Nitric
oxide and its role in health and diabetes.
Thomas
Burke Ph.D.
Part
10. Nitric Oxide (NO) and Its Role in Wound Prevention
and Wound Healing
In
previous articles we have alluded to the positive
effects of NO on wound healing.
In this article we address the overall
implication of NO in wound prevention and wound
healing.
Vasodilation:
By
now, most readers will appreciate that the risk
of developing a lower extremity ulcer in people
with diabetes may be greatly reduced if loss of
sensation due to peripheral neuropathy is either
prevented or can be reversed. To do so, requires
an improved blood flow. NO is a powerful regulator
of acute vasodilation, both for arteries, veins,
and lymphatics. The increase in blood flow fills
capillaries that were underperfused bringing oxygen
and nutrients to the peripheral nerves and tissue.
In addition, the enhanced venous drainage as well
as the increase in lymphatic motility helps to
remove edematous fluid that accumulates in the
wound area. The latter effects of NO allow more
oxygen and nutrient delivery to the wound site
and speeds the removal of metabolic waste products
from the area. Simply put, hypoxia and ischemia
are reversed.
Growth
factors:
Increased
circulation through NO also provides an increased
delivery of platelets, the source of platelet-derived
growth factor. Addtionally, other growth factors
and the cells that produce them will also have
greater access to the wound area. Each of these
growth factors is necessary for complete tissue
remodeling in a healing wound. However, as Dr.
Boykin pointed out, growth factors such as becaplermin,
fail to achieve an acceleration of the wound healing
process if the patient is deficient in NO. Elevation
the concentration of NO locally, in addition to
simple vasodilation, facilitates the action of
all growth factors in speeding cell division to
rapidly replace damaged tissue. Thus, local increase
in NO near the wound site will cause initial cell
proliferation and then differentiation.
These cellular activities relate to all
tissues involved including blood vessels (angiogenesis),
lymph ducts (lymphogenesis), muscles, epithelial
cells, and nerves.
Inflammation:
NO
will down regulate the activity of iNOS, which
produces large amount of peroxynitrite (ONOO).
INOS activity is important to destroy injured
cells, in order to prepare the site of injury
for new cell growth. However, uncontrolled activity
of iNOS continues the inflammatory process and
tissue destruction. Reducing iNOS activity with
small, local amounts of NO will reduce shorten
the inflammatory stage of wound healing and speed
the repair process.
Immune
Response:
It
has been reported that dietary L-arginine will
increase the concentration and activity of T-lymphocytes.
This effect is likely mediated by NO itself rather
than by L-arginine and thus NO is considered to
be a powerful mediator of immune defenses. Therefore,
in addition to NO mediated vasodilation that aids
in the recruitment of white blood cells which
defend against bacterial infections in non-healing
ulcers, NO apparently strengthens the immune system,
especially T-cells.
Skin
flaps:
Wounds
are often covered by grafts from other areas of
the body. To survive, this viable tissue must
be nourished with a good blood supply. We suspect
that local elevations of NO for several days before
as well as after surgery, in diabetic or other
patients with reduced concentrations of NO in
their circulation, would enhance the viability
of these grafts.
In fact, enhanced viability of skin grafts
due to NO has been reported by Suzuki in Plastic
Reconstructive Surgery (1998).
Cardiovascular
integrity:
Diabetes
is accompanied by serious cardiovascular disease.
NO reduces platelet adhesion so in theory, there
should be fewer atherosclerotic events. The ability
of NO to grow new blood vessels reduces ischemia
locally and removes edematous fluid in areas of
low perfusion. Thus, the threat of clot formation,
hypoxic or ischemic injury, and swelling of tissues
are all minimized by elevations of NO toward normal.
Cumulative
effect:
Continued
elevation of local NO availability builds on the
physiologic and biochemical effects, which were
begun, with the first dose of NO. It is similar
to starting up a staircase, where the first elevation
of NO (first step) exerts positive effects on
wound healing. Subsequent NO is important since
the wound is never again as poor biochemically
and physiologically as it was prior to the first
increase in local NO. The first NO exposure stimulates
acute angiogenesis, perhaps only one or two new
capillaries. However, using the staircase analogy,
subsequent NO delivery to the wound site will
result in the progressive development of many
new blood vessels. What starts as a modest acute
vasodilation eventually results in a well perfused,
well healed tissue bed, one in which a subsequent
ulcer is very unlike to occur. This is not to
say that an ulcer won’t occur in another area
of the body based on the underlying disease state.
Approaches
to elevating NO:
There
are caveats to the treatment of wounds with a
source of NO. First, systemic administration of
dietary supplements such as L-arginine must be
able to reach the wound and if swelling, edema,
and tissue damage impinge on the local blood supply,
then dietary supplements will have little value.
Furthermore, acidosis and low oxygen availability
in the immediate wound area, compromise the ability
of the enzyme NOS to make NO from L-arginine.
Adverse
drug interactions:
Many
diabetic patients receive diuretics for kidney
or cardiovascular disease. Diuretics may cause
problems with potassium and magnesium metabolism.
Magnesium is a regulator of intracellular calcium
which itself is a co-factor for NOS activity.
Magnesium also helps regulate intracellular potassium
content and the excretion of potassium by the
kidney. Addressing these possible co-morbid factors
in a diabetic ulcer, may speed the healing of
an otherwise slow healing wound.
Importantly,
potassium imbalance also affects transmembrane
potential in nerves. Clearly, the sensation of
pressure, temperature, balance, and pain can be
adversely affected unless the possible effects
of diuretic usage are considered by the healthcare
professional in the overall approach to diabetic
ulcer management.
In
summary NO, by stimulating vasodilation and normal
membrane potential, may reduce the likelihood
of peripheral neuropathy and thereby the major
risk factor for diabetic ulcers. NO also positively influences wound healing by increasing vasodilation,
promoting cell division and proliferation, angiogenesis,
collagen formation and collagen cross-linking.
Since people with diabetes are often low
in NO, localized increases in NO availability
may speed the healing of refractory diabetic ulcers.
The
next article will discuss our experience with
the Anodyne Therapy System as an adjunctive modality
in wound care.
