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Alfred Bernard - One of the best experts on this subject based on the ideXlab platform.
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urinary club Cell Protein 16 cc16 utility of its assay during acute bronchiolitis
Pediatric Pulmonology, 2020Co-Authors: C Egron, Emmanuelle Rochette, A Labbe, Aurelien Mulliez, Alfred Bernard, Amat FloreAbstract:: Acute bronchiolitis is responsible for high morbidity in infants. Club Cell Protein 16 kDa (CC16) is a major pneumoProtein secreted by club Cells of the bronchial epithelium and eliminated by the renal pathway. CC16 seems to be a biomarker of epithelial damage in asthma. However, its value as a marker of acute bronchiolitis severity and later recurrent wheezing are uncertain, especially the value of its urinary assay for this purpose. A prospective, observational, analytical study was conducted at Clermont-Ferrand University Hospital to correlate serum CC16 level with clinical severity of bronchiolitis in hospitalized infants aged less than 1 year. We analyzed correlations between serum and urinary CC16, CC16 levels and Wainwright score, immediate morbidity due to bronchiolitis, causal viruses, and recurrent wheezing 1 year after inclusion. In 166 infants, serum CC16 did not correlate with acute bronchiolitis severity (P = .49), but urinary CC16 did (P < .001). In multivariate analysis, urinary CC16 correlated mainly with urinary retinol binding Protein (RBP; r = 0.70; P < .001). The logCC16u/logRBPu ratio correlated significantly with severity (P = .02). CC16 levels were not correlated with recurrent wheezing at 1 year. Urinary CC16 could be a useful biomarker in acute bronchiolitis for specific indications. This noninvasive assay would be particularly useful in the young infant population. Several factors must be taken into account in its interpretation, mainly tubular function. Further studies are needed to assess these factors.
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cord blood clara Cell Protein cc16 predicts the development of bronchopulmonary dysplasia
European Journal of Pediatrics, 2008Co-Authors: Alexandra J J Schrama, H M Berger, Alfred Bernard, Ben J H M Poorthuis, Aeilko H. Zwinderman, Frans J WaltherAbstract: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.
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uteroglobin related Protein 1 and clara Cell Protein in induced sputum of patients with asthma and rhinitis
Chest, 2007Co-Authors: Claire De Burbure, Xavier Dumont, Antonio Mutti, Patrizia Pignatti, Massimo Corradi, Mario Malerba, Andre Clippe, G Moscato, Alfred BernardAbstract:Rationale: Uteroglobin-related Protein 1 (UGRP1) and Clara Cell Protein (CC16), members of the secretoglobin family, increasingly appear to play a role in airway inflammatory response. OBJECTIVE: To explore levels of UGRP1 and CC16 in induced sputum of patients with asthma and rhinitis. METHODS: Induced-sputum samples of patients with asthma or rhinitis (n = 32 each; atopic asthma, n = 24; atopic rhinitis, n = 20) and from 19 nonsmoking nonatopic control subjects were analyzed for cytology and levels of UGRP1, CC16, and albumin. Measurements and main results: Sputum UGRP1 increased in both asthma and rhinitis, most strikingly so in asthma, in which changes were most significant in atopic individuals. By contrast, sputum CC16 did not change significantly in either condition, although it was positively correlated with UGRP1 in patients and control subjects. Changes in sputum UGRP1 in atopic asthma were not linked to permeability changes reflected by increased albumin levels but correlated positively with sputum macrophages and negatively with eosinophils. The observed differences in UGRP1 and CC16 may be linked to different Cell populations being responsible for their secretion; UGRP1 is mainly secreted in larger conducting airways, whereas CC16 is mainly secreted by the nasal and peripheral airways epithelium. CONCLUSIONS: The increase in UGRP1 but not of CC16 in asthma and rhinitis suggests that UGRP1 may play a role in these inflammatory diseases.
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exploring the time dependence of serum clara Cell Protein as a biomarker of pulmonary injury in humans
Chest, 2006Co-Authors: Ragnberth Helleday, Gunnar F. Nordberg, Bertil Forsberg, Ian Mudway, Alfred Bernard, Bo Segerstedt, Anders BlombergAbstract:We have previously demonstrated Clara Cell Protein (CC16) [secretoglobin 1A1] in serum to be a highly sensitive biomarker of altered lung epithelial permeability after ozone challenge. As a previous experimental study has indicated a diurnal variation in serum CC16 in humans, the aims of the present investigation were to confirm this observation and to attempt to model the diurnal variation in CC16 concentrations. In 18 healthy nonsmoking subjects, peripheral blood samples were drawn at six sampling points over a 15-h period and repeated twice within 3 to 4 weeks. A clear within-day variation was revealed in serum CC16 concentrations, falling significantly from baseline levels between the 11:30 am and 10:00 pm time points (p = 0.000). Furthermore, it was shown that this within-day variation was reproducible regardless of subject or day, enabling the diurnal variation in serum CC16 to be modeled and fitted a second-degree polynomial for the observed time span. In conclusion, the present data demonstrate a pronounced time-dependent diurnal variation in serum levels of CC16, which can be mathematically compensated for, when addressing the issue of an air pollution-induced effect on CC16 in field studies.
