Interactions Between Oxidative Stress And Wound Bacteria Determine Initiation Of Wound Chronicity In Diabetic Mice
Jane H. Kim, Benjamin K. Yang, Elyson Gavin D. Lebig, Manuela Martins-Green.
University of California, Riverside, Riverside, CA, USA.
It is well known that a balanced redox state in the wound tissue is critical for proper healing. Also critical is the skin microbiome: competition between commensal bacteria and invading biofilm-forming bacteria can increase inflammation and tissue damage. We show that oxidative stress (OS) levels affect wound closure, biofilm development and granulation tissue maturation in a dose-dependent manner. Higher OS levels lead to longer healing times and stronger biofilm development. Granulation tissue formation is delayed and the resulting scar tissue is not well developed. Although the microvessels present in the tissue have well developed basal lamina and the basal lamina under the epidermis seems to be complete, the levels of interstitial collagen are significantly reduced suggesting that the healing tissue is much weaker when the levels of OS are high. How the biological interactions between OS and bacteria in the wound determine wound healing outcomes, is not known. We hypothesize that the levels of OS are critical for establishing a microenvironment that affects the ability of bacteria to colonize the wound. To test this hypothesis, we cleaned the skin to greatly reduce the pre-existing microbiome, created wounds and then inoculated them with bacteria previously isolated from chronic wounds, in the presence or absence of high levels of OS. We inoculated with either an aggressive biofilm-forming bacteria, Pseudomonas aeruginosa, or a more mild biofilm-forming bacteria, Enterobacter cloacae. When inoculated with OS, P. aeruginosa formed biofilm and damaged wound tissue, leading to the development of chronic wounds. Inoculation with E. cloace with OS, however, resulted in little biofilm and less tissue damage. When inoculated with either bacteria without OS, the infection resolved and the wounds healed. These results indicate that high levels of OS are necessary for the bacteria to form biofilm in wounds and lead to chronicity.
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