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Alfred Bernard - One of the best experts on this subject based on the ideXlab platform.

  • cord blood Clara Cell protein cc16 predicts the development of bronchopulmonary dysplasia
    European Journal of Pediatrics, 2008
    Co-Authors: Alexandra J J Schrama, Alfred Bernard, B J H M Poorthuis, Aeilko H Zwinderman, H M Berger, Frans J Walther
    Abstract:

    Clara Cell protein (CC16) is an anti-inflammatory protein and a biomarker of pulmonary epithelial Cells and alveolocapillary membrane injury in adults. We investigated whether low cord blood concentrations of CC16 are associated with the development of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in preterm infants and the relationship between CC16 and its pro-inflammatory counterpart, the secretory phospholipase A(2) (sPLA(2)) enzyme. CC16 concentration, sPLA(2) activity and IL-6 concentration were measured in cord blood plasma from 79 preterm infants (25 controls, 37 infants who developed RDS and 17 infants who developed BPD). After adjustment for gestational age and Apgar score at 5 min, the CC16 concentration was lower in BPD infants than in preterm controls (p < 0.01). sPLA(2) activity was similar in all groups and the IL-6 concentrations were increased in both RDS and BPD infants (p < 0.01 and p < 0.05, respectively, vs. controls). We conclude that low cord blood CC16 concentrations in preterm infants independently predict the development of BPD. Low CC16 levels may reflect early lung injury, which contributes to the severity of RDS and progress towards BPD. Future studies are needed to assess whether the early administration of recombinant human CC16 in preterm infants with low cord blood CC16 prevents the development of BPD.

  • Clara Cell secretory protein cc16 features as a peripheral lung biomarker
    Annals of the New York Academy of Sciences, 2006
    Co-Authors: F Broeckaert, Bernard Knoops, Cedric Hermans, Andre Clippe, Alfred Bernard
    Abstract:

    Clara Cell protein (CC16 or CC10) is a 15.8-kDa protein secreted all along the tracheobronchial tree and especially in the terminal bronchioles where Clara Cells are localized. Even though the exact in vivo function of CC16 remains to be clarified, evidence is accumulating that CC16 plays an important protective role in the respiratory tract against oxidative stress and inflammatory response. CC16, however, presents also a major interest as a peripheral lung marker for assessing the Cellular integrity or the permeability of the lung epithelium. The serum concentrations of CC16 are decreased in subjects with chronic lung damage caused by tobacco smoke and other air pollutants as a consequence of the destruction of Clara Cells. By contrast, serum CC16 increases in acute or chronic lung disorders characterized by an increased airways permeability. The sensitivity of serum CC16 to an increased leakiness of the lung allows for the detection of defects of the epithelial barrier at ozone levels below current air-quality guidelines. Although the clinical significance of these early epithelial changes detected by serum CC16 remains to be determined, these results clearly show that the assay in serum of lung secretory proteins such as CC16 represents a new noninvasive approach to evaluate the integrity of the respiratory tract.

  • Clara Cell protein and surfactant protein b in garbage collectors and in wastewater workers exposed to bioaerosols
    International Archives of Occupational and Environmental Health, 2005
    Co-Authors: D Steiner, Alfred Bernard, S Jeggli, Alois Tschopp, Anne Oppliger, Silvia Hilfiker, Philipp Hotz
    Abstract:

    Objectives: Inhalation of bioaerosols has been hypothesised to cause “toxic pneumonitis” that should increase lung epithelial permeability at the bronchioloalveolar level. Serum Clara Cell protein (CC16) and serum surfactant protein B (SPB) have been proposed as sensitive markers of lung epithelial injury. This study was aimed at looking for increased lung epithelial permeability by determining CC16 and SPB in workers exposed to bioaerosols from wastewater or garbage. Methods: Subjects (778 wastewater, garbage and control workers; participation 61%) underwent a medical examination, lung function tests [American Thoracic Society (ATS) criteria], and determination of CC16 and SPB. Symptoms of endotoxin exposure and several potential confounders (age, gender, smoking, kidney function, obesity) were looked for. Results were examined with multiple linear or logistic regression. Results: Exposure to bioaerosols increased CC16 concentration in the wastewater workers. No effect of exposure on SPB was found. No clue to work-related respiratory diseases was found. Conclusions: The increase in CC16 in serum supports the hypothesis that bioaerosols cause subclinical “toxic pneumonitis”, even at low exposure.

