Semapimod Reduces the Depth of Injury Resulting in Enhanced Re-epithelialization of Partial-Thickness Burns in Swine

Abstract

Studies suggest that tumor necrosis factor alpha (TNF-alpha) plays a role in burn pathogenesis. We conducted a randomized controlled experiment in swine to determine whether a novel macrophage inhibitor, semapimod (formerly known as CNI-1493), would blunt the local production of TNF-alpha, interleukin (IL)-1, and IL-6 in burns leading to less injury extension and faster re-epithelialization. After creating second-degree burns, animals received one or two intravenous boluses of semapimod 1 mg/kg or normal saline, and all burns were treated with silver sulfadiazine. The depth of follicular necrosis and thrombosis was reduced by either one or two doses of semapimod (P=.04 and .02, respectively). However, no differences were noted between groups in cytokine levels. Depth of scarring was similar in all groups. We conclude that Semapimod reduces the depth of follicular necrosis and thrombosis after second-degree burns in swine, indirectly resulting in more rapid re-epithelialization. However, this affect does not appear to be mediated by reduced local TNF-alpha, IL-1, or IL-6 protein levels.

A Review of the Local Pathophysiologic Bases of Burn Wound Progression

“…4,5,[22][23][24]123,49 Perhaps, future research regarding the progression of burn wounds will be centered on the development of small molecules capable of blocking steps in these pathways, which are common to multiple mediators. Indeed, the promise of such intervention is highlighted by the work of Giles et al, 25 who have already successfully used topical administration of c-Jun in burned mice.…”

Reduction of burn progression with topical delivery of (antitumor necrosis factor‐α)‐hyaluronic acid conjugates

“…As previously mentioned, modulating acute inflammation using p38MAPK inhibitor was shown to be effective in reducing cellular apoptosis, but the long‐term effect of such treatment was unclear. Singer and coworkers have also demonstrated 30% reduction in depth of hair follicle necrosis after systemic delivery of semapimod in a pig model, while systemic delivery of curcumin has shown a positive effect in reducing burn wound progression by 50% in a rat comb burn model 7 days after initial burn . However, systemic delivery of anti‐inflammatory agents in a burn patient increases the risk of secondary complications, and local delivery of TNF‐α neutralizing agent from a HA delivery vehicle has reduced necrosis by up to 70% post‐burn in a rat model.…”

“…In a rat model, topical application of inhibitor of p38MAPK, a potent stimulator of pro‐inflammatory cytokine production and promoter of apoptosis, on burn injuries has shown significant reduction of local TNF‐α, IL‐1β, and IL‐6 expression, attenuation of dermal neutrophil sequestration, and a lower level of hair follicle cell apoptosis within 24 hours of the initial burn injury . Intravenous injection of semapimod, a selective inhibitor of macrophage activation, 1 hour after burn in a swine model reduced depth of cellular necrosis and thrombosis, resulting in faster reepithelialization . These studies have successfully demonstrated that early intervention of inflammatory modulation can potentially halt burn wound progression, but developing a targeted method for accomplishing this without significant risks of systemic complications has not been achieved.…”

Dual therapeutic functions of F-5 fragment in burn wounds: preventing wound progression and promoting wound healing in pigs

“… 35 Several groups reported that topical application of inhibitors of tumor necrosis factor α production or anti- tumor necrosis factor α antibodies reduced the inflammatory response and lessened burn wound progression in pigs. 36 , 37 Taira et al . reported that Rosiglitazone, an insulin sensitizer that enhances the responses of the target cells to insulin, reduces burn progression in rats.…”