Lung epithelial damage at low concentrations of ambient ozone.
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Adult↗
Biomedical subjects
C Hermans
Publications and source records attributed to C Hermans.
Human bronchoalveolar lavage fluid: two-dimensional gel electrophoresis, amino acid microsequencing and identification of major proteins.
Although bronchoalveolar lavage has been used as a research and clinical tools for more than two decades to investigate the cellular and soluble components of the lower respiratory tract, its exact protein composition has never been established. In this context, proteins of human bronchoalveolar lavage fluids (BALF), obtained by washing the epithelial lining fluid of the lungs with phosphate-buffered saline, were analyzed by two-dimensional electrophoresis (2-DE) under denaturing and reducing conditions. To characterize the widest amount of proteins, an analytical map of human bronchoalveolar lavage fluid proteins has been created from a pool of BALF from various patients. The resulting map comprises 211 silver-stained spots in the range of pI 3.5-10 and molecular mass 5-100 kDa. We identified 182 spots by microsequence analysis and by matching with human blood plasma and the Macrophage Like Cell line reference 2-DE maps available from the SWISS-2DPAGE database. The human bronchoalveolar lavage fluid was found to contain 61 different proteins or isoforms thereof. Most of the proteins had low molecular masses (< 35 kDa) and rather acidic isoelectric points (pI; 4 < pI < 7). The proteins in the lavage either are produced locally or originate from plasma. Two unknown proteins were identified and are currently under investigation.
Adult↗
Fourier Transform Spectroscopy of the O(2) Herzberg Bands.
The absorption spectra of the O(2) Herzberg band systems (A(3)Sigma(+)(u)-X(3)Sigma(-)(g), c(1)Sigma(-)(u)-X(3)Sigma(-)(g), and A' (3)Delta(u)-X(3)Sigma(-)(g)) lying in the wavelength region 240-300 nm were reinvestigated. The coupling of a long absorption cell and a high-resolution Fourier transform spectrometer has allowed the observation of numerous weak lines which were not reported previously. From the rotational analysis of the line positions, determined with an accuracy of 0.005 cm(-1), the molecular constants of the A(3)Sigma(+)(u), v = 0-12, c(1)Sigma(-)(u), v = 2-19, and A' (3)Delta(u), v = 2-12 levels are improved significantly. The interaction between the A and c states is described quantitatively. A new interpretation of the perturbations observed in the energy region close to the dissociation limit is given which involves a weakly bound (3)Pi(u) state as the most probable perturbing state. Copyright 1999 Academic Press.
Journal Article↗
Benign monoclonal gammopathy turning to AL amyloidosis after kidney transplantation.
The fate of preexisting benign monoclonal gammopathy after organ transplantation is largely unknown. We report the case of a 47-year-old male kidney graft recipient with a pretransplantation IgG kappa monoclonal gammopathy who developed, 10 years after transplantation, de novo augloid light chain (AL) amyloidosis involving skin and kidney graft. The potential role of heavy immunosuppressive treatment in the development of this complication is discussed. The possible occurrence of AL amyloidosis should be kept in mind when a patient with benign monoclonal gammopathy is evaluated for organ transplantation, as well as when a transplanted patient with pre-existing monoclonal gammopathy develops new onset of proteinuria.
Amyloidosis↗
Temozolomide in adult patients with advanced soft tissue sarcoma: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group.
Temozolomide, an oral imidazotetrazine derivative, was given to 31 patients with advanced soft tissue sarcoma. The dose of 750 mg/m2 was divided over 5 consecutive days, and escalated to 1000 mg/m2 over 5 days at cycle 2 if myelosuppression no worse than common toxicity criteria grade 2 was noted in the first 28-day cycle. A total of 99 treatment cycles were given to 31 patients. The drug was well tolerated, with nausea and vomiting as the most common side-effects. Only one partial tumour response was documented, giving a response rate of 3.33%, 95% confidence interval, (CI) 0.1-17.2%. The median time to progression was 8 weeks and the median survival was 27 weeks. These results indicate that temozolomide in this schedule is not active as second-line treatment in advanced soft tissue sarcoma.
Adult↗
Clara cell protein as a marker of Clara cell damage and bronchoalveolar blood barrier permeability.
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.
Animals↗
Phase II study of raltitrexed ('Tomudex') for patients with advanced soft tissue sarcomas refractory to doxorubicin-containing regimens.
