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Attenuating Burn Wound Inflammatory Signaling Reduces Systemic Inflammation and Acute Lung Injury¹

Kyros Ipaktchi^*, Aladdein Mattar^*, Andreas D. Niederbichler^*, Laszlo M. Hoesel, Sabrina Vollmannshauser^*, Mark R. Hemmila^*, Grace L. Su, Daniel G. Remick, Stewart C. Wang^* and Saman Arbabi^2,

^* Department of Surgery, Department of Pathology, and Department of Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; and Department of Surgery, University of Washington, Seattle, WA 98104

The relationship between local inflammation and the subsequent systemic inflammatory response is poorly described. In a burn injury model, the dermal inflammatory response may act as an ongoing trigger for the systemic inflammatory response syndrome (SIRS) and subsequent systemic complications. We hypothesized that topical attenuation of burn wound inflammatory signaling will control the dermal inflammatory source, attenuate SIRS, and reduce acute lung injury. Mice received a 30% total body surface area burn. Subgroups were treated with specific p38 MAPK inhibitor or vehicle, which was topically applied to wounds. Topical p38 MAPK inhibition significantly reduced burn wound inflammatory signaling and subsequent systemic expression of proinflammatory cytokines and chemokines. In vitro macrophage functional assays demonstrated a significant attenuation in serum inflammatory mediators from animals receiving the topical inhibitor. Topical p38 MAPK inhibition resulted in significantly less pulmonary inflammatory response via reduction of pulmonary neutrophil sequestration, pulmonary cytokine expression, and a significant reduction in pulmonary microvascular injury and edema formation. Although dermal activating transcription factor-2, a downstream p38 MAPK target, was significantly reduced, there was no reduction in pulmonary activating transcription factor-2 expression, arguing against significant systemic absorption of the topical inhibitor. These experiments demonstrate a strong interaction between dermal inflammation and systemic inflammatory response. Attenuating local inflammatory signaling appears effective in reducing SIRS and subsequent systemic complications after burn injury.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants K08-GM069437 and P01-GM067189-01, the Surgical Infection Society Foundation, and the American Association for the Surgery of Trauma.

² Address correspondence and reprint requests to Dr. Saman Arbabi, Harborview Medical Center, 325 Ninth Avenue, Box 359796, Seattle, WA 98104. E-mail address: sarbabi{at}u.washington.edu

³ Abbreviations used in this paper: SIRS, systemic inflammatory response syndrome; ALI, acute lung injury; ATF, activating transcription factor; BR, burn animal; BR plus SB, burn and topical SB202190 application; CT, cycle threshold; EB, Evans blue; iNOS, inducible NO synthase; MPO, myeloperoxidase; PMN, polymorphonuclear cell; SH, sham animal.