scholarly journals Exacerbation of Lung Radiation Injury by Viral Infection: The Role of Clara Cells and Clara Cell Secretory Protein

2013 ◽  
Vol 179 (6) ◽  
pp. 617-629 ◽  
Author(s):  
Casey M. Manning ◽  
Carl J. Johnston ◽  
Eric Hernady ◽  
Jen-nie H. Miller ◽  
Christina K. Reed ◽  
...  
Keyword(s):  
Viral Infection ◽  
Radiation Injury ◽  
Secretory Protein ◽  
Clara Cell ◽  
Clara Cells ◽  
Clara Cell Secretory Protein

Clara cell secretory protein deficiency increases oxidant stress response in conducting airways

1998 ◽  
Vol 275 (2) ◽  
pp. L348-L356 ◽  
Author(s):  
Gregory W. Mango ◽  
Carl J. Johnston ◽  
Susan D. Reynolds ◽  
Jacob N. Finkelstein ◽  
Charles G. Plopper ◽  
...  
Keyword(s):  
Stress Response ◽  
Mrna Expression ◽  
Molecular Basis ◽  
Oxidant Stress ◽  
Secretory Protein ◽  
Protective Role ◽  
Clara Cell ◽  
Clara Cells ◽  
Clara Cell Secretory Protein ◽  
Oxidant Sensitivity

Little is known about the molecular basis for differential pulmonary oxidant sensitivity observed between genetically disparate members of the same species. We have generated mice that are deficient in Clara cell secretory protein (CCSP −/−) and that exhibit an oxidant-sensitive phenotype. We characterized the kinetics and distribution of altered stress-response [interleukin-6 (IL-6) and metallothionein (MT)] and epithelial cell-specific [cytochrome P-450 2F2 (CYP2F2)] gene expression to further understand the cellular and molecular basis for altered oxidant sensitivity in 129 strain CCSP −/− mice. Increases in IL-6 and MT mRNA abundance were detected by 2 h of exposure to 1 part/million ozone and preceded reductions in Clara cell CYP2F2 mRNA expression. Despite being qualitatively similar, increases in IL-6 and MT mRNA expression were enhanced in CCSP −/− mice with respect to coexposed 129 strain wild-type mice. Increased MT mRNA expression, indicative of the stress response, localized to the airway epithelium, surrounding mesenchyme, and endothelium of blood vessels. These results demonstrate a protective role for Clara cells and their secretions and indicate potential genetic mechanisms that may influence susceptibility to oxidant stress.

Secretory product expression during Clara cell differentiation in the rabbit and rat

1993 ◽  
Vol 264 (6) ◽  
pp. L543-L552 ◽  
Author(s):  
W. V. Cardoso ◽  
L. G. Stewart ◽  
K. E. Pinkerton ◽  
C. Ji ◽  
G. E. Hook ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Secretory Granules ◽  
Close Association ◽  
Secretory Protein ◽  
Clara Cell ◽  
Secretory Proteins ◽  
Secretory Product ◽  
Secretory Function ◽  
Clara Cells ◽  
Clara Cell Secretory Protein

One function of the nonciliated (Clara) cells of bronchiolar epithelium is to synthesize, store, and release small-molecular-mass (6–12 kDa) secretory proteins or Clara cell secretory protein (CCSP). This study compares the emergence of this secretory function during Clara cell differentiation in rabbits and rats. Lungs of fetal and postnatal animals were evaluated by ultrastructural morphometry and immunohistochemistry. Secretory granules were rarely seen in perinatal animals and increased to adult levels of abundance earlier in rats (1 wk postnatal) than in rabbits (3–4 wk). In contrast, rough endoplasmic reticulum was abundant in perinatal animals and decreased with age. Antibodies raised against CCSP revealed little CCSP in fetal animals; however, after birth CCSP increased to adult levels earlier in rats (1 wk postnatal) than in rabbits (3 wk). We conclude that the maturation of Clara cell secretory function 1) occurs postnatally, 2) involves a decrease in biosynthetic organelles, 3) shows close association between CCSP expression and secretory granule abundance, and 4) varies by species in timing and cellular abundance of biosynthetic machinery.

