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Regulation of compromised wound healing by alpha-v-beta-6 integrin

Kevin John McElwee, MD, University of British Columbia, Vancouver, BC

Hair follicle epithelial cells contribute to skin wound healing. The cells in hair follicles close to a skin wound rapidly proliferate and migrate into the wound to help it heal. Transforming growth factor-beta1 (TGF-ß1) is a naturally occurring molecule present in skin that regulates skin inflammation and healthy tissue maintenance. It is a strong inhibitor of epithelial skin cell growth and it may slow down wound healing. TGF-ß1 is activated by another molecule, avß6 integrin, which is normally expressed on epithelial cells in hair follicles and in wounds. Our previous investigations have demonstrated that skin wounds heal significantly better when avß6 integrin is not present. In its absence, there is much faster epithelial cell proliferation and wound healing. Skin wounds can heal poorly, especially in people taking glucocorticoid drugs, such as dexamethasone. These drugs are frequently used because of their anti-inflammatory and immunosuppressive properties, but they reduce the ability of wounds to heal naturally. The aim of our research proposal is to investigate the function of avß6 integrin in glucocorticoid drug-impaired wound healing. Our hypothesis is that avß6 integrin activates TGF-ß1 which then inhibits hair follicle cell proliferation and stops them contributing to wound healing. We believe that blocking avß6 integrin activity in and around wounds may help them heal much faster. Use of drug inhibitors of avß6 integrin might enhance keratinocyte cell proliferation and could potentially provide a useful treatment to improve wound healing, especially in people taking glucocorticoid drugs.

Peer reviewed publications supported by the Canadian Dermatology Foundation

1. Kang H, Wu WY, Lo BK, Yu M, Leung G, Shapiro J, McElwee KJ. Hair follicles from alopecia areata patients exhibit alterations in immune privilege-associated gene expression in advance of hair loss. J Invest Dermatol. 2010 Nov;130(11):2677-80.
2. Lo BK, Yu M, Zloty D, Cowan B, Shapiro J, McElwee KJ. CXCR3/Ligands are Significantly Involved in the Tumorigenesis of Basal Cell Carcinomas. Am J Pathol. 2010 May;176(5):2435-46.
3. Yu M, Bell RH, Ross EK, Lo BK, Isaac-Renton M, Martinka M, Haegert A, Shapiro J, McElwee KJ. Lichen planopilaris and pseudopelade of Brocq involve distinct disease associated gene expression patterns by microarray. J Dermatol Sci. 2010 Jan;57(1):27-36.
4. Zhang X, Yu M, Yu W, Weinberg J, Shapiro J, McElwee KJ. Development of Alopecia Areata Is Associated with Higher Central and Peripheral Hypothalamic-Pituitary-Adrenal Tone in the Skin Graft Induced C3H/HeJ Mouse Model. J Invest Dermatol. 2009 Jun;129(6):1527-38.
5. McElwee KJ. Etiology of cicatricial alopecias: a basic science point of view. Dermatol Ther. 2008; 21: 212-20.
6. Yu M, Zloty D, Cowan B, Shapiro J, Haegert A, Bell RH, Warshawski L, Carr N, McElwee KJ. Superficial, nodular, and morpheiform basal-cell carcinomas exhibit distinct gene expression profiles. J Invest Dermatol. 2008; 128: 1797-805.
7. Yu M, Kissling S, Freyschmidt-Paul P, Hoffmann R, Shapiro J, McElwee KJ. Interleukin-6 cytokine family member oncostatin M is a hair-follicle-expressed factor with hair growth inhibitory properties. Exp Dermatol. 2008; 17: 12-9.
8. Yu M, Finner A, Shapiro J, Lo B, Barekatain A, McElwee KJ. Hair follicles and their role in skin health. Exp Rev Dermatol. 2006; 1: 855-871.
9. Lu W, Shapiro J, Yu M, Barekatain A, Lo B, Finner A, McElwee KJ. Alopecia areata: pathogenesis and potential for therapy. Exp Rev Mol Med. 2006; 8: 1-19.