RCMI International Symposium on Health Disparities
November 12-15, 2000
San Juan, Puerto Rico

Invited Speakers

KELOIDS: EPIDEMIOLOGIC, CELLULAR
AND THERAPEUTIC ADVANCES



Paul A. Kelly, M.D.
King-Drew Medical Center
Los Angeles, CA

The etiopathogenesis of keloids is unknown and definitive treatment remains a perplexing clinical problem. We first performed an epidemiologic study, motivated by the belief that a better understanding of keloid epidemiology would lead to more focused future investigations. The age of onset ranged from 8 to 60, with the highest incidence (35%) in the 15 to 19 year old group. However, little variation existed between sexes. Trauma was the most common initiating factor (76%) and pruritus the most bothersome symptom (58%). Clinical observations revealed that most large keloids have three distinct areas: an erythematous outer border, an inner non-erythematous raised border (classical border) and a central regressing area.

Despite numerous theories as to the origin of keloids, no qualitative or special etiology has been identified to account for their development. Several evidences strongly implicate a disequilibrium between production and catabolism of matrix in the remodeling stage of wound healing, leading to abnormal accumulation of extracellular matrix in hypertrophic scars and keloids. However, the cause of this disequilibrium is not known. Tuan et al. (Subproject Principal Investigator of the pending Keloid project) reported that keloid fibroblasts exhibited an intrinsically higher level of PAI-1 and a lower level of uPA when compared to normal fibroblasts (Tuan, T. L. et al., 1996). Fibroblasts derived from keloids exhibit fundamental differences, which persist in vitro. Further key findings to elucidate the mechanism of excessive ECM accumulation came from preliminary data by Dr. Le (Subproject Principal Investigator) showing a similarly elevated expression of PAI-1 in keloid microvascular endothelial cells as compared to the normal endothelial cells.

Furthermore, mast cell studies from each of these areas and adjacent clinically normal skin revealed an intimate mast cell-fibroblast relationship in the two border areas but not with the clinically normal skin and central regressing area of the keloid. Immunohistochemical studies reveal an abundant expression of ?-tryptase positive mast cells in the classical border. This pattern of ?-tryptase positive stain correlates with the positive expression of VEGF/anti-VEGF stains in similar sections, which may be explained by the degranulation of heparin sulfate by mast cells at the classical border of keloids. Further analyses using ELISA demonstrate a 2-3 fold level of VEGF secreted in the culture media of fibroblasts derived from the classical border as compared to normal skin and inflammatory border. This finding was further confirmed at the mRNA level by Northern analysis and Ribonuclease Protection Assay (RPA)(Le et al., in preparation). The differential expression of VEGF by keloid fibroblasts derived from classical border, compared to normal skin and inflammatory border, may explain the hypovascularity observed histologically at the classical border; the hypovascular state resulted from a combination of an excess extracellular matrix accumulation and a decrease in angiogenic capability (elevated PAI-1), will trigger the inflammatory response or granulation-tissue-phase-like activity at the inflammatory border, via a constant induction of VEGF by fibroblasts resided at the classical border.

Other molecular and cellular findings will be discussed as well as some new therapeutic alternatives, especially in the eradication of intractable pruritus and/or pain with capsaicin and other agents.