  • Clara Cell protein as a biomarker for ozone induced lung injury in humans
    European Respiratory Journal, 2003
    Co-Authors: Anders Blomberg, Ian Mudway, Mona Svensson, Annika Hagenbjorkgustafsson, L Thomasson, Ragnberth Helleday, Xavier Dumont, Bertil Forsberg, Gunnar F Nordberg, Alfred Bernard
    Abstract:

    Exposure to ozone (O 3 ) impairs lung function, induces airway inflammation and alters epithelial permeability. Whilst impaired lung function and neutrophilia have been observed at relatively low concentrations, altered lung epithelial permeability is only seen after high-dose challenges. The appearance of Clara Cell protein (CC16) in serum has been proposed as a sensitive marker of lung epithelial injury. Here, the use of CC16 as an injury biomarker was evaluated under a controlled exposure to O 3 and the relationship between this marker of lung injury and early lung function decrements was investigated. Subjects (n=22) were exposed on two separate occasions to 0.2 parts per million O 3 and filtered air for 2 h. Blood samples were drawn and lung function assessed at 2 h pre-exposure, immediately before and immediately after exposure as well as 2 and 4 h postexposure. O 3 increased CC16 serum concentrations at 2 h (12.0±4.5 versus 8.4±3.1 µg·L −1 ) and 4 h postexposure (11.7±5.0 versus 7.9±2.6 µg·L −1 ) compared with air concentrations. Archived samples from O 3 studies utilising the same design indicated that this increase was sustained for up to 6 h postexposure (9.1±2.6 versus 7.1±1.7 µg·L −1 ) with concentrations returning to baseline by 18 h (7.7±2.9 versus 6.6±1.7 µg·L −1 ). In these studies, the increased plasma CC16 concentration was noted in the absence of increases in traditional markers of epithelial permeability. No association was observed between increased CC16 concentrations and lung function changes. To conclude, Clara Cell protein represents a sensitive and noninvasive biomarker for ozone-induced lung epithelial damage that may have important uses in assessing the health effects of air pollutants in future epidemiological and field studies.

  • serum Clara Cell protein a sensitive biomarker of increased lung epithelium permeability caused by ambient ozone
    Environmental Health Perspectives, 2000
    Co-Authors: F Broeckaert, Cedric Hermans, K Arsalane, Enrico Bergamaschi, Angelita Brustolin, A Mutti, Alfred Bernard
    Abstract:

    Ozone in ambient air may cause various effects on human health, including decreased lung function, asthma exacerbation, and even premature mortality. These effects have been evidenced using various clinical indicators that, although sensitive, do not specifically evaluate the O(3)-increased lung epithelium permeability. In the present study, we assessed the acute effects of ambient O(3) on the pulmonary epithelium by a new approach relying on the assay in serum of the lung-specific Clara Cell protein (CC16 or CC10). We applied this test to cyclists who exercised for 2 hr during episodes of photochemical smog and found that O(3) induces an early leakage of lung Clara Cell protein. The protein levels increased significantly into the serum from exposure levels as low as 0.060-0.084 ppm. Our findings, confirmed in mice exposed to the current U.S. National Ambient Air Quality Standards for O(3) (0.08 ppm for 8 hr) indicate that above the present natural background levels, there is almost no safety margin for the effects of ambient O(3) on airway permeability. The assay of CC16 in the serum represents a new sensitive noninvasive test allowing the detection of early effects of ambient O(3) on the lung epithelial barrier.

Barry R Stripp - One of the best experts on this subject based on the ideXlab platform.

  • elevation of susceptibility to ozone induced acute tracheobronchial injury in transgenic mice deficient in Clara Cell secretory protein
    Toxicology and Applied Pharmacology, 2006
    Co-Authors: Charles G Plopper, Susan D Reynolds, Gregory W Mango, G E Hatch, Viviana J Wong, Elina Toskala, Brian K Tarkington, Barry R Stripp
    Abstract:

    Increases in Clara Cell abundance or Cellular expression of Clara Cell secretory protein (CCSP) may cause increased tolerance of the lung to acute oxidant injury by repeated exposure to ozone (O{sub 3}). This study defines how disruption of the gene for CCSP synthesis affects the susceptibility of tracheobronchial epithelium to acute oxidant injury. Mice homozygous for a null allele of the CCSP gene (CCSP-/-) and wild type (CCSP+/+) littermates were exposed to ozone (0.2 ppm, 8 h; 1 ppm, 8 h) or filtered air. Injury was evaluated by light and scanning electron microscopy, and the abundance of necrotic, ciliated, and nonciliated Cells was estimated by morphometry. Proximal and midlevel intrapulmonary airways and terminal bronchioles were evaluated. There was no difference in airway epithelial composition between CCSP+/+ and CCSP-/- mice exposed to filtered air, and exposure to 0.2 ppm ozone caused little injury to the epithelium of both CCSP+/+ and CCSP-/- mice. After exposure to 1.0 ppm ozone, CCSP-/- mice suffered from a greater degree of epithelial injury throughout the airways compared to CCSP+/+ mice. CCSP-/- mice had both ciliated and nonciliated Cell injury. Furthermore, lack of CCSP was associated with a shift in airway injury to include proximal airway generations.more » Therefore, we conclude that CCSP modulates the susceptibility of the epithelium to oxidant-induced injury. Whether this is due to the presence of CCSP on the aCellular lining layer surface and/or its intraCellular distribution in the secretory Cell population needs to be defined.« less

