouse alveolar epithelial cell (AEC) monolayers (MAECM) and transdifferentiation of isolated mouse alveolar epithelial type II (AT2) cells into an alveolar epithelial type I (AT1) cell-like phenotype. Primary mouse AT2 cells plated on laminin 5-coated polycarbonate filters formed monolayers with transepithelial resistance (R(T)) and equivalent short-circuit current (I(EQ)) of 1.8 kOmega.cm(2) and 5.3 microA/cm(2), respectively, after 8 days in culture. Amiloride (10 microM), ouabain (0.1 mM), and pimozide (10 microM) decreased MAECM I(EQ) to 40%, 10%, and 65% of its initial value, respectively. Sequential addition of pimozide and amiloride, in either order, revealed that their inhibitory effects are additive, suggesting that cyclic nucleotide-gated channels contribute to amiloride-insensitive active ion transport across MAECM. Ussing chamber measurements of unidirectional ion fluxes across MAECM under short-circuit conditions indicated that net absorption of Na(+) in the apical-to-basolateral direction is comparable to net ion flux calculated from the observed short-circuit current: 0.38 and 0.33 microeq.cm(-2).h(-1), respectively. Between days 1 and 9 in culture, AEC demonstrated increased expression of aquaporin-5 protein, an AT1 cell marker, and decreased expression of pro-surfactant protein-C protein, an AT2 cell marker, consistent with transition to an AT1 cell-like phenotype. These results demonstrate that AT1 cell-like MAECM grown on laminin 5-coated polycarbonate filters exhibit active and passive transport properties that likely reflect the properties of intact mouse alveolar epithelium. This mouse in vitro model will enhance the study of AEC derived from mutant strains of mice and help define important structure-function correlations.
Am J Physiol Lung Cell Mol Physiol 2009 Jun
PMID:Characterization of mouse alveolar epithelial cell monolayers. 1932 39

A subset of protein misfolding diseases, including, for example, Alzheimer's disease, is associated with the formation of highly insoluble amyloid fibrils with a beta-sheet structure. The amyloidogenic human lung surfactant protein C (SP-C) is generated from SP-C precursor, which has a C-terminal domain (CTC) that prevents SP-C amyloid fibril formation. Analysis of the substrate specificity of CTC reveals that it binds to all amino acid residues that promote membrane insertion, provided that they are in a nonhelical conformation. In line with this unexpectedly general substrate specificity, the anti-amyloid function of CTC extends to a transmembrane segment other than that of (pro)SP-C, namely, the amyloid beta-peptide associated with Alzheimer's disease. These findings indicate that CTC is the first known chaperone to be directed towards nonhelical transmembrane segments and that it may be employed for the development of new diagnostics or anti-amyloid therapies.
J Mol Biol 2009 Jun 05
PMID:Preventing amyloid formation by catching unfolded transmembrane segments. 1937 31

The adenosine A(2B) receptor (A(2B)R) has a wide tissue distribution that includes fibroblasts and endothelial and epithelial cells. The recent generation of an A(2B)R(-/-) mouse constructed with a beta-galactosidase (beta-gal) reporter gene under control of the endogenous promoter has provided a valuable tool to quantify A(2B)R promoter activity (29). To determine the sites of expression of the A(2B) receptor in the mouse lung, histological and flow cytometric analysis of beta-gal reporter gene expression in various lung cell populations was performed. The major site of A(2B)R promoter activity was found to be the type II alveolar epithelial cells (AECs), identified by coexpression of prosurfactant protein C, with relatively less expression in alveolar macrophages, bronchial epithelial cells, and cells of the vasculature. Highly purified type II AECs were prepared by fluorescence-activated sorting of enhanced green fluorescent protein (eGFP)-positive cells from transgenic mice expressing eGFP under control of the surfactant protein C promoter (21). The type II cells expressed 89-fold higher A(2B)R mRNA than pulmonary leukocytes, and the A(2B)R was shown to be functional, as treatment of purified type II AECs with the nonspecific adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) induced an increase in intracellular cAMP greater that the beta-adrenergic agonist isoproterenol that was inhibited completely following treatment by ATL-802, a novel, highly potent (K(i) = 8.6 nM), and selective (>900 fold over other adenosine receptor subtypes) antagonist of the mouse A(2B)R.
Am J Physiol Lung Cell Mol Physiol 2009 Sep
PMID:Adenosine A2B receptors are highly expressed on murine type II alveolar epithelial cells. 1957 19