Clara cell secretory protein gene expression in bronchiolar epithelium

1992 ◽  
Vol 262 (4) ◽  
pp. L399-L404 ◽  
Author(s):  
B. P. Hackett ◽  
N. Shimizu ◽  
J. D. Gitlin
Keyword(s):  
Gene Expression ◽  
Lung Tissue ◽  
Prolonged Exposure ◽  
Secretory Protein ◽  
Clara Cell ◽  
Fetal Life ◽  
Clara Cells ◽  
Adult Rats ◽  
Clara Cell Secretory Protein ◽  
Bronchiolar Epithelium

To determine the mechanisms of Clara cell secretory protein (CCSP) gene expression, a cDNA clone was isolated and used in RNA blot analysis. A single 600 bp CCSP specific transcript was detected in the developing rat lung on fetal day 18. This transcript increased in abundance during late fetal life such that adult levels were attained within 2 wk postpartum. CCSP gene expression was tissue specific, being confined to lung and trachea at all developmental stages. The abundance of CCSP mRNA in lung tissue was unchanged after the induction of lung injury in adult rats either with lipopolysaccharide or prolonged exposure to hyperoxia. In situ hybridization of lung tissue revealed that CCSP gene expression is localized to the nonciliated epithelial (Clara) cells of the bronchiolar epithelium throughout fetal and postnatal development. Taken together the results indicate that the gene for CCSP is abundantly expressed in a cell-specific fashion in the lung and suggest that analysis of such expression will be useful in elucidating the role of Clara cells in the growth and development of the bronchiolar epithelium.

Clara cell secretory protein decreases lung inflammation after acute virus infection

1998 ◽  
Vol 275 (5) ◽  
pp. L924-L930 ◽  
Author(s):  
Kevin S. Harrod ◽  
Amber D. Mounday ◽  
Barry R. Stripp ◽  
Jeffrey A. Whitsett
Keyword(s):  
Viral Infection ◽  
Lung Inflammation ◽  
Cell Injury ◽  
Pulmonary Inflammation ◽  
Secretory Protein ◽  
Clara Cell ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Adenoviral Infection ◽  
Clara Cell Secretory Protein

Clara cell secretory protein (CCSP) is an abundant 10-kDa polypeptide synthesized and secreted primarily by nonciliated bronchiolar epithelial cells in the mammalian lung. To determine the potential role of CCSP in pulmonary inflammation after acute viral infection, CCSP gene-targeted {CCSP-deficient [CCSP(−/−)]} mice were exposed to a recombinant E1- and E3-deficient adenoviral vector, Av1Luc1, intratracheally. Lung inflammation was markedly increased in CCSP(−/−) mice compared with wild-type control mice and was associated with an increased number of polymorphonuclear cell infiltrates and epithelial cell injury in both conducting airways and alveolar regions. Histological evidence of pulmonary inflammation in CCSP(−/−) mice was associated with increased production of cytokine (interleukin-1β and -6 and tumor necrosis factor-α) mRNA and protein, as well as chemokine (macrophage inflammatory protein-1α and -2 and monocyte chemoattractant protein-1) mRNA expression within the lung in response to adenoviral infection. Adenoviral-mediated gene transfer was decreased in CCSP(−/−) mice relative to wild-type mice as measured by luciferase enzyme activity in lung homogenates. The present study suggests that CCSP is involved in modulating lung inflammation during viral infection and supports a role for CCSP in lung host defense.

scholarly journals Role of hepatocyte nuclear factor-3α and hepatocyte nuclear factor-3β in Clara cell secretory protein gene expression in the bronchiolar epithelium

1995 ◽  
Vol 308 (1) ◽  
pp. 197-202 ◽  
Author(s):  
C D Bingle ◽  
B P Hackett ◽  
M Moxley ◽  
W Longmore ◽  
J D Gitlin
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Secretory Protein ◽  
Clara Cell ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Clara Cell Secretory Protein ◽  
Region I ◽  
Bronchiolar Epithelium