  • pulmonary phenotype of ccsp ug deficient mice a consequence of ccsp deficiency or altered Clara Cell function
    Annals of the New York Academy of Sciences, 2006
    Co-Authors: Barry R Stripp, Susan D Reynolds, Charles G Plopper, Johan Lund
    Abstract:

    : Clara Cell secretory protein (CCSP) is the most abundant secreted protein within airways of the lung. Moreover, CCSP levels are modulated in human lung disease, supporting a potentially important role for CCSP and/or Clara Cells in lung homeostasis. However, in vivo roles for CCSP remain elusive. A popular hypothesis is that CCSP is a regulator of the inflammatory response. The purpose of this review is to provide an overview of the phenotype of CCSP null mice and relate this phenotype to proposed functions for the protein. Phenotypic analysis of mice homozygous for the CCSP-1 null allele of the CCSP gene (CCSP-/-1) revealed susceptibility to inhaled oxidant gases. Sensitivity of CCSP-/-1 mice to inhaled ozone is unrelated to alterations in antioxidant defenses, but is associated with increased Cellular injury. Additional studies investigating inflammatory control in CCSP deficient mice found no differences between wild-type and CCSP-/-1 mice in their inflammatory response to low-dose inhaled endotoxin exposure, arguing against a role for CCSP in regulation of pulmonary inflammation. The findings among CCSP-/-1 mice of ultrastructural alterations to Clara Cell secretory apparatus, with associated changes in airway lining fluid protein composition, demonstrate that the CCSP-/-1 genotype results in more complex changes to airways than CCSP deficiency per se. It can be concluded that CCSP does not regulate endotoxin-induced pulmonary inflammation. Moreover, CCSP-/-1 mice represent a valuable tool for probing functional roles for Clara Cells in regulation of airway lining fluid composition and lung pollutant susceptibility.

  • Clara Cell secretory protein and phospholipase a2 activity modulate acute ventilator induced lung injury in mice
    Journal of Applied Physiology, 2005
    Co-Authors: S Yoshikawa, Barry R Stripp, Susan D Reynolds, Takashige Miyahara, Mircea Anghelescu, Fabien G Eyal, James C Parker
    Abstract:

    Lung vascular permeability is acutely increased by high-pressure and high-volume ventilation. To determine the roles of mechanically activated cytosolic PLA2 (cPLA2) and Clara Cell secretory protei...

  • Clara Cell secretory protein deficiency alters Clara Cell secretory apparatus and the protein composition of airway lining fluid
    American Journal of Respiratory Cell and Molecular Biology, 2002
    Co-Authors: Barry R Stripp, Susan D Reynolds, Johan Lund, John H T Power, John T Coppens, Virginia Wong, Paul R Reynolds, Charles G Plopper
    Abstract:

    Clara Cells represent the predominant secretory Cell within distal conducting airways of mammals and exhibit functional alterations with chronic lung disease. We previously demonstrated that Clara Cell secretory protein (CCSP) deficiency results in enhanced susceptibility to environmental agents. The present study was undertaken to define changes in Clara Cell secretory function associated with CCSP deficiency in knockout mice. Comparative morphometry of Clara Cell ultrastructure revealed dramatic alterations in secretory apparatus between wild-type (WT) and CCSP knockout (CCSP−/−) mice. Secretory granules, which occupy greater than 2% of Clara Cell cytoplasmic volume in WT mice, were completely absent among Clara Cells of CCSP−/− mice. Moreover, Clara Cells of CCSP−/− mice exhibited a > 95% reduction in rough endoplasmic reticulum and alterations to Golgi apparatus, relative to WT controls. Ultrastructural perturbations to Clara Cells were associated with altered protein composition of airway lining flui...

  • Clara Cell secretory protein decreases lung inflammation after acute virus infection
    American Journal of Physiology-lung Cellular and Molecular Physiology, 1998
    Co-Authors: Kevin S Harrod, Barry R Stripp, Amber D Mounday, Jeffrey A Whitsett
    Abstract:

    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 potentia...

Charles G Plopper - One of the best experts on this subject based on the ideXlab platform.

  • distribution of Clara Cell secretory protein expression in the tracheobronchial airways of rhesus monkeys
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2007
    Co-Authors: John T Coppens, K E Pinkerton, Laura S Van Winkle, Charles G Plopper
    Abstract:

    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 ...

