Topical Application Of A Protein Heals Wounds

Working with a new animal model for delayed wound healing that they produced, researchers at the National Institute of Dental and Craniofacial Research (NIDCR) demonstrated that the protein, called secretory leukocyte protease inhibitor, or SLPI (pronounced slippy), plays a critical role in normal wound healing. When SLPI was applied topically to non-healing wounds, it actually reversed tissue destruction and hastened healing.

Each year, more than four million older people suffer from chronic, non-healing wounds such as diabetic ulcers, bedsores, and venous ulcers. Inflammation and bacterial infection are two of the major problems that often contribute to delayed healing. Even acute wounds sometimes fail to heal properly in the elderly. Not only are non-healing wounds painful, but they are expensive to treat. The cost of wound care is over $3 billion annually.

Previous laboratory studies have suggested that SLPI is involved in the wound healing process. The protein, which is also found in fluids that bathe mucosal surfaces such as bronchial fluids, cervical fluids, and saliva, is a remarkably versatile substance. It has anti-inflammatory, anti-viral, anti-fungal, and anti-bacterial properties. In recent years, NIDCR investigators demonstrated that SLPI found in saliva blocks HIV-1 infection.

Reporting in the October issue of Nature Medicine, the scientists described their development of a new animal model that mimics the major components of non-healing wounds. These SLPI knockout mice--mice that lack the SLPI gene--showed markedly impaired skin wound healing with an increase in inflammation and the activity of the enzyme elastase, which destroys tissue. The researchers demonstrated that without the presence of SLPI to act as a molecular brake, a cascade of events occurs that results in the destruction of tissue and impaired wound healing. But topical application of SLPI actually reverses the abnormal response and enhances the rate of healing.

The researchers believe that SLPI has three major functions in wound healing. It inhibits elastase, controls the activation of leukocytes, and reduces TGF-Beta; activation. When a wound occurs, a wide variety of structural and functional proteins such as proteoglycans, collagen and fibronectin are marshaled to the wound site. Unchecked by SLPI, elastase will degrade these proteins, causing a breakdown in the tissue matrix. Furthermore, SLPI controls the activation of leukocytes. Inflammatory cells are attracted to a wound by multiple stimuli, including the protein TGF-Beta; (transforming growth factor beta), which is produced in wounds and controls cellular proliferation and differentiation. In the absence of SLPI, TGF-Beta; goes into overdrive and exacerbates inflammation.

"SLPI appears to be a component of innate or natural host defense that maintains a balance between protective inflammatory responses and overzealous or uncontrolled inflammation that can lead to tissue destruction and failure to heal," explained Dr. Sharon Wahl, principal investigator on the study and chief of NIDCR's Oral Infection and Immunity Branch.

Interestingly, the researchers note that the fact that animals tend to lick their wounds may be nature's way of delivering SLPI to the wound site via saliva.

Plans are underway for a clinical trial to test SLPI as a treatment for delayed healing of skin wounds in the elderly. The researchers also suggest that findings from their current study may be extended to other conditions that involve excessive elastase activity, such as gingivitis and bullous pemphigoid.

Collaborating with Dr. Wahl on the study were Drs. Gillian S. Ashcroft, Ke-jian Lei, Wenwen Jin, Teresa Greenwell-Wild, Hollie Hale-Donze, George McGrady, and Xiao-Yu Song from the NIDCR Oral Infection and Immunity Branch, and Drs. Glenn Longnecker and Ashok B. Kulkarni from the NIDCR Gene Targeting Facility. The National Institute of Dental and Craniofacial Research is one of the federal National Institutes of Health, located in Bethesda, MD.