Research Projects

Project at a Glance

Title: Effects of ozone on proteases and protease inhibitors of the human and rat lung

Principal Investigator / Author(s): Mautz, William

Contractor: UC Irvine

Contract Number: a033-175


Research Program Area: Health & Exposure

Topic Areas: Health Effects of Air Pollution, Vulnerable Populations


Abstract:

Animal studies have clearly shown that 03 have the potential to cause irreversible connective tissue alteration in the form of pulmonary fibrosis. However, it is not known if exposure of humans to ambient Southern California levels Of 03 in a chronic episodic pattern is likely to cause connective tissue damage. The objective of this project was to perform a detailed analysis of the biochemical events that are believed to precede connective tissue disruption, i.e. changes in connective tissue protease and protease inhibitors, in the lung lavage fluid of animals episodically exposed to moderate to low levels Of 03 over long periods of time. Similar measurements were made on the lung lavage fluid of humans following a single exposure to near ambient levels of 03. Since nitric acid (HN03) also has oxidant properties, the effect of HN03 exposure (alone and in combination with 03) on lung lavage fluid protease activity was also examined.

An important feature of this project is that the lung lavage fluid samples used in most of these studies were obtained from three other ARB-funded studies. The use of lavage fluid samples from other studies resulted in considerable savings of resources for this project and allowed the animal use of the previously funded studies to be maximized. The principal investigators generously agreed to supply surplus lung lavage fluid from both chronic animal and acute human exposures. In addition, a short-term exposure of rats was used to aid in extrapolation of the results from the acute human exposures to the chronic animal exposures. The 03 concentrations ranged from 0.15 - 0.40 PPM. An episodic exposure pattern consisting of four hours of exposure / day on three consecutive days per week was used for all the animal exposure studies. The duration of the episodic exposure studies ranged from 1-40 weeks. The specific endpoints that were examined and characterized in lung favage fluid were protein content, elastase-like activity, coliagenase activity, and neutrophil elastase inhibitory capacity. In addition, lung lavage fluid was also assayed for low molecular weight elastase inhibitors.

Acute, subacute, and chronic episodic exposure to 03 did not result in increased levels of free neutrophil elastase or coliagenase in lung lavage fluid even though acute 03 exposure was associated with increased numbers of neutrophils in the lavage fluid. In contrast, acute exposure of humans and rats to 03 resulted in substantial increases in the elastase inhibitory capacity of favage fluid. Although this result may seem to indicate that acute 03 exposure had a beneficial effect on the proteaselantiprotease balance, the increase in elastase inhibitory capacity was caused by increased lung permeability and serum transudation and thus is indicative of lung injury. Acute exposure of humans to 03 had no effect on the activity of the low molecular weight elastase inhibitors. Acute exposure studies in humans indicated that sequential exposure to HN03 followed by 03 did not enhance the 03-induced increases in lavage fluid protein or elastase inhibitory capacity.

Chronic and subchronic episodic exposure of laboratory animals to 03 had no effect on any of the parameters measured. These negative results may be due in part to the low concentration Of 03 and the relative insensitivity of animals exposed at rest (as opposed to humans exposed during exercise) to the effects Of 03 exposure. However, a concentration of 03 that was only slightly higher than that used in some of the chronic studies had striking effects on lavage fluid parameters during a short-term one-week exposure. Thus, it is likely that attenuation of sensitivity (adaptation response) occurred during the longer exposures despite the episodic nature of the exposure.


 

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