The mast cell stabilizer ketotifen prevents development of excessive skin wound contraction and fibrosis in red Duroc pigs

Abstract

Skin wound healing in Yorkshire pigs closely approximates human wound healing. Conversely, red Duroc pigs form fibroproliferative, hypercontractile scars. As mast cells have been implicated in several fibrotic conditions, the present study used these models to evaluate the potential role of mast cells in wound contraction and fibrosis. Immediately following the creation of full-thickness excisional wounds, the mast cell stabilizer ketotifen was used to treat both Yorkshire and red Durocs. Control red Durocs showed significantly more wound contraction than Yorkshires, both before and after reepithelialization. Ketotifen treatment significantly reduced the first phase of contraction in red Duroc wounds to a level equivalent to Yorkshire wounds, but had no detectable effect on the postepithelialization phase of contraction. Cessation of drug treatment after 10 weeks did not lead to resumption of excessive contraction in red Durocs, indicating that ketotifen blocked rather than delayed such contraction during a critical phase of healing. Ketotifen treatment also reduced the deposition of collagen within the red Duroc wounds, but did not affect Yorkshire wound contraction or collagen deposition. These results suggest that ketotifen may be an effective treatment for the reduction of excessive wound contraction and fibrosis in human cutaneous injuries, without affecting the normal healing process.

The Importance of Mast Cells in Dermal Scarring

“…54 Reduced wound contraction and scar formation were reported in ketotifen-treated animals. Scars from pigs receiving ketotifen also displayed thinner and less dense collagen fibers and reduced numbers of alpha-smooth muscle actin-positive myofibroblasts.…”

“…These include drugs like cromolyn (disodium cromoglycate) and ketotifen, which have shown promise in animal models. 54,59,60 However, while these drugs are able to prevent mast cell degranulation, they may also affect other cell types and it is unclear whether the release of mast cell mediators via secretory vesicles is affected by Figure 6. Methods to target mast cells.…”

Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell-Stabilizing Properties

“…Given such pharmacological properties of ketotifen, the administration of this drug could also be useful in the treatment of organ fibrosis in addition to its primary efficacy for allergic diseases. Recently, several animal studies have actually shown the therapeutic efficacy of ketotifen in the treatment of post-traumatic dermal or joint capsular fibrosis [58,59].…”

The mast cell stabilizer ketotifen reduces joint capsule fibrosis in a rabbit model of post-traumatic joint contractures

“…Ketotifen has been FDA approved as an adjuvant treatment for adult and pediatric populations with asthma for over 15 years and more recently has been FDA approved for treatment of allergic conditions of the eye [16]. Ketotifen administration has also been shown to impair abnormal wound fibrosis and hypercontractile scar formation in the red Duroc pig [17]. Recently, we have shown in a rabbit model that treatment with ketotifen significantly reduced the biomechanical severity of post-traumatic joint contractures [18], although the effects of ketotifen treatment at the molecular level in this animal model have yet to be determined.…”