Disordered wound healing is a significant clinical problem resulting in both the exaggerated healing of post-bum hypertrophic scar and the inadequate healing that results in chronic wounds. We and others have documented significant changes in the relative concentration of three particular cytokines in these clinical situations. These are transforming growth factor-beta, TGF-beta, tumor necrosis factor-alpha, TNF-alpha and interleukin-8, IL-8. These mediators are present in increased amounts in abnormally healing wounds and induce changes in the cells that populate the wounds and the matrix environment in which the cells reside. For example, we have shown increased burn scar production of autocrine and paracrine TGF-beta induces dermal fibrob lasts to synthesize excessive Types I and III collagen and contract matrix at an increased rate. TNF-alpha up-regulates both MMP-2 and -9, two proteases which have been linked to wound chronicity. IL-8 decreases keratinocyte replication and the ability of fibroblasts to contract matrix. The Goal of this proposal is to determine the mechanisms whereby these mediators regulate the interactions between skin cells and matrix. The experimental strategy is based on two primary aims. First, cytokine induced changes in content, synthesis, phosphorylation and organization of cytoskeletal proteins; alpha-smooth muscle actin, talin, vinculin, and alpha2Beta1 integrin in response to cytokine treatment will be characterized using biochemical and molecular biologic approaches. Particular attention will be directed to the role of Rho/GTPases as a critical signaling system in fibroblast reorganization of matrix. Second, the effects of these cytokines on the induction, synthesis and activation of matrix metalloproteases will be determined. We will analyze the promoter regions of MMP-2 and -9 for response elements to cytokines and individual matrix proteins as a specific mechanism for their regulation. Finally, the effects of cytokine-mediated modulation of MMPs on collagen contraction will be documented. These studies will increase our understanding for the mechanism of cytokine-induced abnormalities of wound healing. The long-term goal of this project is to uncover key mechanisms underlying hypertrophic scarring that may lead to improved therapeutic and, perhaps, preventive strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050967-08
Application #
6739055
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1995-01-09
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
8
Fiscal Year
2004
Total Cost
$305,500
Indirect Cost
Name
University of Southern California
Department
Surgery
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Lee, Lily F; Jiang, Ting Xin; Garner, Warren et al. (2011) A simplified procedure to reconstitute hair-producing skin. Tissue Eng Part C Methods 17:391-400
Reiss, Matthew J; Han, Yan-Ping; Garcia, Edwin et al. (2010) Matrix metalloproteinase-9 delays wound healing in a murine wound model. Surgery 147:295-302
Reiss, Matthew J; Han, Yuan-Ping; Garner, Warren L (2009) Alpha1-antichymotrypsin activity correlates with and may modulate matrix metalloproteinase-9 in human acute wounds. Wound Repair Regen 17:418-26
Zhou, Ling; Yan, Chunli; Gieling, Roben G et al. (2009) Tumor necrosis factor-alpha induced expression of matrix metalloproteinase-9 through p21-activated kinase-1. BMC Immunol 10:15
Goldberg, Mytien T; Han, Yuan-Ping; Yan, Chunli et al. (2007) TNF-alpha suppresses alpha-smooth muscle actin expression in human dermal fibroblasts: an implication for abnormal wound healing. J Invest Dermatol 127:2645-55
Nien, Yih-Dar; Han, Yuan-Ping; Tawil, Bill et al. (2003) Fibrinogen inhibits fibroblast-mediated contraction of collagen. Wound Repair Regen 11:380-5
Han, Yuan-Ping; Nien, Yih-Dar; Garner, Warren L (2002) Tumor necrosis factor-alpha-induced proteolytic activation of pro-matrix metalloproteinase-9 by human skin is controlled by down-regulating tissue inhibitor of metalloproteinase-1 and mediated by tissue-associated chymotrypsin-like proteinase. J Biol Chem 277:27319-27
Han, Y P; Tuan, T L; Hughes, M et al. (2001) Transforming growth factor-beta - and tumor necrosis factor-alpha -mediated induction and proteolytic activation of MMP-9 in human skin. J Biol Chem 276:22341-50