  • elevation of susceptibility to ozone induced acute tracheobronchial injury in transgenic mice deficient in Clara Cell secretory protein
    Toxicology and Applied Pharmacology, 2006
    Co-Authors: Charles G Plopper, Susan D Reynolds, Gregory W Mango, G E Hatch, Viviana J Wong, Elina Toskala, Brian K Tarkington, Barry R Stripp
    Abstract:

    Increases in Clara Cell abundance or Cellular expression of Clara Cell secretory protein (CCSP) may cause increased tolerance of the lung to acute oxidant injury by repeated exposure to ozone (O{sub 3}). This study defines how disruption of the gene for CCSP synthesis affects the susceptibility of tracheobronchial epithelium to acute oxidant injury. Mice homozygous for a null allele of the CCSP gene (CCSP-/-) and wild type (CCSP+/+) littermates were exposed to ozone (0.2 ppm, 8 h; 1 ppm, 8 h) or filtered air. Injury was evaluated by light and scanning electron microscopy, and the abundance of necrotic, ciliated, and nonciliated Cells was estimated by morphometry. Proximal and midlevel intrapulmonary airways and terminal bronchioles were evaluated. There was no difference in airway epithelial composition between CCSP+/+ and CCSP-/- mice exposed to filtered air, and exposure to 0.2 ppm ozone caused little injury to the epithelium of both CCSP+/+ and CCSP-/- mice. After exposure to 1.0 ppm ozone, CCSP-/- mice suffered from a greater degree of epithelial injury throughout the airways compared to CCSP+/+ mice. CCSP-/- mice had both ciliated and nonciliated Cell injury. Furthermore, lack of CCSP was associated with a shift in airway injury to include proximal airway generations.more » Therefore, we conclude that CCSP modulates the susceptibility of the epithelium to oxidant-induced injury. Whether this is due to the presence of CCSP on the aCellular lining layer surface and/or its intraCellular distribution in the secretory Cell population needs to be defined.« less

  • pulmonary phenotype of ccsp ug deficient mice a consequence of ccsp deficiency or altered Clara Cell function
    Annals of the New York Academy of Sciences, 2006
    Co-Authors: Barry R Stripp, Susan D Reynolds, Charles G Plopper, Johan Lund
    Abstract:

    : Clara Cell secretory protein (CCSP) is the most abundant secreted protein within airways of the lung. Moreover, CCSP levels are modulated in human lung disease, supporting a potentially important role for CCSP and/or Clara Cells in lung homeostasis. However, in vivo roles for CCSP remain elusive. A popular hypothesis is that CCSP is a regulator of the inflammatory response. The purpose of this review is to provide an overview of the phenotype of CCSP null mice and relate this phenotype to proposed functions for the protein. Phenotypic analysis of mice homozygous for the CCSP-1 null allele of the CCSP gene (CCSP-/-1) revealed susceptibility to inhaled oxidant gases. Sensitivity of CCSP-/-1 mice to inhaled ozone is unrelated to alterations in antioxidant defenses, but is associated with increased Cellular injury. Additional studies investigating inflammatory control in CCSP deficient mice found no differences between wild-type and CCSP-/-1 mice in their inflammatory response to low-dose inhaled endotoxin exposure, arguing against a role for CCSP in regulation of pulmonary inflammation. The findings among CCSP-/-1 mice of ultrastructural alterations to Clara Cell secretory apparatus, with associated changes in airway lining fluid protein composition, demonstrate that the CCSP-/-1 genotype results in more complex changes to airways than CCSP deficiency per se. It can be concluded that CCSP does not regulate endotoxin-induced pulmonary inflammation. Moreover, CCSP-/-1 mice represent a valuable tool for probing functional roles for Clara Cells in regulation of airway lining fluid composition and lung pollutant susceptibility.

  • Clara Cell secretory protein deficiency alters Clara Cell secretory apparatus and the protein composition of airway lining fluid
    American Journal of Respiratory Cell and Molecular Biology, 2002
    Co-Authors: Barry R Stripp, Susan D Reynolds, Johan Lund, John H T Power, John T Coppens, Virginia Wong, Paul R Reynolds, Charles G Plopper
    Abstract:

    Clara Cells represent the predominant secretory Cell within distal conducting airways of mammals and exhibit functional alterations with chronic lung disease. We previously demonstrated that Clara Cell secretory protein (CCSP) deficiency results in enhanced susceptibility to environmental agents. The present study was undertaken to define changes in Clara Cell secretory function associated with CCSP deficiency in knockout mice. Comparative morphometry of Clara Cell ultrastructure revealed dramatic alterations in secretory apparatus between wild-type (WT) and CCSP knockout (CCSP−/−) mice. Secretory granules, which occupy greater than 2% of Clara Cell cytoplasmic volume in WT mice, were completely absent among Clara Cells of CCSP−/− mice. Moreover, Clara Cells of CCSP−/− mice exhibited a > 95% reduction in rough endoplasmic reticulum and alterations to Golgi apparatus, relative to WT controls. Ultrastructural perturbations to Clara Cells were associated with altered protein composition of airway lining flui...

