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(American Journal of Pathology. 2006;168:1848-1860.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050980

Loss of Tumor Necrosis Factor Potentiates Transforming Growth Factor ß-mediated Pathogenic Tissue Response during Wound Healing

Shizuya Saika^*, Kazuo Ikeda, Osamu Yamanaka^*, Kathleen C. Flanders, Yuka Okada^*, Takeshi Miyamoto^*, Ai Kitano^*, Akira Ooshima, Yuji Nakajima, Yoshitaka Ohnishi^* and Winston W.-Y. Kao

From the Departments of Ophthalmology^* and Pathology, Wakayama Medical University, Wakayama, Japan; the Department of Anatomy, Graduate School of Medicine, Osaka City University, Osaka, Japan; the Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and the Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio

Animal cornea is an avascular transparent tissue that is suitable for research on wound healing-related scarring and neovascularization. Here we show that loss of tumor necrosis factor (TNF) potentiates the undesirable, pathogenic response of wound healing in an alkali-burned cornea in mice. Excessive invasion of macrophages and subsequent formation of a vascularized scar tissue were much more marked in TNF-null knockout (KO) mice than in wild-type mice. Such an unfavorable outcome in KO mice was abolished by Smad7 gene introduction, indicating the involvement of transforming growth factor ß or activin/Smad signaling. Bone marrow transplantation from wild-type mice normalized healing of the KO mice, suggesting the involvement of bone marrow-derived inflammatory cells in this phenomenon. Co-culture experiments showed that loss of TNF in macrophages, but not in fibroblasts, augmented the fibroblast activation as determined by detection of -smooth muscle actin, the hallmark of myofibroblast generation, mRNA expression of collagen I2 and connective tissue growth factor, and detection of collagen protein. TNF in macrophages may be required to suppress undesirable excessive inflammation and scarring, both of which are promoted by transforming growth factor ß, and for restoration of tissue architecture in a healing alkali-burned cornea in mice.

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