Emphysema and bronchitis are major components of chronic obstructive pulmonary disease (COPD). Pleomorphic adenoma gene like-2 (PLAGL2), a zinc finger DNA-binding protein, is a transcription factor of the surfactant protein C (SP-C) promoter. Using an inducible transgenic mouse model, PLAGL2 and SP-C were ectopically expressed in lung epithelial cells of terminal bronchiole including the bronchoalveolar duct junction (BADJ), where only few cells express both genes under normal conditions. Ectopic PLAGL2 was also expressed in alveolar type II cells of induced mice. The overexpression of PLAGL2 was associated with the development of air space enlargement in the distal airways of adult mice. Defective alveolar septa and degraded airway fragments were found in the lesions of emphysematous lungs, indicating chronic airway destruction. Female mice were particularly sensitive to the effects of PLAGL2 overexpression with more dramatic emphysematous changes compared with male mice. In addition, analysis of the respiratory system mechanics in the mice indicated that the induction of PLAGL2 resulted in a significant increase in respiratory system compliance. Both TdT-mediated dUTP nick end labeling (TUNEL) and caspase-3 analyses showed that apoptotic activity was increased in epithelial cells within the emphysematous lesions as well as at the BADJ. Our results indicate that increased cell injury and/or death could be caused directly by the upregulation of PLAGL2 downstream gene, bNip3, a preapoptotic molecule that dimerizes with Bcl-2, or indirectly by the aberrant expression of SP-C-induced endoplasmic reticulum stress in epithelial cells. Finally, increased expression of PLAGL2 in alveolar epithelial cells correlated with the development of emphysema in the lung of COPD patients. In summary, our data from both animal and human studies support a novel pathogenic role of PLAGL2 in pulmonary emphysema, a critical aspect of severe COPD.
Am J Physiol Lung Cell Mol Physiol 2009 Sep
PMID:PLAGL2 expression-induced lung epithelium damages at bronchiolar alveolar duct junction in emphysema: bNip3- and SP-C-associated cell death/injury activity. 1957 21

CTP:phosphocholine cytidylyltransferase (CCTalpha) plays a key role in the biosynthesis of surfactant phosphatidylcholine. In this study, we investigated the role of its membrane-binding (M) domain in modulating its structure, function, and cellular distribution. Multiple enhanced green fluorescent protein-CCTalpha constructs were generated to evaluate the subcellular distribution in A549 cells. The M domain targeted CCTalpha to the perinuclear (membrane-rich) region. Microinjections with glutathione-S-transferase fusion protein containing the M domain corroborated the perinuclear targeting. Deletion of the M domain or substitutions of the hydrophobic residues with arginine/serine in the VEEKS(267-277) motif of the M domain resulted in a nuclear appearance and indented nuclei. Membrane binding of CCTalpha decreased gradually as the number of positively charged arginine residues increased in the VEEKS motif. To identify whether membrane-protein interactions cause structural alterations in CCTalpha, we visualized the protein in the absence and presence of lipids by transmission electron microscopy. These studies revealed that CCTalpha forms a dimer-like complex that condenses upon binding to lipid vesicles, but not lipid monolayers. The influence of the M domain on CCTalpha activity was assessed in transgenic mice overexpressing the N-terminal catalytic domain (CCTalpha(1-239)), N-terminal catalytic plus M domain (CCTalpha(1-290)), or full-length CCTalpha(1-367) in fetal type II cells by using the surfactant protein C promoter. Only overexpression of CCTalpha(1-367) increased surfactant phosphatidylcholine synthesis. Thus, the M domain influences membrane binding, cellular distribution, and topology of CCTalpha, but the domain alone is not sufficient to confer CCT activity in alveolar type II cells in vivo.
Am J Respir Cell Mol Biol 2010 Jul
PMID:Functions of membrane binding domain of CTP:phosphocholine cytidylyltransferase in alveolar type II cells. 1968 6

