title: Tumor necrosis factor-alpha (TNF-α) is a therapeutic target for impaired cutaneous wound healing.
abstract: Impaired wound healing states lead to substantial morbidity and cost with treatment resulting in an expenditure of billions of dollars per annum in the U.S. alone. Both chronic wounds and impaired acute wounds are characterized by excessive inflammation, enhanced proteolysis, and reduced matrix deposition. These confounding factors are exacerbated in the elderly, in part, as we report here, related to increased local and systemic tumor necrosis factor-alpha (TNF-α) levels. Moreover, we have used a secretory leukocyte protease inhibitor (SLPI) null mouse model of severely impaired wound healing and excessive inflammation, comparable to age-related delayed human healing, to demonstrate that topical application of anti-TNF-α neutralizing antibodies blunts leukocyte recruitment and NFκB activation, alters the balance between M1 and M2 macrophages, and accelerates wound healing. Following antagonism of TNF-α, matrix synthesis is enhanced, associated with suppression of both inflammatory parameters and NFκB binding activity. Our data suggest that inhibiting TNF-α is a critical event in reversing the severely impaired healing response associated with the absence of SLPI, and may be applicable to prophylaxis and/or treatment of impaired wound healing states in humans.
authors.affiliation: Oral Infection and Immunity Branch, National Institute of Dental & Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Ashcroft
authors.forename: Moon-Jin
authors.initials: MJ
authors.lastname: Jeong
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Ashworth
authors.forename: Matthew
authors.initials: M
authors.lastname: Hardman
authors.forename: Wenwen
authors.initials: W
authors.lastname: Jin
authors.forename: Niki
authors.initials: N
authors.lastname: Moutsopoulos
authors.forename: Teresa
authors.initials: T
authors.lastname: Wild
authors.forename: Nancy
authors.initials: N
authors.lastname: McCartney-Francis
authors.forename: Davis
authors.initials: D
authors.lastname: Sim
authors.forename: George
authors.initials: G
authors.lastname: McGrady
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Song
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Wahl
mesh_terms: D000279:Administration, Cutaneous; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001706:Biopsy; D002478:Cells, Cultured; D015986:Confounding Factors, Epidemiologic; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008875:Middle Aged; D052002:NF-kappa B p50 Subunit / Q000187:drug effects; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014647:Varicose Ulcer / Q000473:pathology*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D057134:Antibodies, Neutralizing; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; D014409:Tumor Necrosis Factor-alpha