"Heal small cuts 10 days faster"
Deferoxamine could help diabetics heal wounds
28. July 2009 02:08
A drug used to remove iron from the body could help
doctors fight one of diabetes' cruelest complications:
poor wound healing, which can lead to amputation of
patients' toes, feet and even legs.
The drug, deferoxamine, helped diabetic mice heal small
cuts 10 days faster than those who did not receive treatment,
according to researchers from Stanford University School
of Medicine and the Albert Einstein College of Medicine.
The team is now working to arrange human trials for deferoxamine.
If the results translate, it could help doctors combat such
diabetic complications as foot ulcers, an "unmet medical need
of gigantic proportions," said Geoffrey Gurtner, MD, professor
of surgery and senior author on the paper to be published
Monday, July 27, in the Proceedings of the National Academy
of Science.
"As soon as some more studies are done on its efficacy,
it's not going to be difficult to get clinicians to pick
[deferoxamine] up," said Richard Clark, MD, a biomedical
engineer at Stony Brook University of New York who
researches treatments for wound healing and was not
involved in the study. "It's quite a significant work."
Blisters, cuts or pressure sores on diabetic patients'
lower limbs often heal slowly or not at all, putting
patients at risk for infection and amputation.
Internal injuries are an issue, as well: More than 40 percent
of patients hospitalized for heart attacks have clinical
diabetes, and they are less likely to recover fully than
their non-diabetic counterparts.
The reason, say researchers, is that diabetic tissue fails
to reconnect oxygen-deprived areas to the bloodstream with
new vessels.
What they didn't know was why the vessels don't form.
Now, Gurtner and colleagues say the culprit is a transcription
factor that can't thrive in the high-sugar environment of
diabetic tissue.
Their potential treatment, deferoxamine, is already Food and
Drug Administration-approved for the management of chronic
iron-overload disorders.
To tease out a treatment, the researchers first focused on
the mechanisms of healing.
They isolated fibroblasts, the cells that secrete fibers to
heal wounds and bind cells together in an extracellular
matrix.
Normally, such fibroblasts ramp up production of a protein
called vascular endothelial growth factor in response to
low oxygen.
This factor prompts the formation of new blood vessels.
In diabetic cells, however, growth factor production
remained flat.
Previous studies suggested that high glucose-a symptom
of diabetes-might be to blame.
To investigate, the researchers grew healthy fibroblasts
in low or high glucose environments for four weeks,
mimicking healthy and diabetic tissue.
They then exposed the cells to low oxygen.
In response, cells grown in high-glucose ramped up production
of growth factor by only 20 percent, compared with 200 percent
in cells grown in low glucose.
Similar experiments with diabetic and non-diabetic mice
confirmed the findings: High glucose was consistently associated
with minimal growth factor production in low-oxygen environments.
But what was the glucose doing to hobble growth factor production?
The team next looked at hypoxia-inducible factor-1a (HIF-1a), a
protein that acts, Gurtner said, as a "second-to-second oxygen
sensor" in the cell.
When oxygen gets low, HIF-1a binds to DNA to trigger a cellular
response, including production of vascular endothelial growth
factor.
To work efficiently, HIF-1a must bind with a molecule called p300.
That's where the system broke down, the researchers found.
When cells were grown in high-sugar environments, the two molecules
decreased their binding by half.
The problem, said Michael Brownlee, MD, a molecular cell biologist
at the Einstein College of Medicine in New York and co-author on
the paper, is that high glucose inside cells results in the creation
of free radicals, which oxidize iron.
The iron then interacts with other cellular molecules to form
DNA-damaging hydroxyl radicals.
That damage causes a cascade of problems, including malformation
of the p300 protein.
Once damaged, p300 can't effectively bond with HIF-1a.
"What you need to do is interrupt this cascade," Brownlee said.
To do so, the team chose deferoxamine, an off-patent drug that
binds to and removes iron from the environment.
Experiments in cell cultures suggested that deferoxamine brought
hypoxia-inducible factor-1a and p300 back together, but would
that translate to better wound healing?
To find out, the researchers gave diabetic mice small cuts.
Rodents, unlike people, have a thin muscle layer under their
skin that allows them to pull the edges of wounds together.
That makes it difficult to compare a mouse's healing process
to a human's.
To solve this problem, the researchers glued a tiny,
washer-shaped stent around the wounds, preventing muscle
contraction.
They then treated some of the mice with deferoxamine cream.
The results were promising: Mice treated with the drug healed
in 13 days, compared with 23 days in untreated mice.
Treated mice also produced almost threefold more vascular
endothelial growth factor.
"By understanding the science of why is it that diabetics
generate wounds more readily and don't heal wounds, we're
able to start to target those mechanisms," Gurtner said.
The next step, said Gurtner and Brownlee, is to test the
drug on human wounds.
Deferoxamine is currently given in the form of an injection
and can have side effects ranging from mild stomach upset to,
in rare cases, susceptibility to serious bacterial infection.
However, in collaboration with Stanford chemical engineer
Jayakumar Rajadas, PhD, the team is now developing a
dissolvable sheet, similar in consistency to a Listerine
breath strip, which could be placed on the wound to deliver
the medication.
This dressing would keep the dose and side effects low,
Gurtner said, as well as making application of the drug
less painful for patients.
The first author on the paper is Hariharan Thangarajah, MD,
of the Department of Surgery at Stanford.
Other researchers at Stanford and Einstein participated in
the study.
The research was funded by the National Institute of Diabetes
and Digestive and Kidney Diseases.
No comments:
Post a Comment