  • early events in naphthalene induced acute Clara Cell toxicity ii comparison of glutathione depletion and histopathology by airway location
    American Journal of Respiratory Cell and Molecular Biology, 2001
    Co-Authors: Charles G Plopper, Michelle V. Fanucchi, L S Van Winkle, S R C Malburg, Susan J Nishio, A Chang, Alan R. Buckpitt
    Abstract:

    : One of the presumed roles of intraCellular glutathione (GSH) is the protection of Cells from injury by reactive intermediates produced by the metabolism of xenobiotics. To establish whether GSH depletion is a critical step in the initiation of events that lead to cytotoxicity by P450-activated cytotoxicants, naphthalene, a well-defined Clara Cell cytotoxicant, was administered to mice (200 mg/kg) by intraperitoneal injection. Shortly after injection (1, 2, and 3 h), intraCellular GSH content was assessed by high performance liquid chromatography or quantitative epifluorescent imaging microscopy and compared with the degree of cytotoxicity as assessed by high resolution histopathology. In highly susceptible airways (distal bronchioles), GSH decreased by 50% in 1 h. Cytoplasmic vacuolization was not visible until 2 h, when GSH had decreased by an additional 50%. By 3 h, cytoplasmic blebbing was extensive. In minimally susceptible airways (lobar and proximal bronchi), GSH depletion varied widely within the population; a small proportion of the Cells lost greater than 50% of their GSH by 2 h and a significant percentage of the Cells retained most of their GSH throughout the entire 3 h. Cytoplasmic vacuolization was apparent in some of the Cells at 2 h but not visible in any Cells at 3 h. We conclude that (1) loss of intraCellular GSH is an early event that precedes initial signs of Cellular damage in Clara Cell cytotoxicity; (2) this pattern of loss in relation to early injury is found both in highly susceptible and minimally susceptible airway sites; (3) there is wide Cell-to-Cell heterogeneity in the response; (4) the heterogeneity in the response profile varies between populations in highly susceptible and minimally susceptible sites; and (5) once the intraCellular GSH concentration within the entire Cell population drops below a certain threshold, the initial phase of injury becomes irreversible.

Robert Lauwerys - One of the best experts on this subject based on the ideXlab platform.

  • potential role of Clara Cell protein an endogenous phospholipase a2 inhibitor in acute lung injury
    European Respiratory Journal, 1995
    Co-Authors: Philippe G Jorens, N J Goulding, A G Herman, Wout De Backer, L Bossaert, Frans J. Van Overveld, Yves Sibille, Robert Lauwerys, Roderick J. Flower, Alfred Bernard
    Abstract:

    It is now recognized that epithelial Cells lining airways and alveoli are capable of releasing various mediators, which have the potential to modulate local inflammatory reactions. The amount of the 16 kDa Clara Cell protein (CC16), an inhibitor of phospholipase A2 activity produced by pulmonary epithelial Cells, was measured by means of a sensitive immunoassay in the unconcentrated bronchoalveolar lavage fluid (BALF) of 13 control subjects, and in patients with acute lung injury (14 with the full-blown adult respiratory distress syndrome (ARDS); 21 after standard cardiopulmonary bypass surgery, a known risk factor for ARDS). The level of CC16 was compared with other markers of inflammation with a wide range of molecular weights: albumin (nephelometry); total protein (spectrophotometry); beta 2-microglobulin (latex immunoassay); cystatin C (latex immunoassay); alpha 1-antitrypsin (immunoradiometry), and lipocortin-1 (enzyme-linked immunosorbent assay (ELISA)). The Clara Cell protein (CC16) was detectable in all BALF, and significantly higher levels of this protein were observed in BALF from patients with acute lung injury. Changes in BALF Clara Cell protein levels differed from those of alpha 2-macroglobulin and the natural phospholipase inhibitor lipocortin-1. Alpha 2-macroglobulin levels were not significantly enhanced in patients at risk for ARDS, but were increased in patients with ARDS; whereas, lipocortin 1 levels were not elevated in either group. Pretreatment of patients at risk for ARDS with high dose methylprednisolone did not alter the amount of Clara Cell protein recovered in BALF. The mean CC16 level in BALF from patients with ARDS who died was significantly lower than from those who survived. The data presented in this study suggest that pulmonary epithelial Cells secrete a natural anti-inflammatory protein during acute lung injury, which might have a protective and immunosuppressive role.

