Validation of serum clara cell protein as a non invasive test of lung epithelium damage caused by ambient ozone
(2001)
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- Authors
- Supervisors
- Bernard, Alfred
- Abstract
- Clara cell protein (CC16) is an anti-inflammatory protein secreted in large amounts by the non-ciliated bronchiolar Clara cell. Recent studies have shown that CC16 is a promising biomarker measurable in serum, diffusing from the respiratory tract into the blood. CC16 presents a great sensitivity to lesions of the lung, the principal target organ of most air pollutants [Broeckaert et al, 1999a; Broeckaert et all, 2000a]. The use of CC16 as marker of acute lung injury was validated in rodents when exposed to ozone (O3) [Broeckaert et all, 2001, submitted; Arsalane et al, 1999] and lipopolysaccharides [Arsalane et al., 2000]. Its value as an effect marker for exposure to O3 in humans was clearly established by an experiment where cyclists were exposed for 2 hours to photochemical smog in episodes. Significant increases of CC16 concentrations were observed in serum after exposure to O3 levels as low as 60 to 84 ppb [Broeckaert et al., 1999,; Broeckaert et al., 2000b]. These findings were confirmed in mice exposed to the recently promulgated US EPA ambient air quality standard for O3 i.e. 80 ppb for 8 hours [Broeckaert et al., 2000b]. <BR> The relationships between serum CC16, hyperpermeability of the alveolar/blood barrier and O3 toxicity appear to be more complicated when the findings using O3-susceptible strains of mice are considered [Broeckaert et al., 2001, submitted]. In this study, we found that the susceptibility of five strains of mice to O3 was closely related to the hyperpermability of their alveolar/blood barrier, which can be assessed by measuring serum CC16. Hyperpermeability enhances the loss of CC16 and probably other proteins from the lung, which renders them more vulnerable to inflammatory agents. Particularly interesting was the lungs of a sensitive mouse strain to O3. The role of genetic polymorphism in the responsiveness of 03-induced injury in humans was demonstrated by the implication of different genes governing the detoxification of reactive oxygen species (ROS), including O3 [Bergamaschi et al., 2001, accepted]. We observed that subjects with NADPH:quinone oxidoreductase (NQO1wt/wt) and glutathione-S-transferase μ-1null (GSTM1nu) genotypes were mire sensitive to O3 than other subjects in terms of lung functional changes and increased serum CC16. people carrying the NQO1wt/wt genotype, but lacking GSTM1, are less able to conjugate hydroquinones, a condition which could favour their responsiveness to O3. The increased urinary excretion of 80H-dG, a marker of oxidative stress, provided in these subjects an indirect evidence of their sensitivity to ROS. <BR> In conclusion, the application of a new, non-invasice test to evaluate the effects of O3 on the permeability of the lung epithelial barrier shows that the pulmonary epithelium is much more sensitive to O3 than reported using classical methods. These results imply that current air quality standards are based on insufficiently sensitive health-related endpoints and are not stringent enough to adequately protect public health, and the most sensitive individuals in particular. The levels at which O3 elicits epithelial injury are close to the current background concentration of O3 which has increased over the past century by a factor of three as compared to pre-industrial times. Although the health significance of the 03-induced disruption of the epithelial barrier remains to be established, it can be assumed that repetitive exposures over several days or weeks can initiated the development of lung diseases, including asthma. In view of the similarity of CC16 metabolism and anti-inflammatory function between humans and rodents, our data in mice suggest that humans with a very permeable lung epithelium, such as new-borns and babies, are the most sensitive to ambient O3. Markers of lung epithelium integrity that can be measured in serum, such as CC16, represent new tools that undoubtedly will improve the assessment of health risks from air pollutants and the subsequent derivation of health-based air quality standards.
- Affiliations
Citations
Broeckaert, F. (2001). Validation of serum clara cell protein as a non invasive test of lung epithelium damage caused by ambient ozone. https://hdl.handle.net/2078.5/111102