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clara Cell Protein and surfactant Protein b in garbage collectors and in wastewater workers exposed to bioaerosols
International Archives of Occupational and Environmental Health, 2005Co-Authors: D Steiner, S Jeggli, Alois Tschopp, Anne Oppliger, Silvia Hilfiker, Alfred Bernard, Philipp HotzAbstract: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.
Robert Lauwerys - One of the best experts on this subject based on the ideXlab platform.
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potential role of clara Cell Protein an endogenous phospholipase a2 inhibitor in acute lung injury
European Respiratory Journal, 1995Co-Authors: Philippe G. Jorens, Wout De Backer, Frans J. Van Overveld, Yves Sibille, Robert Lauwerys, Roderick J. Flower, N. J. Goulding, Leo Bossaert, A. G. Herman, Alfred BernardAbstract: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.
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clara Cell Protein cc 16 induces a phospholipase a2 mediated inhibition of fibroblast migration in vitro
American Journal of Respiratory and Critical Care Medicine, 1995Co-Authors: Olivier Lesur, Robert Lauwerys, K Arsalane, Alfred Bernard, R Begin, Andre M Cantin, Denis LaneAbstract:Clara Cell Protein (CC-16, also designated CC-10) is synthesized by the bronchiolar epithelium and has been suggested as an inhibitor of phospholipase A(2) (PLA(2)) activity. Therefore, CC-16 is a candidate for controlling inflammatory events in the lung. Because CC-16 amounts and function may be altered in fibrosing lung diseases in which bronchiolar injury has been reported, it was measured in alveolar fluids and sera. Secretory PLA(2) activity in alveolar fluids and the influence of CC-16 on platelet-derived growth factor-induced human fibroblast chemotaxis and cytosolic PLA(2) activity were also explored. CC-16 content was decreased in alveolar fluids from idiopathic pulmonary fibrosis (IPF: 1.3 +/- 0.1 mg/L) and bleomycin lung (1.1 +/- 0.2 versus 2.1 +/- 0.2 mg/L in controls, p < 0.05), whereas there was a three- to ninefold increase in secretory PLA(2) activity (p < 0.05 versus controls). CC-16 inhibited fibroblast chemotaxis in a dose-dependent manner (90% inhibition at 30 mu g/ml CC-16). This inhibition was reversed by reducing CC-16. CC-16 was also able to lower fibroblastic cytosolic PLA(2) activity by 50% in vitro. In summary, CC-16 is able to inhibit fibroblast chemotaxis in vitro by mechanisms that may be related to a blockage of cytosolic PLA(2) activity. It can be postulated that CC-16 deficiency may contribute to fibroblast burden activity in fibrosing lung diseases.
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early decrease of serum clara Cell Protein in silica exposed workers
European Respiratory Journal, 1994Co-Authors: Alfred Bernard, Eduard Siles, J M Gonzalezlorenzo, G Trujillano, Robert LauwerysAbstract: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.
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serum clara Cell Protein an indicator of bronchial Cell dysfunction caused by tobacco smoking
Environmental Research, 1994Co-Authors: Alfred Bernard, Harry Roels, Jeanpierre Buchet, Robert LauwerysAbstract: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.
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clara Cell Protein in serum and bronchoalveolar lavage
European Respiratory Journal, 1992Co-Authors: Alfred Bernard, F X Marchandise, Robert Lauwerys, Suzanne Depelchin, Yves SibilleAbstract: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.
Michel L Tremblay - One of the best experts on this subject based on the ideXlab platform.
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t Cell Protein tyrosine phosphatase deficiency results in spontaneous synovitis and subchondral bone resorption in mice
Arthritis & Rheumatism, 2012Co-Authors: Karen M Doody, Stephanie Bussieresmarmen, Marilene Paquet, Janet E Henderson, Michel L TremblayAbstract:Objective T Cell Protein tyrosine phosphatase (TC-PTP) is an important regulator of hematopoiesis and cytokine signaling. Recently, several genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) in the locus of TC-PTP that are associated with rheumatoid arthritis and juvenile idiopathic arthritis, among other autoimmune diseases. The aim of this study was to evaluate the effect of TC-PTP deficiency on the bone and joint environment using a knockout mouse model. Methods Radiographic and micro–computed tomography analyses were performed on femurs of 3-week-old mice. In addition, the femorotibial joints were assessed by histology, flow cytometry, and cytokine detection. Results Deficiency of TC-PTP resulted in decreased bone volume as well as an increase in osteoclast density within the mouse femurs. In addition, synovitis, characterized by infiltration of mixed inflammatory Cell types and proinflammatory cytokines, developed in the knee joints of TC-PTP−/− mice. Conclusion These findings demonstrate that loss of TC-PTP expression results in synovitis with several hallmarks of inflammatory arthritis. The inflammatory environment observed in the knee joints of TC-PTP−/− mice differs from the systemic inflammation previously described in these mice and merits further research into the role of TC-PTP in the synovium. Furthermore, the results support recently described associations between SNPs in the TC-PTP locus and arthritis incidence.