Advanced soft tissue sarcomas (ASTS) refractory to therapy with doxorubicin and/or ifosfamide are highly resistant to therapy with other cytotoxic agents. The efficacy and safety of raltitrexed ('Tomudex') was assessed in patients with ASTS refractory to one or two doxorubicin- and/or ifosfamide-containing regimens in eight centers of the EORTC STBSG group. Raltitrexed was given at 3 mg/m2 as a 15 min i.v. infusion once every 3 weeks. Among the 23 patients [mean age 54 (range 25-73) years] included, 22 patients (15 males and seven females) were eligible and evaluable for response to therapy and 21 were evaluable for toxicity. Patients had previously received chemotherapy in metastatic phase (n=16), as adjuvant treatment (n=5) or both (n=1). The primary tumor was located in the trunk (n=11), in the limbs (n=8) or in the head and neck (n=3). Most patients (n=13) received two courses of raltitrexed (range 1-8). The best response was stable disease in five (23%) patients, while disease progression was noted in 17 patients (77%); the median time to disease progression was 6 weeks. The treatment was well tolerated with only one patient experiencing grade 4 neutropenia and thrombocytopenia, one patient experiencing grade 3 nausea, one lethargy, one headache, and one asthenia. Only one patient experienced febrile neutropenia. Raltitrexed as monotherapy is not an effective treatment for patients with ASTS who failed conventional chemotherapy with doxorubicin and ifosfamide.
Adult↗
Lung epithelium-specific proteins: characteristics and potential applications as markers.
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Adult↗
Determinants of Clara cell protein (CC16) concentration in serum: a reassessment with two different immunoassays.
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.
Adolescent↗
Clara cell protein (CC16) in pleural fluids: a marker of leakage through the visceral pleura.
Pleural fluid (PF) proteins either derive from serum by diffusion or are locally secreted within the pleural space. Another hypothetical origin is a leakage of lung secretory proteins across the visceral pleura. To test this hypothesis, we investigated the occurrence, sources, and determinants in PF of CC16, a small-size and readily diffusible protein of 16 kDa secreted by bronchiolar Clara cells. CC16 concentration was determined by a sensitive latex immunoassay in serum and PF of 117 subjects (86 exudates and 31 transudates) and, for purpose of comparison, in ascites samples from another group of 38 subjects (7 exudates and 31 transudates). CC16 was also studied in serum and PF of normal rats and in rats with pleural exudate induced by alpha-naphthyl-thiourea (ANTU). The levels of CC16 in PF and ascites were highly correlated with that in serum, suggesting a diffusional exchange across the pleural/blood and peritoneal/blood barriers. Whereas CC16 occurs at similar levels in ascites and serum, the protein was found to be more concentrated in PF than in serum in both humans (geometric mean in microg/L, 26.2 versus 14.6, p < 0.0001) and rats (213 versus 16.2, p < 0.001). A local synthesis of CC16 appeared unlikely in view of the lack of CC16-immunostaining in pleura of both species. The only plausible explanation for these findings is that CC16 in PF originates from two sources: diffusion from plasma and a leakage from the lung into the pleural space across the semipermeable visceral pleura. This interpretation is supported by a markedly increased leakage of CC16 in experimental exudates induced by ANTU and the finding of high CC16 concentrations in human transudates associated with congestive heart failure, two conditions wherein PF has been shown to arise from the interstitial spaces of the lung.
Aged↗
Clearance of Clara cell secretory protein 16 (CC16) and surfactant proteins A and B from blood in acute respiratory failure.
Surfactant proteins A and B (SP-A and SP-B) enter the circulation in a manner that acutely reflects changes in pulmonary function in patients with acute respiratory failure (ARF). There is a small but significant gradient in SP-A and SP-B from arterial to mixed venous (A-V) blood, and since we have detected both proteins in urine, the kidney may be a major site of their systemic clearance. Clara cell secretory protein 16 (CC16), which leaks from the respiratory tract, is known to be freely eliminated by the kidney. Lung plasma protein levels will depend on the rates of both protein entry into and clearance from plasma. In order to study the limiting variable determining these levels, we compared plasma CC16, SP-A, and SP-B in matching A-V blood samples from 37 ARF patients with indices of lung dysfunction and glomerular filtration rate (GFR) (of plasma cystatin C and creatinine). Cystatin C, CC16, SP-A, and SP-B were reduced in mixed venous plasma (all p < 0.001) and their A-V gradients were directly related to their arterial levels (all p < 0.03). Whereas CC16, SP-A, and SP-B reflected blood oxygenation (all p < 0.05), only SP-A and SP-B were related to lung injury score (LIS) (both p < 0.05). In contrast, whereas the clearances of both CC16 and cystatin C were related to that of creatinine (p < 0.02 for both), the clearances of SP-A and SP-B were not. Our study confirms that all three lung proteins are acutely cleared from the circulation of patients with ARF (half-lives < 18 min), and we conclude that whereas the plasma concentration of CC16 depends on GFR, plasma concentrations of SP-A and SP-B reflect lung function independently of this variable.