The 5′ flanking region of the Clara cell secretory protein (CCSP) gene contains two cis-acting elements which bind hepatocyte nuclear factor (HNF)-3 alpha and HNF-3 beta in vitro. To determine the role of these proteins in mediating CCSP gene expression in the bronchiolar epithelium, chimeric CCSP-reporter gene constructs containing various regions of the CCSP 5′ flanking region were co-transfected into H-441 cells with HNF-3 alpha or HNF-3 beta expression plasmids. These studies indicate that each of these transcription factors positively regulates CCSP gene expression and revealed that CCSP region I (-132 to -76) is sufficient to mediate this effect. Gel-mobility-shift assays with oligonucleotides corresponding to CCSP region I, nuclear extract from bronchiolar epithelial cells and HNF-3-specific antibodies indicate that HNF-3 alpha and HNF-3 beta are the only proteins in bronchiolar epithelial cells which directly interact with this region. Consistent with these observations, HNF-3 alpha and HNF-3 beta transcripts were found to be enriched in this cell population and in situ hybridization of adult lung revealed HNF-3 gene expression in non-ciliated bronchiolar epithelial cells expressing the CCSP gene. Finally, experiments with CCSP region I and a heterologous promoter indicate that this region acts in a promoter-specific context, suggesting that additional factors interacting via the minimal CCSP promoter region are essential in determining the effects of HNF-3 on cell-specific CCSP gene expression in the bronchiolar epithelium.

scholarly journals Maternal exposure to environmental tobacco smoke alters Clara cell secretory protein expression in fetal rat lung

1998 ◽  
Vol 275 (5) ◽  
pp. L870-L876 ◽  
Author(s):  
Chun-Mei Ji ◽  
Fred H. Royce ◽  
Uyen Truong ◽  
Charles G. Plopper ◽  
Gurmukh Singh ◽  
...  
Keyword(s):  
Secretory Protein ◽  
Maternal Exposure ◽  
Clara Cell ◽  
Developmental Expression ◽  
Clara Cells ◽  
Rat Lung ◽  
Differentiation Markers ◽  
Clara Cell Secretory Protein ◽  
Fetal Rat ◽  
Fetal Rat Lung

We have previously demonstrated that aged and diluted sidestream cigarette smoke (ADSS) alters the development of bronchiolar epithelial cells in postnatal animals (C. M. Ji, C. G. Plopper, H. P. Witschi, and K. E. Pinkerton. Am. J. Respir. Cell Mol. Biol. 11: 312–320, 1994). This study was designed to examine the effects of maternal exposure to ADSS on the development of fetal Clara cells in rats with Clara cell 10-kDa protein (CC10; also designated Clara cell secretory protein) and CC10 mRNA as differentiation markers. Immunohistochemistry, Northern blots, and in situ hybridization were used to determine the abundance and distribution of CC10 at gestational days 14, 18, and 21. CC10 and CC10 mRNA were absent at gestational day 14 but were detectable at gestational day 18 and further increased by gestational day 21. Maternal exposure to ADSS was found to significantly increase fetal expression of CC10 and CC10 mRNA by gestational day 21 but not by gestational day 14 or 18. These findings demonstrate that in utero exposure to ADSS alters the normal developmental expression of CC10 in the fetal rat lung.

scholarly journals Purification, characterization and proteinase-inhibitory activity of a Clara-cell secretory protein from the pulmonary extracellular lining of rabbits

1987 ◽  
Vol 248 (2) ◽  
pp. 337-344 ◽  
Author(s):  
R P Gupta ◽  
S E Patton ◽  
A M Jetten ◽  
G E R Hook
Keyword(s):  
Inhibitory Activity ◽  
Polyacrylamide Gel Electrophoresis ◽  
Secretory Protein ◽  
Clara Cell ◽  
Gel Chromatography ◽  
Secretory Product ◽  
Clara Cells ◽  
Rabbit Lung ◽  
Clara Cell Secretory Protein ◽  
Reducing Conditions

