The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

 

Johns Hopkins School of Public Health

Research Grants 1983-1984

Detection of Potential Inflammatory Agents

Sharon S. Krag, PhD
The Johns Hopkins School of Public Health, Baltimore, Maryland

Problem

Drugs and other chemical agents may interact with certain skin cells, specifically fibroblasts, to cause tissue damage and inflammation by triggering the release of degradative enzymes contained within the cell.

Normally, fibroblasts secrete structural components of the skin. These cells also synthesize enzymes to degrade those same components. Most degradative enzymes are packaged inside the cell in a membrane-bound particle called a lysosome. However, chemical agents may alter the fibroblast and increase the levels of these enzymes outside the cell, causing damage and inflammation.

This study will accomplish two goals. It will examine changes in the lysosome structure that may result from treatment of fibroblasts with drugs, or from mutations within the cell. It would define changes inside the cell that lead to disruption of the typical ratio of packaged to secreted enzyme, or can alter the membrane of the lysosome. Ultimately, the study would determine which cellular processes must remain unaltered to ensure that the potentially destructive enzymes within the lysosomal membranes remain intact. The study also will further develop a rapid and easy test to monitor a drug's (or other chemical agent's) ability to alter distribution of the destructive enzymes. Currently, the test uses Chinese hamster ovary cells, which are cultured in vitro, and for which much is known about the synthesis and packaging of lysosomal enzymes.

Impact of the Research

It is hoped the in vitro test would be an inexpensive and accurate gauge of a drug's (or chemical's) potential for causing inflammation or tissue damage. This study may also identify ways of tailoring drugs to avoid alterations in fibroblasts and lysosome membranes that otherwise would lead to secretion of the destructive enzymes.