Studies performed in an in vitro model involving an immortalized line of human dermal microvascular endothelial cells suggest ATP (adenosine 5'-triphosphate) may be involved in the development of rosacea and other stress-associated cutaneous inflammatory diseases by inducing release of proinflammatory cytokines and chemokines and upregulation of ICAM-1.
New York - Researchers believe they may have identified a previously unknown mechanism for the development of inflammation in the skin, which is mediated through the actions of ATP (adenosine 5'-triphosphate) or other purinergic agonists on endothelial cells.
"If the initial findings are confirmed in ongoing investigations, they have important potential implications for the development of new therapies," says Richard D. Granstein, M.D., lead investigator and chairman, department of dermatology, Weill Medical College of Cornell University.
Familiar with its physiologic profile of activity and recognizing that ATP is a neurotransmitter released by sympathetic nerves, Dr. Granstein and colleagues wondered if ATP might play a role in the pathogenesis of rosacea.
"In addition, recognizing that the sympathetic nerves innervate cutaneous blood vessels, and that rosacea has both prominent vascular and inflammatory components, further suggested ATP as a likely candidate in the biochemical processes underlying that disease," Dr. Granstein tells Dermatology Times.
They conducted in vitro studies designed to explore the hypothesis that ATP might contribute to inflammation via an effect on vascular endothelial cells. Their experimental model used an immortalized line of transformed human dermal microvascular endothelial cells (HMEC-1), which feature most of the characteristics of vascular endothelial cells, and ATP-gamma-S, a more stable, structural analog of ATP that was considered to offer a good surrogate for initial experimentation.
When cultured with ATP-gamma-S, the endothelial cells produced a number of proinflammatory cytokines and chemokines, including interleukin-8 (IL-8), growth-regulated oncogene-alpha (GRO-alpha), monocyte chemotactic protein-1 (MCP-1), and IL-6. In addition, expression of ICAM-1, a surface receptor on the endothelial cells that binds leukocytes, was upregulated by exposure to ATP-gamma-S.
"IL-8 and GRO-alpha are chemoattractants for neutrophils, MCP-1 attracts the migration of monocytes and some types of lymphocytes, and IL-6 is a broad stimulator of immune responses. Therefore, we are speculating that ATP-induced stimulation of the release of these compounds by endothelial cells may attract inflammatory cells that could bind to the endothelial cells and then transmigrate into the interstitium to amplify inflammation," Dr. Granstein says.
Researchers are conducting further studies to establish this hypothesis, and have obtained some corroborating evidence from those investigations.
If they confirm that ATP contributes to the development of inflammation in the skin in rosacea and other disorders, the next step would be to identify substances for inhibiting that pathway, as they might represent new therapeutic modalities.
Indeed, in preliminary experiments, tetracycline, known to be useful in rosacea and some other inflammatory skin disorders, appears to inhibit these actions of ATP-gamma-S on HMEC-1 cells.
Disclosure: This research is being funded by the National Rosacea Society and Clinique Laboratories, LLC.