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t Cell Protein tyrosine phosphatase attenuates t Cell signaling to maintain tolerance in mice
Journal of Clinical Investigation, 2011Co-Authors: Florian Wiede, Michel L Tremblay, Benjamin J Shields, Sock Hui Chew, Konstantinos Kyparissoudis, Catherine Julia Van Vliet, Sandra Galic, Sarah M Russell, Dale I Godfrey, Tony TiganisAbstract:Many autoimmune diseases exhibit familial aggregation, indicating that they have genetic determinants. Single nucleotide polymorphisms in PTPN2, which encodes T Cell Protein tyrosine phosphatase (TCPTP), have been linked with the development of several autoimmune diseases, including type 1 diabetes and Crohn's disease. In this study, we have identified TCPTP as a key negative regulator of TCR signaling, which might explain the association of PTPN2 SNPs with autoimmune disease. We found that TCPTP dephosphorylates and inactivates Src family kinases to regulate T Cell responses. Using T Cell-specific TCPTP-deficient mice, we established that TCPTP attenuates T Cell activation and proliferation in vitro and blunts antigen-induced responses in vivo. TCPTP deficiency lowered the in vivo threshold for TCR-dependent CD8(+) T Cell proliferation. Consistent with this, T Cell-specific TCPTP-deficient mice developed widespread inflammation and autoimmunity that was transferable to wild-type recipient mice by CD8(+) T Cells alone. This autoimmunity was associated with increased serum levels of proinflammatory cytokines and anti-nuclear antibodies, T Cell infiltrates in non-lymphoid tissues, and liver disease. These data indicate that TCPTP is a critical negative regulator of TCR signaling that sets the threshold for TCR-induced naive T Cell responses to prevent autoimmune and inflammatory disorders arising.
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t Cell Protein tyrosine phosphatase attenuates stat3 and insulin signaling in the liver to regulate gluconeogenesis
Diabetes, 2010Co-Authors: Atsushi Fukushima, Michel L Tremblay, Florian Wiede, Benjamin J Shields, Sandra Galic, Kim Loh, Barbara C Fam, Matthew J Watt, Sofianos Andrikopoulos, Tony TiganisAbstract:OBJECTIVE Insulin-induced phosphatidylinositol 3-kinase (PI3K)/Akt signaling and interleukin-6 (IL-6)-instigated JAK/STAT3-signaling pathways in the liver inhibit the expression of gluconeogenic genes to decrease hepatic glucose output. The insulin receptor (IR) and JAK1 tyrosine kinases and STAT3 can serve as direct substrates for the T-Cell Protein tyrosine phosphatase (TCPTP). Homozygous TCPTP-deficiency results in perinatal lethality prohibiting any informative assessment of TCPTP's role in glucose homeostasis. Here we have used Ptpn2 +/− mice to investigate TCPTP's function in glucose homeostasis. RESEARCH DESIGN AND METHODS We analyzed insulin sensitivity and gluconeogenesis in chow versus high-fat–fed (HFF) Ptpn2 +/− and Ptpn2 +/+ mice and insulin and IL-6 signaling and gluconeogenic gene expression in Ptpn2 +/− and Ptpn2 +/+ hepatocytes. RESULTS HFF Ptpn2 +/− mice exhibited lower fasted blood glucose and decreased hepatic glucose output as determined in hyperinsulinemic euglycemic clamps and by the decreased blood glucose levels in pyruvate tolerance tests. The reduced hepatic glucose output coincided with decreased expression of the gluconeogenic genes G6pc and Pck1 and enhanced hepatic STAT3 phosphorylation and PI3K/Akt signaling in the fasted state. Insulin-induced IR-β–subunit Y1162/Y1163 phosphorylation and PI3K/Akt signaling and IL-6–induced STAT3 phosphorylation were also enhanced in isolated Ptpn2 +/− hepatocytes. The increased insulin and IL-6 signaling resulted in enhanced suppression of G6pc and Pck1 mRNA. CONCLUSIONS Liver TCPTP antagonises both insulin and STAT3 signaling pathways to regulate gluconeogenic gene expression and hepatic glucose output.