A low-Mr Clara-cell secretory protein, CCSP, previously shown to be a major secretory product of Clara cells, was isolated from rabbit lung lavage effluents. CCSP accounted for 4.4 +/- 0.5% of the protein in the soluble phase of cell- and surfactant-free pulmonary lavage effluents (LE). Purification of this protein from LE was achieved in two steps. First, the LE was acidified with HCIO4 and, secondly, CCSP was isolated by gel-exclusion chromatography on Sephadex G-50. Purified CCSP was homogeneous by SDS/polyacrylamide-gel electrophoresis (PAGE), consisting of a single major isoform with a pI of 6.0. The Mr of CCSP was 5800 according to SDS/PAGE under reducing conditions and 12,600 under non-reducing conditions. However, by gel chromatography the Mr of the protein under non-reducing conditions was 12,400 and under reducing conditions it increased to 15,000. The discrepancy obtained by using these two techniques was attributed to anomalous electrophoretic mobilities of the protein in its reduced state. The molecule contained three half-cystine residues, but no free thiol groups, and tryptophan was not detectable. The first seven N-terminal amino acid residues were Gly-Ile-Xaa-Pro-Arg-Phe-Ala-. The third residue was not identified. CCSP showed inhibitory activity against the thiol proteinase papain (50% inhibition at 4 microM-CCSP), but only weak activities against human polymorphonuclear-leucocyte elastase, and bovine trypsin. The molecule was not digested by, and did not complex with, trypsin. CCSP was immunochemically different from surfactant apoprotein B (Mr 10,000) present in rabbit lung surfactant. This study is the first partial characterization of the major secretory protein of rabbit lung Clara cells.

Distribution of Clara cell secretory protein expression in the tracheobronchial airways of rhesus monkeys

2007 ◽  
Vol 292 (5) ◽  
pp. L1155-L1162 ◽  
Author(s):  
John T. Coppens ◽  
Laura S. Van Winkle ◽  
Kent Pinkerton ◽  
Charles G. Plopper
Keyword(s):  
Airway Epithelium ◽  
Rhesus Monkeys ◽  
Three Dimensional ◽  
Lavage Fluid ◽  
Secretory Protein ◽  
Clara Cell ◽  
Primate Species ◽  
Clara Cells ◽  
Western Blots ◽  
Clara Cell Secretory Protein

Clara cell secretory protein (CCSP) is a protective lung protein that is believed to have antioxidant, immunomodulatory, and anticarcinogenic properties; to be present in all adult mammals; and to be well conserved in rodents, humans, and nonhuman primates. The rationale for this study is to define the distribution and abundance of CCSP in the airway epithelium and lavage fluid of the adult rhesus monkey and to provide information for evaluating CCSP as a marker of Clara cells and as a biomarker of lung health. Lung tissue and lavage fluid from 3-yr-old rhesus monkeys were examined using histopathology and immunohistochemistry. Proximal bronchi, midlevel bronchi, and terminal/respiratory bronchioles were compared for immunohistochemical localization of CCSP in three-dimensional whole mounts as well as in paraffin and Araldite sections. Immunoreactive CCSP was found in nonciliated cells throughout the airway epithelium. Proximal and midlevel airways had the highest labeling. CCSP decreased in distal airways, and respiratory bronchioles had little to no CCSP. CCSP in the most distal airways was in tall cuboidal cells adjacent to the pulmonary artery. Although a large number of cells were present in the terminal bronchioles that would be classified as Clara cells based on morphology (nonciliated cells with apical protrusions), only a small number stained positively for immunoreactive CCSP. Semiquantitative analysis of Western blots indicated that changes in lavage CCSP are consistent with, and may be predictive of, overall CCSP levels in the airway epithelium in this primate species that is phylogenetically similar to humans.

scholarly journals Bone Marrow Cells Expressing Clara Cell Secretory Protein Increase Epithelial Repair After Ablation of Pulmonary Clara Cells

2013 ◽  
Vol 21 (6) ◽  
pp. 1251-1258 ◽  
Author(s):  
Martha L Bustos ◽  
Marco Mura ◽  
Paula Marcus ◽  
David Hwang ◽  
Olga Ludkovski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Secretory Protein ◽  
Clara Cell ◽  
Clara Cells ◽  
Epithelial Repair ◽  
Clara Cell Secretory Protein ◽  
Marrow Cells

Airway regeneration: the role of the Clara cell secretory protein and the cells that express it

Cytotherapy ◽  
2009 ◽  
Vol 11 (6) ◽  
pp. 676-687 ◽  
Author(s):  
Amy P. Wong ◽  
Armand Keating ◽  
Thomas K. Waddell
Keyword(s):  
Secretory Protein ◽  
Clara Cell ◽  
Clara Cell Secretory Protein
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