Abstract

Venous ulcers affect up to a million Americans.The investigators have previously reported that a striking feature of venous ulceration is the presence of dermal and subcutaneous fibrosis (termed lipodermatosclerosis or LDS) in and around the non-healing wound. LDS represents a fundamental aspect of venous disease. Evidence linking LDS to the pathogenesis of venous disease include the findings that ulcers almost always are preceded by LDS, develop and recur within LDS, their failure to heal correlates with the severity of LDS, and grafts often fail when placed over a fibrotic ulcer bed. Although the specific mechanisms of excessive collagen deposition in LDS are unknown, the investigators believe it may in part be due to elevated levels of transforming growth factor-beta-1 (TGF-beta), a potent and general mediator of fibrosis. Investigators present preliminary evidence that the fibrotic dermis in venous ulcers is characterized by increased amounts of TGF-beta. The cause of this enhanced deposition of TGF-beta is unclear, but they have shown a dramatic upregulation of both TGF-beta synthesis and collagen mRNA level in dermal fibroblasts exposed to levels of hypoxia well within the range consistently found in LDS. Their hypothesis is that LDS fibroblasts synthesize excessive amounts of collagen and TGF-beta, at least in part through the stimulatory action of low oxygen tension.
Their first aim i s to determine the distribution and expression of collagen and TGF-beta in LDS sites, ulcer sites, acute wound sites and normal skin using in situ hybridization and immunohistochemistry.
The second aim i s to measure by Northern analysis and run-off experiments TGF-beta and collagen synthesis by dermal fibroblasts cultured from normal and LDS tissue.
The third aim i s to determine the effect of hypoxia/re-oxygenation and lactate on TGF- beta and collagen synthesis (types I and II) in normal and LDS cultured dermal fibroblasts by Northern blot and run-off studies. The level of collagenases will also be quantitated. Finally, the fourth aim is to identify cis-acting elements responsive to hypoxia using transient transfection with TGF-beta promoter-CAT chimeric plasmids.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042936-02
Application #
2082490
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1994-08-01
Project End
1999-07-31
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
University of Miami School of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146

  Publications

Falanga, Vincent; Butmarc, Janet; Cha, Jisun et al. (2007) Migration of the epidermal over the dermal component (epiboly) in a bilayered bioengineered skin construct. Tissue Eng 13:21-8
Panuncialman, Jaymie; Falanga, Vincent (2006) Basic approach to inflammatory ulcers. Dermatol Ther 19:365-76
Falanga, Vincent; Saap, Liliana J; Ozonoff, Alexander (2006) Wound bed score and its correlation with healing of chronic wounds. Dermatol Ther 19:383-90
Donohue, Kevin G; Carson, Polly; Iriondo, Manuel et al. (2005) Safety and efficacy of a bilayered skin construct in full-thickness surgical wounds. J Dermatol 32:626-31
Falanga, Vincent (2005) Wound healing and its impairment in the diabetic foot. Lancet 366:1736-43
Falanga, Vincent (2004) The chronic wound: impaired healing and solutions in the context of wound bed preparation. Blood Cells Mol Dis 32:88-94
Butmarc, Janet; Yufit, Tatyana; Carson, Polly et al. (2004) Human beta-defensin-2 expression is increased in chronic wounds. Wound Repair Regen 12:439-43
Falanga, Vincent; Schrayer, David; Cha, Jisun et al. (2004) Full-thickness wounding of the mouse tail as a model for delayed wound healing: accelerated wound closure in Smad3 knock-out mice. Wound Repair Regen 12:320-6
Nahm, Walter K; Philpot, Benjamin D; Adams, Michelle M et al. (2004) Significance of N-methyl-D-aspartate (NMDA) receptor-mediated signaling in human keratinocytes. J Cell Physiol 200:309-17
Saap, Liliana; Fahim, Simone; Arsenault, Emily et al. (2004) Contact sensitivity in patients with leg ulcerations: a North American study. Arch Dermatol 140:1241-6

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