  • early decrease of serum Clara Cell protein in silica exposed workers
    European Respiratory Journal, 1994
    Co-Authors: Alfred Bernard, J M Gonzalezlorenzo, E Siles, G Trujillano, Robert Lauwerys
    Abstract:

    Clara Cell protein (CC16) is a 16 kDa protein secreted by nonciliated Cells of the tracheobronchial tree; it has recently been proposed as a peripheral marker of respiratory epithelial injury. The concentration of CC16 was measured in the serum and, when available, in the sputum of 86 miners exposed to silica and of 86 control subjects matched for age, body mass index and smoking status (26 lifelong nonsmokers and 60 current smokers in both groups). Workers were exposed to silica-rich dust in a quarry for 15.2 months on average. No difference between exposed and control workers could be detected with regard to respiratory symptoms, chest radiographs or lung function tests. By contrast, the concentration of CC16 in serum was decreased in silica-exposed workers (geometric mean 12.3 micrograms.l-1) compared to controls (16.3 micrograms.l-1). The decrease was found both in lifelong nonsmokers (14.7 vs 21.9) and current smokers (11.3 vs 14.5). In the latter, tobacco smoking caused a decrease of serum CC16 that was additional to that associated with silica exposure. The determination of CC16 in sputum samples, judged to be reliable on the basis of the CC16/alpha-amylase concentration ratio (mostly from smokers), also revealed a reduction of CC16 following silica exposure (46.2 vs 106 mg.l-1). We conclude that alterations in the serum concentrations of CC16 probably reflect very early toxic effects of silica particles on the respiratory epithelium. This reinforces the view that serum CC16 is a sensitive marker, which might improve our ability to detect exposure to chemicals potentially harmful to the respiratory tract.

  • serum Clara Cell protein an indicator of bronchial Cell dysfunction caused by tobacco smoking
    Environmental Research, 1994
    Co-Authors: Alfred Bernard, Harry Roels, Jeanpierre Buchet, Robert Lauwerys
    Abstract:

    Clara Cell protein (CC16) is a 16-kDa protein secreted by Clara Cells and other nonciliated Cells of both the bronchiolar and bronchial epithelium. CC16 is present in high concentrations in the respiratory tract secretions but occurs also in other fluids such as serum. In this study, CC16 has been measured in the sera from 65 female and 69 male current smokers and in a sex- and age-matched control group of 135 neversmokers. Lifetime smoking averaged (geometric mean) 12.7 (range, 0.6 to 61.3) and 17.9 (range, 0.8 to 126) pack-years in female and male smokers, respectively. A significant reduction of Clara Cell protein was found in the sera of smokers of both sexes. In neversmokers serum CC16 was independent of sex but significantly increased with age. In current smokers serum CC16 was also negatively correlated with both the current and lifetime cigarette consumption and with the 24-h urinary excretion of thiocyanate. After adjustment for age, a linear dose-response relation was apparent between smoking history and serum CC16, the latter decreasing on average by about 15% for each 10 pack-year smoking history. The present study supports the concept that CC16 in serum is a marker of bronchial dysfunction caused by tobacco smoke. As CC16 appears to be a natural immunosuppressor of the respiratory tract, its decreased production might explain some inflammatory changes associated with smoking.

  • Clara Cell protein in serum and bronchoalveolar lavage
    European Respiratory Journal, 1992
    Co-Authors: Alfred Bernard, Robert Lauwerys, F X Marchandise, Suzanne Depelchin, Yves Sibille
    Abstract:

    The 10 kDa Clara Cell protein was measured in serum and bronchoalveolar lavage (BAL) from 39 healthy subjects (14 smokers, 25 nonsmokers) and from 41 patients with respiratory disease (chronic obstructive pulmonary disease (COPD), sarcoidosis, lung cancer). Clara Cell protein appears as one of the most abundant respiratory tract derived proteins, with values averaging 7% of the total protein content of lung lavages from healthy nonsmokers. A significant reduction of Clara Cell protein was found in BAL from smokers and patients with COPD or lung cancer. The same pattern of change was found in the concentrations of Clara Cell protein in serum. Pulmonary sarcoidosis did not affect absolute values of Clara Cell protein in lung lavages but was associated with elevated levels in serum. Changes in lung lavage Clara Cell protein differed from that of albumin, beta 2-microglobulin or the secretory component, since the latter were unaffected by smoking or COPD but increased in sarcoidosis and lung cancer. These results indicate that Clara Cell protein in BAL or serum might serve as a sensitive indicator of nonciliated bronchial Cell dysfunction.

  • human urinary protein 1 evidence for identity with the Clara Cell protein and occurrence in respiratory tract and urogenital secretions
    Clinica Chimica Acta, 1992
    Co-Authors: Alfred Bernard, Robert Lauwerys, Harry Roels, Raphael Witters, Constant Gielens, A Soumillion, Julie Van Damme
    Abstract:

    Protein 1 (P1), a low mol mass urinary protein of unknown function, has been purified, sequenced and quantified in human biological fluids. The molecular size, subunit composition and partial amino acid sequence of P1 are similar to those of the 10 kDa Clara Cell protein (CC10), a lung secretory protein. P1 is found in high concentrations in sputum, bronchoalveolar lavages, urine and semen of healthy individuals and in urine of some pregnant women. Contrary to what is claimed, P1 or CC10 is not a specific and unique product of the lung, but like its homologue in rabbits (uteroglobulin) it is also present in urogenital secretions. P1 or CC10 may act as a natural immunosuppressor protecting the respiratory and urogenital tracts from unwanted inflammatory reactions.

