TY - JOUR
T1 - Generating and reversing chronic wounds in diabetic mice by manipulating wound redox parameters
AU - Dhall, Sandeep
AU - Do, Danh C.
AU - Garcia, Monika
AU - Kim, Jane
AU - Mirebrahim, Seyed H.
AU - Lyubovitsky, Julia
AU - Lonardi, Stefano
AU - Nothnagel, Eugene A.
AU - Schiller, Neal
AU - Martins-Green, Manuela
N1 - Publisher Copyright:
© 2014 Sandeep Dhall et al.
PY - 2014
Y1 - 2014
N2 - By 2025, more than 500 M people worldwide will suffer from diabetes; 125 M will develop foot ulcer(s) and 20 M will undergo an amputation, creating a major health problem. Understanding how these wounds become chronic will provide insights to reverse chronicity. We hypothesized that oxidative stress (OS) in wounds is a critical component for generation of chronicity. We used the db/db mouse model of impaired healing and inhibited, at time of injury, two major antioxidant enzymes, catalase and glutathione peroxidase, creating high OS in the wounds. This was necessary and sufficient to trigger wounds to become chronic. The wounds initially contained a polymicrobial community that with time selected for specific biofilm-forming bacteria. To reverse chronicity we treated the wounds with the antioxidants -tocopherol and N-acetylcysteine and found that OS was highly reduced, biofilms had increased sensitivity to antibiotics, and granulation tissue was formed with proper collagen deposition and remodeling. We show for the first time generation of chronic wounds in which biofilm develops spontaneously, illustrating importance of early and continued redox imbalance coupled with the presence of biofilm in development of wound chronicity. This model will help decipher additional mechanisms and potentially better diagnosis of chronicity and treatment of human chronic wounds.
AB - By 2025, more than 500 M people worldwide will suffer from diabetes; 125 M will develop foot ulcer(s) and 20 M will undergo an amputation, creating a major health problem. Understanding how these wounds become chronic will provide insights to reverse chronicity. We hypothesized that oxidative stress (OS) in wounds is a critical component for generation of chronicity. We used the db/db mouse model of impaired healing and inhibited, at time of injury, two major antioxidant enzymes, catalase and glutathione peroxidase, creating high OS in the wounds. This was necessary and sufficient to trigger wounds to become chronic. The wounds initially contained a polymicrobial community that with time selected for specific biofilm-forming bacteria. To reverse chronicity we treated the wounds with the antioxidants -tocopherol and N-acetylcysteine and found that OS was highly reduced, biofilms had increased sensitivity to antibiotics, and granulation tissue was formed with proper collagen deposition and remodeling. We show for the first time generation of chronic wounds in which biofilm develops spontaneously, illustrating importance of early and continued redox imbalance coupled with the presence of biofilm in development of wound chronicity. This model will help decipher additional mechanisms and potentially better diagnosis of chronicity and treatment of human chronic wounds.
UR - http://www.scopus.com/inward/record.url?scp=84920527789&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84920527789&partnerID=8YFLogxK
U2 - 10.1155/2014/562625
DO - 10.1155/2014/562625
M3 - Article
C2 - 25587545
AN - SCOPUS:84920527789
SN - 2314-6745
VL - 2014
JO - Journal of diabetes research
JF - Journal of diabetes research
M1 - 562625
ER -