The process of wound healing involves a series of carefully orchestrated biological events permitting the host to eliminate the injurious agents and then systematically repair the damages. Various cellular infiltrates and mediators (cytokines and lymphokines) released during wound healing are known to facilitate the healing process. Transforming growth factor-alpha and beta-I (TGF-alpha and TGF-beta-1) are two well-studied multifunctional cytokines known to promote wound healing. Considerable evidence now indicates that there are endogenous cellular sources that deliver these cytokines to wound sites. However, the detailed identities of cytokine producing cells at wound sites remain elusive. Furthermore the molecular mechanisms by which these cells and their secreted cytokines influence the process of wound healing remain incompletely understood. The applicants have recently identified a novel mechanism by which eosinophils can importantly influence the wound healing process: the production of TGF-alpha and TGF-beta-1. Eosinophils are part of the cellular infiltrate typically found in significant numbers in healing wounds. Eosinophils infiltrated into cutaneous wounds of the rabbit and hamster are the major producers of TGF-alpha and TGF-beta-1. Among their many activities, TGF-alpha and TGF-beta-1 together can influence epithelial migration, promote angiogenesis, and tissue remodeling. Based on these findings, we have formulated the hypothesis that the eosinophil and its derived TGFs are responsible for many of the coordinated activities during the wound healing. To test this hypothesis, we wish to pursue the following two specific aims: 1. To establish the skin and oral mucosa of the Syrian hamster as models of cutaneous and oral wound healing. At each site, the kinetics of eosinophil infiltration and their production of TGF-alpha and TGF-beta-1 will be determine by the techniques of in-situ hybridization and immunohistochemistry, using hamster specific reagents (cDNAs and antisera). 2. To evaluate the biological significance of the eosinophil and eosinophil-derived TGFs in wound healing. Using hamster as experimental models for oral and cutaneous wound healing, influx of eosinophils into wound sites will be selectively prevented or reduced by either blocking the adherence of circulating eosinophils to the vascular cellular adhesion molecule- 1 (VCAM- 1) by masking eosinophil cell surface very late activation antigen-4 (VLA-4) using specific monoclonal antibodies (mAb), or by the use of anti-IL-5 mAb to block the development and maturation of eosinophils. The contributions of eosinophil-derived TGF-alpha and TGF-beta-1 to wound healing will be investigated by the administration of specific neutralization antibodies.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Dentistry
United States
Zip Code
Yamakawa, M; Weinstein, R; Tsuji, T et al. (2000) Age-related alterations in IL-1beta, TNF-alpha, and IL-6 concentrations in parotid acinar cells from BALB/c and non-obese diabetic mice. J Histochem Cytochem 48:1033-42
Nagai, M; Yoshida, A; Sato, N et al. (1999) Messenger RNA level and protein localization of transforming growth factor-beta1 in experimental tooth movement in rats. Eur J Oral Sci 107:475-81
Tyler, L W; Matossian, K; Todd, R et al. (1999) Eosinophil-derived transforming growth factors (TGF-alpha and TGF-beta 1) in human periradicular lesions. J Endod 25:619-24
Elovic, A E; Ohyama, H; Sauty, A et al. (1998) IL-4-dependent regulation of TGF-alpha and TGF-beta1 expression in human eosinophils. J Immunol 160:6121-7
Tanda, N; Ohyama, H; Yamakawa, M et al. (1998) IL-1 beta and IL-6 in mouse parotid acinar cells: characterization of synthesis, storage, and release. Am J Physiol 274:G147-56
Yang, J; Tyler, L W; Donoff, R B et al. (1996) Salivary EGF regulates eosinophil-derived TGF-alpha expression in hamster oral wounds. Am J Physiol 270:G191-202
Elovic, A E; Gallagher, G T; Kabani, S et al. (1996) Lack of TGF-alpha and TGF-beta 1 synthesis by human eosinophils in chronic oral ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:672-81
Wong, D T; Todd, R; Tsuji, T et al. (1996) Molecular biology of human oral cancer. Crit Rev Oral Biol Med 7:319-28
Elovic, A; Wong, D T; Weller, P F et al. (1994) Expression of transforming growth factors-alpha and beta 1 messenger RNA and product by eosinophils in nasal polyps. J Allergy Clin Immunol 93:864-9
Song, B Z; Donoff, R B; Tsuji, T et al. (1993) Identification of rabbit eosinophils and heterophils in cutaneous healing wounds. Histochem J 25:762-71