Cedric Hermans - One of the best experts on this subject based on the ideXlab platform.

  • Clara Cell secretory protein cc16 features as a peripheral lung biomarker
    Annals of the New York Academy of Sciences, 2006
    Co-Authors: F Broeckaert, Bernard Knoops, Cedric Hermans, Andre Clippe, Alfred Bernard
    Abstract:

    Clara Cell protein (CC16 or CC10) is a 15.8-kDa protein secreted all along the tracheobronchial tree and especially in the terminal bronchioles where Clara Cells are localized. Even though the exact in vivo function of CC16 remains to be clarified, evidence is accumulating that CC16 plays an important protective role in the respiratory tract against oxidative stress and inflammatory response. CC16, however, presents also a major interest as a peripheral lung marker for assessing the Cellular integrity or the permeability of the lung epithelium. The serum concentrations of CC16 are decreased in subjects with chronic lung damage caused by tobacco smoke and other air pollutants as a consequence of the destruction of Clara Cells. By contrast, serum CC16 increases in acute or chronic lung disorders characterized by an increased airways permeability. The sensitivity of serum CC16 to an increased leakiness of the lung allows for the detection of defects of the epithelial barrier at ozone levels below current air-quality guidelines. Although the clinical significance of these early epithelial changes detected by serum CC16 remains to be determined, these results clearly show that the assay in serum of lung secretory proteins such as CC16 represents a new noninvasive approach to evaluate the integrity of the respiratory tract.

  • serum Clara Cell protein a sensitive biomarker of increased lung epithelium permeability caused by ambient ozone
    Environmental Health Perspectives, 2000
    Co-Authors: F Broeckaert, Cedric Hermans, K Arsalane, Enrico Bergamaschi, Angelita Brustolin, A Mutti, Alfred Bernard
    Abstract:

    Ozone in ambient air may cause various effects on human health, including decreased lung function, asthma exacerbation, and even premature mortality. These effects have been evidenced using various clinical indicators that, although sensitive, do not specifically evaluate the O(3)-increased lung epithelium permeability. In the present study, we assessed the acute effects of ambient O(3) on the pulmonary epithelium by a new approach relying on the assay in serum of the lung-specific Clara Cell protein (CC16 or CC10). We applied this test to cyclists who exercised for 2 hr during episodes of photochemical smog and found that O(3) induces an early leakage of lung Clara Cell protein. The protein levels increased significantly into the serum from exposure levels as low as 0.060-0.084 ppm. Our findings, confirmed in mice exposed to the current U.S. National Ambient Air Quality Standards for O(3) (0.08 ppm for 8 hr) indicate that above the present natural background levels, there is almost no safety margin for the effects of ambient O(3) on airway permeability. The assay of CC16 in the serum represents a new sensitive noninvasive test allowing the detection of early effects of ambient O(3) on the lung epithelial barrier.

  • Clara Cell protein as a marker of Clara Cell damage and bronchoalveolar blood barrier permeability
    European Respiratory Journal, 1999
    Co-Authors: Cedric Hermans, Bernard Knoops, Murielle Wiedig, K Arsalane, Gerard Toubeau, Paul Falmagne, Alfred Bernard
    Abstract:

    The 16 kDa Clara Cell protein (CC16), an abundant component of airway secretions, has recently been proposed in humans as a pulmonary marker measurable not only in bronchoalveolar lavage fluid (BALF) but also in serum. The aim of the present study was to investigate the changes and determinants of CC16 concentrations in these fluids in normal rats and rats with lung injury. Female Sprague-Dawley rats were given a single i.p. injection of arachis oil (n=20) or chemicals in arachis oil (n=10) that mainly damage Clara Cells (4-ipomeanol (IPO) 8 mg x kg(-1) and methylcyclopentadienyl manganese tricarbonyl (MMT) 5 mg x kg(-1)) or endothelial Cells (alpha-naphthylthiourea (ANTU) 5 mg x kg(-1)). CC16 concentration (mean+/-sD in microg x L(-1)), measured by a sensitive latex immunoassay, was significantly reduced in BALF of all treated groups (IPO 380+/-100; MMT 730+/-200; ANTU 1,070+/-200; controls 1,700+/-470). The same pattern of decrease was observed in the labelling of Clara Cells with an anti-CC16 antiserum as well as in the CC16 messenger ribonucleic acid levels assessed by Northern enzyme-linked immunosorbent assay. In serum, by contrast, CC16 was significantly increased in all treated groups (IPO 31+/-7; MMT 22+/-12; ANTU 52+/-24; controls 15+/-6). This rise of CC16 in serum was associated with an elevation of albumin in BALF which is an index of increased bronchoalveolar/blood barrier permeability. In conclusion, lung injury induces a decrease of the 16 kDa Clara Cell protein in bronchoalveolar lavage fluid owing to a reduced production by damaged Clara Cells, and an increase in serum protein levels resulting from its enhanced leakage across the bronchoalveolar/blood barrier. This study provides new insights into the understanding of the changes of lung secretory proteins in bronchoalveolar lavage fluid and serum.

