Attenuating burn wound inflammatory signaling reduces systemic inflammation and acute lung injury.

Abstract

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.

• Authors: Kyros Ipaktchi, Aladdein Mattar, Andreas D Niederbichler, Laszlo M Hoesel, Sabrina Vollmannshauser, Mark R Hemmila, Grace L Su, Daniel G Remick, Stewart C Wang, Saman Arbabi
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 177 Issue 11 Pg. 8065-71 (Dec 01 2006) ISSN: 0022-1767 [Print] United States
• PMID: 17114480 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Enzyme Inhibitors
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Burns (complications, immunology)
• Cytokines (biosynthesis)
• Enzyme Inhibitors (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression
• Inflammation (immunology)
• Mice
• Mice, Inbred C57BL
• Respiratory Distress Syndrome (etiology, immunology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects, immunology)
• Skin (immunology, pathology)
• Systemic Inflammatory Response Syndrome (etiology, prevention & control)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, drug effects)