Understanding Inflammation

Inflammatory skin diseases are the most common problem in dermatology. They come in many forms, from occasional rashes accompanied by skin itching and redness, to chronic conditions such as dermatitis (eczema), rosacea, seborrheic dermatitis, and psoriasis. Skin inflammation can be characterized as acute or chronic. Acute inflammation can result from exposure to UV radiation (UVR), ionizing radiation, allergens, or to contact with chemical irritants (soaps, hair dyes, etc.). This type of inflammation is typically resolved within 1 to 2 weeks with little accompanying tissue destruction. In contrast, chronic inflammation results from a sustained immune cell mediated inflammatory response within the skin itself. This inflammation is long lasting and can cause significant and serious tissue destruction. Inflammatory skin conditions affect over 35 million Americans who annually spend over $2 billion to treat their symptoms.

The process of skin inflammation is complex and is still not completely understood. When the skin is exposed to a “triggering” stimulus, such as UV radiation, an irritant (e.g. soaps or fragrances), or to allergens, the cells in the skin produce a variety of inflammatory “hormones” called cytokines and chemokines. These “inflammatory messengers” bind to specific receptors on target cells and stimulate the production of additional inflammatory signaling “hormones”. Some of these cause vasodilation while others activate nerve cells. Still other cytokines cause immune cells to leave the blood and migrate into the skin where they then produce more inflammatory hormones, as well as enzymes, free radicals, and chemicals that damage the skin. The end result of the initial triggering event is the amplification of a large inflammatory response that, while designed to help the skin fight infection from invading bacteria, actually causes considerable damage to the skin.

By far the most effective and commonly used prescription drugs for treating inflammation are the corticosteroids, particularly the glucocorticoid related steroids. They are very effective for many forms of eczema, including atopic dermatitis, allergic contact dermatitis, seborrheic dermatitis (in concert with an anti-fungal agent), and are fairly effective in ameliorating the symptoms of psoriasis. They are not particularly effective, however, in treating acute inflammation, like UVR induced sunburn, which is not primarily an immune cell driven inflammatory response. Corticosteroids can be used topically or orally. Topical corticosteroids have been classified into groups based on potency. For example, the corticosteroid clobetasol proprionate, is ranked as a very potent steroid, while betametasone diproprionate and fluocinolone acetonide can range from potent to moderately potent. OTC topicals containing hydrocortisone are, of course, the least potent. While current treatment regimens for most inflammatory skin diseases are dominated by topical or oral orticosteroids, these are typically used for only short periods of time because they exert some negative side effects on skin, including:

  1. Anti-proliferative/thinning effect on the skin.
  2. Suppression of the skin’s ability to respond to infection (immunosuppression).
  3. Elevation of blood glucose levels (hyperglycemia).
  4. Impairment of adrenal gland function.

By understanding the cellular and biochemical events that are involved in skin inflammation, it has been possible to develop newer and more potent topical and injectable drugs to treat inflammatory skin problems. For example, recently injectable "biological response modifiers" or simply "biologics" have been made available to treat psoriasis and arthritis. Many of these biologics work by targeting and inhibiting the action of an inflammatory cytokine, TNF-alpha, that plays a key role in immune cell recruitment and activation. These immune cells cause many of the symptoms of psoriasis, and thus, by inhibiting these cells, the symptoms are diminished. Similarly, the immune suppressive effects of tacrolimum and pimecrolimus have led to the development of topical dermatologics, such as Protopic and Elidel, to control atopic dermatitis.While  effective, these newer drugs can cause serious side effects by virtue of their potent immunosuppressive effects.

Natural Antioxidant Compounds To Address Skin Problems

In contrast to the development of synthetic immunosuppressive drugs to fight inflammatory skin diseases, research conducted at the University of Oklahoma Health Sciences Center as well as at other universities has focused on identifying compounds from nature that may have anti-inflammatory benefits without the negative immunosuppressive side effects of potent prescription drugs. Because of the potential benefits of "natural" compounds to address skin problems, a considerable amount of this "botanically-based" research has been funded by the National Institutes of Health, as well as by other government health agencies worldwide. This research has led to the identification of many botanically-derived "antioxidants" that also have significant anti-inflammatory activities. One of the most potent natural anti-inflammatories discovered to date is Curcumin. This yellow phenolic compound is a constituent of Tumeric and is present curry.  Curcumin has been one of the most widely researched natural compounds to date and its anti-inflammatory and anti-cancer effects have led to the development of chemical deriviatives of the compound for use in topical and oral therapeutics. Other botanically-derived compounds that are antioxidants with anti-inflammatory activities include Quercetin (found in apples), Resveratrol (found in wine), Epigallocatechin Gallate (found in green tea), and Bisabolol (found in Chamomile).

Key Inflammatory "Mediators" Inhibited by Natural Compounds

What makes a botanical compound a "good" anti-inflammatory candidate depends primarily on the ability of the compound to block key "inflammatory mediators" produced by skin and immune cells. Two of the most important inflammatory mediators involved in skin disorders are TNF-alpha, as mentioned above, and PGE-2. While TNF-alpha plays a key role in psoriasis, PGE-2 is a major participant in all types of skin inflammation, and is perhaps the most important hormone "mediator" involved in sunburn. Pain, redness and swelling are all due, in part to PGE-2, and studies conducted over many years have implicated PGE-2 as a key participant in the development of skin cancer. Further, PGE-2 suppresses collagen formation in the skin and thus, participates in photoaging. Since PGE-2 is produced in skin cells in response to exposure of the skin to UVR (sunlight) it is no wonder that chronic exposure to the sun can lead to premature aging and skin cancer. Natural anitoxidant compounds that can prevent the production of PGE-2 in skin exposed to sunlight could be extremely useful in preventing skin aging and in reducing the risk of skin cancer.

Cell and molecular biology research carried out at the University of Oklahoma Heatlh Science Center over the past 12 years has examined the effects of over 200 natural antioxidants on inflammatory pathways that are activated in skin and immune cells by "triggers" such as UVR and chemical irritants. The results of this research have shown that not all "antioxidants" have anti-inflammatory activities, and that some of the weakest anti-oxidants have the best anti-inflammatory and anti-aging effects on human skin cells. In addition to curcumin, bisabolol, quercetin, EGCG, gallic acid, vitamin C and vitamin A derivatives, University of Oklahoma scientists discovered a group of very small, phenolic antioxidants that had wide ranging anti-inflammatory and anti-aging properties. These antioxidants are commonly found in low amounts in basil, nutmeg, bourbon, rum, cheese, and in other foods, and in fact several of these phenolic compounds have been used for many years as food flavoring agents. Interestingly, these compounds were all found to display a very unique "'cell-specific" profile with some compounds being extremely good at blocking inflammation in keratinocytes but poor in preventing inflammation in fibroblasts while others had just the opposite profile. What accounts for these differences in cell specificity is still under investigation. The rights to this "library" of small phenolic anti-inflammatory compounds (SPAC) was transferred to DermaMedics which has been conducting clinical studies in partnership with pharmaceutical companies to determine the efficacy of topical formulations in addressing skin problems.  DermaMedics intends to license all or parts of this technology to pharmaceutical partners.