Alveolar type I (TI) cells are large, squamous cells that cover 95-99% of the internal surface area of the lung. Although TI cells are believed to be terminally differentiated, incapable of either proliferation or phenotypic plasticity, TI cells in vitro both proliferate and express phenotypic markers of other differentiated cell types. Rat TI cells isolated in purities of >99% proliferate in culture, with a sixfold increase in cell number before the cells reach confluence; >50% of the cultured TI cells are Ki67+. At cell densities of 1-2 cells/well, approximately 50% of the cells had the capacity to form colonies. Under the same conditions, type II cells do not proliferate. Cultured TI cells express RTI40 and aquaporin 5, phenotypic markers of the TI cell phenotype. By immunofluorescence, Western blotting, and Q-PCR, TI cells express OCT-4A (POU5F1), a transcription factor associated with maintenance of the pluripotent state in stem cells. Based on the expression patterns of various marker proteins, TI cells are distinct from either of two recently described putative pulmonary multipotent cell populations, the bronchoalveolar stem cell or the OCT-4+ stem/progenitor cell. Although TI cells in adult rat lung tissue do not express either surfactant protein C (SP-C) or CC10, respective markers of the TII and Clara cell phenotypes, in culture TI cells can be induced to express both SP-C and CC10. Together, the findings that TI cells proliferate and exhibit phenotypic plasticity in vitro raise the possibility that TI cells may have similar properties in vivo.
Am J Physiol Lung Cell Mol Physiol 2009 Dec
PMID:Rat alveolar type I cells proliferate, express OCT-4, and exhibit phenotypic plasticity in vitro. 1983 48

Recent studies indicate that the antiapoptotic Bcl-X(L), one of five isoforms expressed by the Bcl-X gene, protects a variety of cell lines exposed to hyperoxia. However, its role in lung development and protection against oxidative stress in vivo is not known. Here, we show Bcl-X(L) is the predominant isoform expressed in the lung, and the only isoform detected in respiratory epithelium. Because loss of Bcl-X(L) is embryonically lethal, Bcl-X(L) was ablated throughout the respiratory epithelium by mating mice with a floxed exon II of the Bcl-X gene with mice expressing Cre under control of the surfactant protein-C promoter. Interestingly, the loss of Bcl-X(L) in respiratory epithelium was perinatally lethal in approximately 50% of the expected offspring. However, some adult mice lacking the gene were obtained. The epithelial-specific ablation of Bcl-X(L) did not disrupt pulmonary function, the expression of epithelial cell-specific markers, or lung development. However, it shifted the lung toward a proapoptotic state, defined by a reduction in antiapoptotic Mcl-1, an increase in proapoptotic Bak, and increased sensitivity of the respiratory epithelium to hyperoxia. Intriguingly, increased 8-oxoguanine lesions seen during hyperoxia were also evident as lungs transitioned to room air at birth, a time when perinatal lethality in some mice lacking Bcl-X(L) was observed. These findings reveal that the epithelial-specific expression of Bcl-X(L) is not required for proper lung development, but functions to protect respiratory epithelial cells against oxygen-induced toxicity, such as during hyperoxia and the lung's first exposure to ambient air.
Am J Respir Cell Mol Biol 2010 Sep
PMID:Epithelial ablation of Bcl-XL increases sensitivity to oxygen without disrupting lung development. 1988 Aug 21

Mechanical forces are critical for fetal lung development. Using surfactant protein C (SP-C) as a marker, we previously showed that stretch-induced fetal type II cell differentiation is mediated via the ERK pathway. Caveolin-1, a major component of the plasma membrane microdomains, is important as a signaling protein in blood vessels exposed to shear stress. Its potential role in mechanotransduction during fetal lung development is unknown. Caveolin-1 is a marker of type I epithelial cell phenotype. In this study, using immunocytochemistry, Western blotting, and immunogold electron microscopy, we first demonstrated the presence of caveolin-1 in embryonic day 19 (E19) rat fetal type II epithelial cells. By detergent-free purification of lipid raft-rich membrane fractions and fluorescence immunocytochemistry, we found that mechanical stretch translocates caveolin-1 from the plasma membrane to the cytoplasm. Disruption of the lipid rafts with cholesterol-chelating agents further increased stretch-induced ERK activation and SP-C gene expression compared with stretch samples without disruptors. Similar results were obtained when caveolin-1 gene was knocked down by small interference RNA. In contrast, adenovirus overexpression of the wild-type caveolin-1 or delivery of caveolin-1 scaffolding domain peptide inside the cells decreased stretch-induced ERK phosphorylation and SP-C mRNA expression. In conclusion, our data suggest that caveolin-1 is present in E19 fetal type II epithelial cells. Caveolin-1 is translocated from the plasma membrane to the cytoplasm by mechanical stretch and functions as an inhibitory protein in stretch-induced type II cell differentiation via the ERK pathway.
Am J Physiol Lung Cell Mol Physiol 2010 Jun
PMID:A role for caveolin-1 in mechanotransduction of fetal type II epithelial cells. 2017 52


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