Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis

Abstract

Keloids and hypertrophic scars are caused by cutaneous injury and irritation, including trauma, insect bite, burn, surgery, vaccination, skin piercing, acne, folliculitis, chicken pox, and herpes zoster infection. Notably, superficial injuries that do not reach the reticular dermis never cause keloidal and hypertrophic scarring. This suggests that these pathological scars are due to injury to this skin layer and the subsequent aberrant wound healing therein. The latter is characterized by continuous and histologically localized inflammation. As a result, the reticular layer of keloids and hypertrophic scars contains inflammatory cells, increased numbers of fibroblasts, newly formed blood vessels, and collagen deposits. Moreover, proinflammatory factors, such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor-α are upregulated in keloid tissues, which suggests that, in patients with keloids, proinflammatory genes in the skin are sensitive to trauma. This may promote chronic inflammation, which in turn may cause the invasive growth of keloids. In addition, the upregulation of proinflammatory factors in pathological scars suggests that, rather than being skin tumors, keloids and hypertrophic scars are inflammatory disorders of skin, specifically inflammatory disorders of the reticular dermis. Various external and internal post-wounding stimuli may promote reticular inflammation. The nature of these stimuli most likely shapes the characteristics, quantity, and course of keloids and hypertrophic scars. Specifically, it is likely that the intensity, frequency, and duration of these stimuli determine how quickly the scars appear, the direction and speed of growth, and the intensity of symptoms. These proinflammatory stimuli include a variety of local, systemic, and genetic factors. These observations together suggest that the clinical differences between keloids and hypertrophic scars merely reflect differences in the intensity, frequency, and duration of the inflammation of the reticular dermis. At present, physicians cannot (or at least find it very difficult to) control systemic and genetic risk factors of keloids and hypertrophic scars. However, they can use a number of treatment modalities that all, interestingly, act by reducing inflammation. They include corticosteroid injection/tape/ointment, radiotherapy, cryotherapy, compression therapy, stabilization therapy, 5-fluorouracil (5-FU) therapy, and surgical methods that reduce skin tension.

Verapamil as Alternative Treatment in Hypertrophic and Keloid Scars

“…The latter is characterized by continuous and histologically localized inflammation. As a result, the reticular dermis in keloid and hypertrophic scars contains inflammatory cells, increased number of fibroblasts, newly formed blood vessels, and collagen deposits [5].…”

Presence of galectin-1 in the epidermal and dermal thickening of keloid tissues

“…forces as a predisposing factor of keloid formation [9]. Moreover, there is evidence suggesting that epigenetic modifications would be involved in the pathogenesis of keloids by regulation of fibroblasts activation, proliferation and apoptosis, as well as collagen and elastin synthesis [3,[20][21][22].…”

“…However, recent studies describe the epidermis of keloids as thickened, primarily due to hyperproliferation [4,7,17] and altered terminal differentiation [18] of keratinocytes,; some of them, indicating that keratinocytes also participate in the regulation of fibroblasts activity and might contribute to keloid pathogenesis [4,7,19]. On the other hand, several studies consider genetic predisposition as an important factor in the keloid formation and progression [2,5,9,20] whilst others deem the role of local mechanical Hematoxylin staining (H&E) from a biopsy of keloid showing reduced rete ridges, epidermal thickening, hyperkeratosis and spongiosis. Note the presence in the dermis of thin collagen bundles parallel to the epidermis, numerous fibroblasts, microvessels (arrowheads), inflammatory cells, nodule (dashed line) containing elongated fibroblasts attached to randomly oriented collagen fibers, and thick compact collagen bundles with elongated fibroblasts attached (arrows).…”

“…frequently occur on the anterior portion of the chest, shoulders, upper back, arms, cheeks and earlobes [1,2,[5][6][7][8][9][10]. Histopathologically, keloids are defined as inflammatory disorders characterized by exhibiting a thickened dermis containing numerous fibroblasts, abnormal vascularization, increased inflammatory immune cells, abundant hyalinised collagen bundles (keloidal collagen) and extracellular matrix (ECM) components including collagen, elastin, fibronectin and proteoglycans such as syndecan and versican, mainly produced by activated fibroblasts [1][2][3][4][5][6][7][8][9][10][11][12][13][14].…”

“…Histopathologically, keloids are defined as inflammatory disorders characterized by exhibiting a thickened dermis containing numerous fibroblasts, abnormal vascularization, increased inflammatory immune cells, abundant hyalinised collagen bundles (keloidal collagen) and extracellular matrix (ECM) components including collagen, elastin, fibronectin and proteoglycans such as syndecan and versican, mainly produced by activated fibroblasts [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. These histological alterations proper of the keloid tissue have been associated with the elevated production of growth factors such as TGF-β, FGF-2, PDGF, EGF, IGF and VEGF which regulate fibroblast proliferation, ECM synthesis and angiogenesis, and pro-inflammatory cytokines including IL-1α, IL-1β, IL-6 and TNFα which promote fibroblast activation and consequently an excessive deposition of ECM components [1,2,[5][6][7]9,10,15,16]. This is why most studies on keloids focus on dermis and few on epidermis [4,17].…”