Acute Disease↗
Pneumoproteinaemia: a new perspective in the assessment of lung disorders.
Here we make the hypothesis that the determination of the concentration of lung specific secretory proteins in serum or pneumoproteinaemia could be used in the evaluation of lung disorders with a similar utility as proteinuria in kidney diseases involving the glomeruli. Human and experimental data indicate that comparable structural and functional features govern the passage of proteins across the lung epithelium/blood barrier and the glomerular filter. The concentrations in serum of some lung-specific secretory proteins, such as the bronchiolar Clara cell 16 kDa protein (CC16) and alveolar surfactant-associated proteins A and B (SP-A and SP-B, respectively), might be used to assess the integrity of the bronchoalveolar/blood barrier known to be disrupted in many lung disorders. In addition, if this barrier is intact or slightly compromised, these proteins might serve as peripheral markers to detect changes in secretory epithelial cells in the lung.
Biomarkers↗
Quantification of Clara cell protein in rat and mouse biological fluids using a sensitive immunoassay.
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.
Animals↗
Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). The TSC1 gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase TSC1 transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein of unknown function. Thirty-two distinct mutations were identified in TSC1, 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin acts as a tumor suppressor.
Amino Acid Sequence↗
Biomonitoring of early effects on the kidney or the lung.
Biomarkers of toxicity are usually altered before the onset of functional changes or clinical manifestations. Peripheral biomarkers of toxicity present an additional advantage in that they can be applied on easily accessible biological materials (blood or urine). They represent useful tools that can be used for identifying subjects or groups at risk in the industry or environment, or for establishing acceptable exposure levels. In the case of the kidney, for instance, a relatively large battery of peripheral markers has been developed during the last decade. These markers are either constituents of the renal parenchyma whose urinary excretion can signal lesions or an abnormal secretion, or plasma proteins reflecting the integrity of nephron structures involved in their selective filtration or reabsorption. The epidemiological application of these tests has revealed that widespread occupational or environmental pollutants such as lead, cadmium, crystalline silica or perchloroethylene may cause very early effects on different segments of the nephron. In the case of the lung, we have recently identified a lung toxicity biomarker applicable not only on bronchoalveolar lavage fluid but also or sputum provided some precautions are taken. This biomarker called Clara cell protein (CC16) is a kDa protein secreted in the respiratory tract by the non-ciliated Clara cells known for their vulnerability to toxic insult. Studies on occupationally exposed workers and experimental animals indicate that the assay of CC16 in serum is a sensitive and a relatively specific test to detect early acute or chronic effects of toxicants on the tracheobronchial tree. The ultimate goal, however, is the development and validation of biomarkers that have a sufficient toxicological relevance to be used for health risk assessment. It is thus of premier importance to establish in health significance of early biomarkers of toxicity by determining to what extent they reflect critical steps in, and are predictive of the development of a chronic and irreversible disease.
Biomarkers↗
A 1.7-megabase sequence-ready cosmid contig covering the TSC1 candidate region in 9q34.
The disease gene TSC1 has been genetically mapped to human chromosome region 9q34, in a 4-cM interval between the markers D9S149 and D9S114. Within this interval there is conflicting genetic evidence as to the finer localization of the gene. We have used finger-printing methods and hybridization to produce a 1.7-Mb overlapping clone map covering the TSC1 candidate region, with a single gap of 20 kb. We have localized 12 previously cloned genes and 17 genetic markers on this map and have confirmed the order of the genetic map. This deep set of overlapping clones is now ready to be used for candidate gene isolation, for transcription studies, or for sequencing.
Chromosome Mapping↗
Sporadic case of listeriosis associated with the consumption of a Listeria monocytogenes-contaminated 'Camembert' cheese.
Listeria monocytogenes is an intracellular gram-positive organism responsible for severe infections in both humans and animals. Whereas the food-borne transmission of listeriosis was demonstrated in several outbreaks, most cases of listeriosis occur sporadically and are rarely linked with consumption of contaminated foods. In this paper a case of septicaemia with L. monocytogenes in a 73-year-old immunocompromised man is described. Evidence for the association of this case of listeriosis with the consumption of a contaminated 'Camembert' cheese is provided by serotyping, esterase typing, DNA macrorestriction patterns analysis and level of virulence of the isolated strains for mice.
Aged↗
Transient increase of serum Clara cell protein (CC16) after exposure to smoke.
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.
Adult↗