Delayed Topical p38 MAPK Inhibition Attenuates Full-Thickness Burn Wound Inflammatory Signaling

Abstract

Objective Inflammatory signaling pathways, such as p38 MAPK play a central role in host responses to injury. In our previous studies, topical p38 MAPK inhibitors effectively attenuated inflammatory signaling in a partial-thickness scald burn model, when applied to the burn wound immediately after injury. However, clinically relevant full-thickness scald burn wounds may act as a barrier to topical immune modulators and delayed application of topical p38 MAPK inhibitors may not be effective. In this study, we evaluate the efficacy of topical p38 MAPK inhibition on full-thickness scald burns with immediate and delayed treatment. Methods C57/BL6 mice received `Sham' or 30% TBSA full-thickness scald burn injury. After injury, the burn wounds were treated with a topical p38 MAPK inhibitor or vehicle. The treatment group received topical p38 MAPK inhibitor either immediately after burn or 4 hours (delayed) after injury. All animals were sacrificed at 12 or 24 h. Burn wounds underwent histological analyses. Skin and plasma were analyzed by ELISA or RT-qPCR for cytokine expression. Results Full-thickness scald burns resulted from immersion in 62°C water for 25 s. Topical p38 MAPK inhibitor attenuated dermal IL-6, MIP-2, and IL-1β expression and plasma IL-6 and MIP-2 cytokine expression. In addition, delayed application of topical p38 MAPK inhibitors significantly reduced dermal and plasma cytokine expression compared to vehicle control. Conclusion Topical p38 MAPK inhibitors remain potent in reducing full-thickness burn wound inflammatory signaling, even when treatment is delayed by several hours post injury. Topical application of p38 MAPK inhibitor may be a clinically viable treatment after burn injury.

Toll-Like Receptor Signaling in Burn Wound Healing and Scarring

“…58 In addition, in a full-thickness burn (30% TBSA) model in mouse, topical p38 MAPK inhibitors applied 4 h postburn reduced cytokines in the dermis and circulating leukocytes. 59 Thus, p38 inhibitor treatment could penetrate the full-thickness burn eschar and be effective within a 4 h window, which suggests the feasibility of using early topical treatments to suppress inflammation that can damage tissue locally and systemically. However, these studies did not evaluate end points past 24 h.…”

Therapeutic Effect and Mechanism of Oxytropis falcata Gel on Deep Second‐Degree Burn in Rats

“…And they showed significant anti-inflammatory action ( Table 2 ). Immediate or delayed topical application for p38 inhibitor remains potent in reducing full-thickness burning inflammatory signaling [ 21 ]. Similar findings were observed in our study where the expressions of p38 and IL-1 β were significantly decreased in OFG-treated rats on days 1, 4, and 7 after burn injury.…”

Kupffer Cell p38 Mitogen-Activated Protein Kinase Signaling Drives Postburn Hepatic Damage and Pulmonary Inflammation When Alcohol Intoxication Precedes Burn Injury

“…The ability to manipulate hepatic IL-6 production through specifically targeting Kupffer cell p38 may be a more viable clinical approach than global p38 inhibition or impairment of Kupffer cell function which work at the expense of other critical functions of this pathway and cell, respectively. Inhibition of p38 in animal models has been shown to benefit local wound inflammation and remote organ damage after a burn when applied topically (45) or given systemically (29–33). However, clinical trials of p38 inhibitors for chronic inflammatory conditions have been disappointing in efficacy and fraught with adverse events, likely due to the ubiquitous and multi-functional nature of p38.…”