Table 1.

Molecular mediators are implicated in the pathophysiology of burn injury progression, fibrosis, and fistula development

Soluble factors, mediators, circulating chemokines, remodeling enzymes	Action in burns	Action in fistula formation	Action in fibrosis	Temperature effects	Effect of cooling on activity or expression
TNF- α	Proinflammatory cytokine	Triggers EMT, onset and progression of fistula formation	Induces apoptosis of fibrotic progenitors	Cooling significantly reduces activity
TGF-β	Worsens scar formation	Triggers EMT, onset and progression of fistula formation	Induces fibrosis	Cooling reduces mRNA expression
Angiotensin II	Possible synergistic signal to TGF-β in burn scarring	Unclear actions	Expression of genes related to fibrosis	Lowers body temperature when administered systemically
IL-1	Proinflammatory cytokine (inhibited by IL-1ra)	Inhibition alleviates severe fistulae in hidradenitis suppurativa	Profibrotic cytokine induces apoptosis of fibrotic progenitors	Downregulated or unchanged with cooling
IL-4	Anti-inflammatory cytokine	Implicated in oronasal fistula formation	Facilitates muscle regeneration	Expression levels of IL-4 anti-inflammatory cytokines increased
IL-6	Proinflammatory cytokine associated with mortality	Induced by TNF-α, increases permeability of the endothelial layer	Triggers cardiac fibrogenic signaling cascade	Reduces IL-6 expression
IL-7	Proinflammatory cytokine	Unclear actions	May inhibit high glucose-induced renal proximal tubular fibrosis	Uncertain
IL-8	Enhances neutrophil transmigration; proinflammatory cytokine associated with ARDS	Putative role in the pathogenesis of cryptoglandular anal fistula	Dominates the inflammatory profile in cystic fibrosis	Higher levels may determine severity hypoxic ischemia
IL-10	Anti-inflammatory cytokine, associated with burn mortality	Impaired IL-10 signaling implicated in inflammatory bowel fistulas	Profibrotic cytokine	Elevations delayed with hypothermia
IL-12	Proinflammatory cytokine stimulates the production of TNF-α	Elevated levels linked to enterocutaneous fistulas	Induces apoptosis of fibrotic progenitors	Reduced expression with hypothermia
IL-13	Anti-inflammatory cytokine induces metaplasia	Triggers EMT, onset and progression of fistula formation	Effects muscle regeneration by resident mesenchymal progenitor cells	Expression levels increased with hypothermia
IL-17	Proinflammatory cytokine increased during burn injuries	Proinflammatory mediator; key role in fistula formation in hidradenitis suppurativa	Mediator in foreign body response and fibrosis	Gene expression levels significantly downregulated with local cryotherapy
Matrix metalloproteinases (MMPs): MMP-1, MMP-3, MMP-9	Upregulated in vascular inflammation	Activated by EMT, causing further tissue damage and inflammation	Associated with fibrotic processes underlying right ventricular remodeling	Downregulatory effects on expression
Histamine	Increases wound edema, microvascular permeability	Unclear actions	Unclear actions	Decreases or prevents histamine release
Reactive oxygen species	Induce burn progression, edema formation, and microvascular permeability	Implicated in enterocutaneous fistula development	Associated with severity of cystic fibrosis	Reduced with hypothermia

Both fibrosis and epithelial-to-mesenchymal transition (EMT) are drivers of fistula development after an initial thermal injury, and the soluble mediators of these processes are also implicated in burn wound conversion, which further facilitates the progression of thermal injury. The activity of many proinflammatory markers is inhibited by cooling.

ARDS = acute respiratory distress syndrome; IL-1 through IL-17 = interleukin 1 through 17; MMP = matrix metalloproteinase; TGF-β = tumor growth factor beta; TNF-α = tumor necrosis factor alpha.