Scientists have discovered that a multipurpose protein found in
several bodily fluids has another important function--it can promote
the healing of abnormal skin wounds, which are a significant problem
in the elderly.
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-b 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-b (transforming growth factor beta), which
is produced in wounds and controls cellular proliferation and differentiation.
In the absence of SLPI, TGF-b
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.