Rosacea is a fairly common inflammatory skin condition that can prove challenging to treat. Current therapeutic strategies empirically target the signs and symptoms of the disease, because the details of its pathophysiology have not yet been completely understood.
San Diego - Rosacea is a fairly common inflammatory skin condition that can prove challenging to treat. Current therapeutic strategies empirically target the signs and symptoms of the disease, because the details of its pathophysiology have not yet been completely understood.
"Cathelicidins play an intricate role in the pathogenesis of rosacea," says Richard Gallo, M.D., Ph.D., professor of medicine and pediatrics, chief of the division of dermatology, University of California, San Diego, La Jolla, Calif. "Until now, many treatments such as antibiotics, azelaic acid and others were used with a 'hit-or-miss' approach, resulting in mixed therapeutic outcomes. However, the elucidation of a more precise etiology of rosacea can support more specific treatments and brings us a step closer to more targeted future therapeutic strategies."
In a recent study, Dr. Gallo and fellow researchers investigated the effects of AzA on cathelicidin and kallikrein expression in skin (in vitro and in vivo), and examined the possible molecular mechanisms of azelaic acid in rosacea and skin inflammation.
In the two-pronged experiment, the effect of AzA on the production of kallikrein (KLK5) and protease activity was assessed in cultured human keratinocytes. The study also evaluated the effect of topical AzA gel 15 percent on cathelicidin, KLK5 and toll-like receptor 2 (TLR2) gene expression in mice.
Results showed that AzA decreased the KLK5 protein in the human keratinocytes treated in culture and was shown to suppress KLK5 protein production in differentiated and undifferentiated human keratinocyte cells.
Interestingly, lower concentrations of AzA were found to be more effective, suggesting that AzA interferes in the post-transcriptional regulation of KLK5. In live mice, results showed that the topical application of AzA gel 15 percent could suppress the gene expression of cAMP, KLK5 and TLR2. According to Dr. Gallo, the downregulation possibly contributes to AzA's anti-inflammatory mechanism of action.
"We believe that the AzA-induced downregulation of TLR (toll-like receptor) may in turn downregulate cathelicidins that are typically at higher levels in rosacea-affected skin. This suggests that AzA can specifically target rosacea-generating proteins, resulting in an improvement of the signs and symptoms of the disease," Dr. Gallo says.
Cathelicidins are peptides produced by the skin that play an important role in innate immunity with their broad-spectrum antimicrobial, chemotactic and angiogenic function.
In normal skin, the precursors of cathelicidin are processed by kallikrein into peptides, which have a potent antimicrobial activity and less proinflammatory function. In rosacea-involved skin, however, kallikrein levels are high, resulting in increased angiogenesis, proinflammatory activities and antibacterial function.
Both cathelicidins and TLRs are intricately involved in the differentiation pathway of keratinocytes and serve to modulate the inflammatory response in the skin.
"The factors that determine who gets rosacea and who does not are likely a combination of genetics and environment. We know that the triggers for the genes linked to the kallikrein and cathelicidin pathway are environmental, but the sensors for that environment are genetic and this correlates with our clinical observation of rosacea," Dr. Gallo says. "Of course, rosacea can be more easily exacerbated by certain 'environments,' particularly in those patients who have a genetic predisposition, eating spicy foods, a lot of sun exposure as well as the colonization of the wrong kinds of microbes on the skin."
Azelaic acid is a naturally occurring dicarboxylic acid with anti-inflammatory, antimicrobial, antikeratinizing, antioxidant and antityrosinase mechanisms of action. It is approved by the Food and Drug Administration (FDA) as AzA gel 15 percent (Finacea, Bayer/Intendis) for the treatment of the papules and pustules seen in mild-to-moderate rosacea and associated erythema.