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.

Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity

“…Images were acquired for each experiment using the same gamma settings for all samples and processed using Photoshop II software (Adobe). (Ipaktchi et al, 2006;Wilson et al, 2007). In brief, animals were anaesthetized by 3% isoflurane inhalant, weighed, and pretreated for 30 min by intravenous administration of either sterile HBSS vehicle or fasudil at 20 µg/kg mouse, as previously described (Yamashita et al, 2007;Slotta et al, 2008), and EB (500 µg/25 g mouse).…”

An Oligodeoxynucleotide with AAAG Repeats Significantly Attenuates Burn-induced Systemic inflammatory Responses by inhibiting interferon Regulatory Factor 5 Pathway

“…ALI has been attributed with burn-induced systemic production of a large amount of TNF-α (45). In rodents, a burn-induced elevation of TNF-α in serum was correlated with ALI (20,46). In humans, elevated serum levels of TNF-α was considered to have predictive value for development of ALI/ adult respiratory distress syndrome and associated with patient mortality (47).…”

“…Owing to a high risk of multiple organ failure seen in burn-induced ALI (19,20), we tested whether the AAAG ODN could reduce the lung injury of the model mice. Histopathologically, at 24 h post burn injury, the lungs of burn-injured mice treated with PBS and control ODN displayed thickened and congested alveolar walls and numerous infiltrated inflammatory cells.…”

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

“…Studies have shown that p38 (67)(68)(69) and JNK (70,71) contribute to ALI after burn; furthermore, it has been reported that activation of p38 upregulates COX-2 levels in the gastrointestinal tract after burn (72), but not in the lungs. ERK1/2 has been implicated in many trauma or stress-related injury models, such as ischemic injury (73,74), hemorrhage (75), sepsis (34), and acute pancreatitis (76).…”