  • determinants of Clara Cell protein cc16 concentration in serum a reassessment with two different immunoassays
    Clinica Chimica Acta, 1998
    Co-Authors: Cedric Hermans, Brittinger Nyberg, Christer Peterson, Alfred Bernard
    Abstract:

    Clara Cell protein (CC16) is a 16 kiloDalton protein secreted by Clara Cells in the lining fluid of bronchiolar and bronchial epithelium. Recently, Nomori et al., using a nephelometric latex immunoassay, reported a strong correlation between serum CC16 (sCC16) and serum lipids as well as the body mass index (BMI) [Nomori H, Horio H, Takagi M Kobayashi Y, Hirabayashi Y. Clara Cell protein correlation with hyperlipidemia. Chest 1996;110:680-4]. The same authors found higher values of sCC16 in males compared to females and did not detect any significant influence of tobacco smoking. Since these results are in disagreement with previous observations showing consistently a decrease of sCC16 in smokers and no influence of sex, we have reassessed in healthy subjects the determinants of sCC16 using two different assays: a particle counting-based latex immunoassay (LIA) using polyclonal antibodies and a fluorescence enzyme immunoassay (FEIA) using monoclonal antibodies. sCC16 was determined in a group of 52 female and 44 male healthy subjects (age 18 to 66 years), including 35 smokers and 61 nonsmokers. sCC16 measured by LIA and FEIA were well correlated (r = 0.92, n = 96, P < 0.0001) with values (geometric mean and range) of 13.3 (5.2-34.5) and 14.7 (4.1-53.1) microg/l, respectively. The determinants of sCC16 measured by both techniques were traced by stepwise regression analysis using as independent variables age, sex, smoking status, BMI or serum lipids (total cholesterol and triglycerides) and the glomerular filtration rate (GFR) estimated on the basis of serum creatinine or beta2-microglobulin. Only two significant determinants emerged: tobacco smoking which correlated negatively and the GFR which correlated positively with sCC16. No influence of serum lipids, BMI, age and sex on sCC16 was detected. We think that an analytical interference with serum lipids explains the results by Nomori et al. which are not confirmed here by two independent techniques and are inconsistent with the current understanding of the physiopathology of the Clara Cell and its main secretory product, CC16.

  • quantification of Clara Cell protein in rat and mouse biological fluids using a sensitive immunoassay
    European Respiratory Journal, 1998
    Co-Authors: T Halatek, Cedric Hermans, Murielle Wiedig, Gerard Toubeau, Paul Falmagne, F Broeckaert, Ruddy Wattiez, Alfred Bernard
    Abstract:

    Clara Cell protein is a 16-17 kDa protein (CC16) secreted by Clara Cells in the bronchiolar lining fluid of the lung. In order to investigate the potential of this protein as a pulmonary marker in animals, CC16 was isolated from rat bronchoalveolar lavage fluid (BALF) and a sensitive latex immunoassay applicable to both rat and mouse CC16 was developed. The pattern of CC16 concentrations in rat biological fluids determined by the immunoassay was consistent with the hypothesis of a passive diffusion of the protein across the bronchoalveolar/blood barriers showing a difference of more than 5,000 fold between the concentration in the epithelial lining fluid (mean, 140 mg x L(-1)) and that in serum (20 microg x L(-1)) or urine (3 microg x L(-1)). In BALF, the CC16 concentration averaged 5,500 microg x L(-1) and was of the same magnitude as that determined on lung and trachea homogenates. CC16 was also detectable in amniotic fluid with a mean value of 800 microg x L(-1) before delivery. Damage of Clara Cells produced by methylcyclopentadienyl manganese tricarbonyl resulted in a significant decrease of CC16 in BALF but did not affect the serum levels of the protein. The nephrotoxicant sodium chromate by contrast had no influence on the CC16 content of BALF but markedly increased CC16 levels in both serum and urine as a result of impaired glomerular filtration and tubular reabsorption, respectively. In conclusion, mouse or rat Clara Cell protein of 16-17 kDa can easily be quantified, not only in bronchoalveolar lavage fluid, but also in extrapulmonary fluids such as serum or urine. Thus, in rodents, Clara Cell protein of 16-17 kDa follows the same metabolic pathway as in humans, diffusing from the respiratory tract into serum where it is eliminated by the kidneys. This serum Clara Cell protein of 16-17 kDa may be useful as a peripheral marker of events taking place in the respiratory tract.