title: Complement Activation and STAT4 Expression Are Associated with Early Inflammation in Diabetic Wounds.
abstract: Diabetic non-healing wounds are a major clinical problem. The mechanisms leading to poor wound healing in diabetes are multifactorial but unresolved inflammation may be a major contributing factor. The complement system (CS) is the most potent inflammatory cascade in humans and contributes to poor wound healing in animal models. Signal transducer and activator of transcription 4 (STAT4) is a transcription factor expressed in immune and adipose cells and contributes to upregulation of some inflammatory chemokines and cytokines. Persistent CS and STAT4 expression in diabetic wounds may thus contribute to chronic inflammation and delayed healing. The purpose of this study was to characterize CS and STAT4 in early diabetic wounds using db/db mice as a diabetic skin wound model. The CS was found to be activated early in the diabetic wounds as demonstrated by increased anaphylatoxin C5a in wound fluid and C3-fragment deposition by immunostaining. These changes were associated with a 76% increase in nucleated cells in the wounds of db/db mice vs.
  
  
  METHODS
  The novel classical CS inhibitor, Peptide Inhibitor of Complement C1 (PIC1) reduced inflammation when added directly or saturated in an acellular skin scaffold, as reflected by reduced CS components and leukocyte infiltration. A significant increase in expression of STAT4 and the downstream macrophage chemokine CCL2 and its receptor CCR2 were also found in the early wounds of db/db mice compared to non-diabetic controls. These studies provide evidence for two new promising targets to reduce unresolved inflammation and to improve healing of diabetic skin wounds.
authors.affiliation: Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States of America.|Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States of America.|Children's Specialty Group, Children's Hospital of The King's Daughters, Norfolk, VA, United States of America.
authors.forename: Kenji M
authors.initials: KM
authors.lastname: Cunnion
authors.affiliation: Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States of America.|Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States of America.
authors.forename: Neel K
authors.initials: NK
authors.lastname: Krishna
authors.affiliation: Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States of America.
authors.forename: Haree K
authors.initials: HK
authors.lastname: Pallera
authors.affiliation: Department of Plastic Surgery, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Pineros-Fernandez
authors.affiliation: Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States of America.
authors.forename: Magdielis Gregory
authors.initials: MG
authors.lastname: Rivera
authors.affiliation: Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States of America.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Hair
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States of America.
authors.forename: Brittany P
authors.initials: BP
authors.lastname: Lassiter
authors.affiliation: Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Huyck
authors.affiliation: Department of Dermatology, Eastern Virginia Medical School, Norfolk, VA, United States of America.|Department of Pathology, Eastern Virginia Medical School, Norfolk, VA, United States of America.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Clements
authors.affiliation: Department of Dermatology, Eastern Virginia Medical School, Norfolk, VA, United States of America.|Department of Pathology, Eastern Virginia Medical School, Norfolk, VA, United States of America.
authors.forename: Antoinette F
authors.initials: AF
authors.lastname: Hood
authors.affiliation: Department of Plastic Surgery, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: George T
authors.initials: GT
authors.lastname: Rodeheaver
authors.affiliation: Department of Plastic Surgery, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: Patrick S
authors.identifier: http://orcid.org/0000-0002-2542-6142
authors.initials: PS
authors.lastname: Cottler
authors.affiliation: Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, VA, United States of America.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.affiliation: Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States of America.
authors.forename: Anca D
authors.initials: AD
authors.lastname: Dobrian
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000502:physiology*; D015936:Complement C5a / Q000502:physiology; D048909:Diabetes Complications / Q000503:physiopathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014945:Wound Healing / Q000502:physiology; D014947:Wounds and Injuries / Q000150:complications / Q000503:physiopathology*
chemical_list: D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015936:Complement C5a