Serum clara cell protein: a sensitive biomarker of increased lung epithelium permeability caused by ambient ozone.

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.ImagesFigure 1Figure 2Figure 3

Clara cell protein as a biomarker for ozone-induced lung injury in humans

“…As CC16 is synthesised and secreted almost exclusively by the lung Clara cells, the enhanced serum concentration can only be explained by a leakage of the protein across the lung epithelial barrier [16,26]. This finding is in agreement with the enhanced serum levels of CC16 obtained from cyclists exposed to O 3 in the environment, as the main oxidant in summer photochemical smog [21,27]. Notably, no association was observed between the magnitude of the O 3 -induced lung function decrements and CC16 responses, suggesting that impaired lung function was not related to epithelial injury.…”

“…Support for this notion has been demonstrated in mice where O 3 -induced increases in serum CC16 are accompanied by neutrophil influx into the airways. In this study the authors also demonstrated an increased concentration in bronchoalveolar lavage fluid albumin [27]. In the present study, as in the field study of cyclists, no measurements of airway inflammation were performed.…”

“…Here, volunteers were exposed to a higher O 3 concentration 0.2 ppm versus 0.033-0.103 ppm [21,27]. Despite this quantitative difference, it is likely that the overall dose may have been much closer, due to the exercise level of the training cyclists.…”

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

“…Levels of CCSP in serum have been shown to rise after exposure to ozone (7,9,11), smoke (5), or LPS (2). The leading hypothesis is that there is increased leakage of CCSP from the airways into the blood when the epithelial layer is damaged.…”

“…The leading hypothesis is that there is increased leakage of CCSP from the airways into the blood when the epithelial layer is damaged. This has led many to consider serum CCSP as a new noninvasive biomarker of acute epithelial damage (7,9,10,15). To properly assess the potential clinical benefits of CCSP, it is necessary to understand the steady-state distribution of CCSP in the airway and in the various epithelial cell types.…”