title: Burn Injury Alters Epidermal Cholinergic Mediators and Increases HMGB1 and Caspase 3 in Autologous Donor Skin and Burn Margin.
abstract: Burn wound healing complications, such as graft failure or infection, are a major source of morbidity and mortality in burn patients. The mechanisms by which local burn injury alters epidermal barrier function in autologous donor skin and surrounding burn margin are largely undefined. We hypothesized that defects in the epidermal cholinergic system may impair epidermal barrier function and innate immune responses. The objective was to identify alterations in the epidermal cholinergic pathway, and their downstream targets, associated with inflammation and cell death. We established that protein levels, but not gene expression, of the α7 nicotinic acetylcholine receptor (CHRNA7) were significantly reduced in both donor and burn margin skin. Furthermore, the gene and protein levels of an endogenous allosteric modulator of CHRNA7, secreted mammalian Ly-6/ urokinase-type plasminogen activator receptor-related protein-1, and acetylcholine were significantly elevated in donor and burn margin skin. As downstream proteins of inflammatory and cell death targets of nAChR activation, we found significant elevations in epidermal High Mobility Group Box Protein 1 and caspase 3 in donor and burn margin skin. Lastly, we employed a novel in vitro keratinocyte burn model to establish that burn injury influences the gene expression of these cholinergic mediators and their downstream targets. These results indicate that defects in cholinergic mediators and inflammatory/apoptotic molecules in donor and burn margin skin may directly contribute to graft failure or infection in burn patients.
authors.affiliation: *Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Campus, Maywood, Illinois †Department of Surgery, Loyola University Chicago, Health Sciences Campus, Maywood, Illinois ‡Infectious Disease and Immunology Research Institute, Loyola University Chicago, Health Sciences Campus, Maywood, Illinois.
authors.forename: Casey J
authors.initials: CJ
authors.lastname: Holmes
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Plichta
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gamelli
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Radek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000950:Antigens, Ly / Q000378:metabolism; D015153:Blotting, Western; D002056:Burns / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology; D055815:Young Adult; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; C579167:Chrna7 protein, human; D024243:HMGB1 Protein; C048963:SLURP1 protein, human; D064569:alpha7 Nicotinic Acetylcholine Receptor; D014568:Urokinase-Type Plasminogen Activator; D053148:Caspase 3