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impaired bone marrow microenvironment and immune function in t Cell Protein tyrosine phosphatase deficient mice
Journal of Experimental Medicine, 1997Co-Authors: Kong E Youten, Eric S Muise, Annick Itie, Eva Michaliszyn, John Wagner, Serge Jothy, Wayne S Lapp, Michel L TremblayAbstract:The T Cell Protein tyrosine phosphatase (TC-PTP) is one of the most abundant mammalian tyrosine phosphatases in hematopoietic Cells; however, its role in hematopoietic Cell function remains unknown. In this report, we investigated the physiological function(s) of TC-PTP by generating TC-PTP–deficient mutant mice. The three genotypes (+/+, +/−, −/−) showed mendelian segregation at birth (1:2:1) demonstrating that the absence of TC-PTP was not lethal in utero, but all homozygous mutant mice died by 3–5 wk of age, displaying runting, splenomegaly, and lymphadenopathy. Homozygous mice exhibited specific defects in bone marrow (BM), B Cell lymphopoiesis, and erythropoiesis, as well as impaired T and B Cell functions. However, myeloid and macrophage development in the BM and T Cell development in the thymus were not significantly affected. BM transplantation experiments showed that hematopoietic failure in TC-PTP −/− animals was not due to a stem Cell defect, but rather to a stromal Cell deficiency. This study demonstrates that TC-PTP plays a significant role in both hematopoiesis and immune function.
Cedric Hermans - One of the best experts on this subject based on the ideXlab platform.
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serum clara Cell Protein a sensitive biomarker of increased lung epithelium permeability caused by ambient ozone
Environmental Health Perspectives, 2000Co-Authors: F Broeckaert, K Arsalane, Enrico Bergamaschi, Angelita Brustolin, Antonio Mutti, Cedric Hermans, Alfred BernardAbstract: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.
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clara Cell Protein as a marker of clara Cell damage and bronchoalveolar blood barrier permeability
European Respiratory Journal, 1999Co-Authors: Cedric Hermans, Murielle Wiedig, K Arsalane, Gerard Toubeau, Paul Falmagne, Bernard Knoops, Alfred BernardAbstract: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.
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determinants of clara Cell Protein cc16 concentration in serum a reassessment with two different immunoassays
Clinica Chimica Acta, 1998Co-Authors: Cedric Hermans, Brittinger Nyberg, Christer Peterson, Alfred BernardAbstract: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.
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quantification of clara Cell Protein in rat and mouse biological fluids using a sensitive immunoassay
European Respiratory Journal, 1998Co-Authors: Tadeusz Halatek, Murielle Wiedig, Gerard Toubeau, Paul Falmagne, F Broeckaert, Ruddy Wattiez, Cedric Hermans, Alfred BernardAbstract: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.
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transient increase of serum clara Cell Protein cc16 after exposure to smoke
Occupational and Environmental Medicine, 1997Co-Authors: Alfred Bernard, Cedric Hermans, G Van HouteAbstract:OBJECTIVES: Smoke inhalation is a well known cause of airways injury in firefighting personnel. The aim of this study was to evaluate whether toxic effects of smoke on the respiratory tract can be detected by measuring Clara Cell Protein (CC16), a recently described serum marker of lung function. METHODS: CC16 was measured by a sensitive latex immunoassay in the serum of six voluntary firefighters from a chemical plant who had inhaled smoke from the combustion of polypropylene for about 20 minutes. The Protein was measured immediately after the fire and 10 days later. The values were compared with those of six control workers examined simultaneously. RESULTS: The mean (SD) concentration of CC16 in the serum of firefighters after the fire (54.4 (34.9) micrograms/l) was significantly higher than that of controls (19.5 (11.7), P = 0.04). 10 days later, serum CC16 from firefighters had returned to the concentrations found in controls (15.9 (2.76) v 17.7 (12.5)). With the values at day 10 as a baseline, the rise of serum CC16 was estimated at 328% on average (range 100%-564%). These changes were found in the absence of any functional sign of lung impairment. CONCLUSION: Acute exposure to smoke results in a transient increase of CC16 in serum due most likely to an increased permeability of the bronchoalveolar/blood barrier. Serum CC16 seems potentially to be a new biomarker for the early detection of acute airways injury caused by smoke.
Philipp Hotz - One of the best experts on this subject based on the ideXlab platform.
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clara Cell Protein and surfactant Protein b in garbage collectors and in wastewater workers exposed to bioaerosols
International Archives of Occupational and Environmental Health, 2005Co-Authors: D Steiner, S Jeggli, Alois Tschopp, Anne Oppliger, Silvia Hilfiker, Alfred Bernard, Philipp HotzAbstract: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.