Editors' ChoiceSepsis

Patients Point the Way

See allHide authors and affiliations

Science Translational Medicine  07 Mar 2012:
Vol. 4, Issue 124, pp. 124ec42
DOI: 10.1126/scitranslmed.3003953

In The Year of Magical Thinking, author Joan Didion recounts her daughter’s devastating progression to septic shock, a time that “cut loose any fixed idea” she “ever had about death, about illness …” Biomedical researchers have had a tough time designing therapies for sepsis—a deadly syndrome characterized by a systemic infection that can lead to a subsequent systemic inflammatory response and multisystem organ dysfunction. Sepsis is the 10th leading cause of death in the United States and remains one of the most common reasons for admission to both adult and pediatric intensive care units. Years of research and countless clinical trials have failed to yield a therapeutic regimen that goes beyond antibiotic administration and supportive care. Now, Solan and colleagues report on their translational study that linked data from critically ill children with severe sepsis and septic shock to mechanistic mouse models of severe sepsis, with a focus on matrix metalloproteinase–8 (MMP-8). Originally identified as proteolytic enzymes, MMPs are now also thought to function in the innate immune response, and prior research has suggested both pro- and anti-inflammatory roles for MMPs in sepsis. In the new work, Solan and colleagues showed that both MMP-8 gene expression and MMP-8 plasma activity were significantly higher among children with severe sepsis than in healthy controls. Likewise, both MMP-8 gene expression and plasma activity were associated with poor clinical outcomes—multisystem organ failure and death—in these patients. These clinical observations drove the authors back to the research lab, where they used mice in which MMP-8 had been knocked out and pharmacological inhibition of MMP-8 to further tease apart the role of the enzyme in sepsis. The researchers used a cecal ligation and puncture model of sepsis to demonstrate that MMP-8–deficient animals had higher survival rates and dampened inflammatory responses, as measured in both plasma and in whole-lung homogenates, as compared with controls. Last, the authors describe experiments using isolated mouse macrophages and further analyses of their knockout mouse models to suggest that MMP-8 may exert its proinflammatory effects via direct activation of the nuclear factor κB signaling pathway.

Although much remains to be learned about MMP-8 and its various biological roles in the body’s response to severe infection, this bedside-to-bench approach demonstrated the relevance of the enzyme in both human subjects afflicted with severe sepsis and more classically mechanistic animal studies. Moreover, this work showed that pharmacological inhibition of MMP effectively blunted the inflammatory response and reduced mortality in a mouse model of severe sepsis—a finding of particular importance given prior research showing that commercially available derivatives of the antibiotic tetracycline inhibit MMP activity at sub-antimicrobial doses. Thus, this study that began at the bedside and moved to the bench may point the way back to the clinical realm, and perhaps to a new role for an old therapeutic agent targeting this important inflammatory pathway.

P. D. Solan et al., A novel role for matrix metalloproteinase-8 in sepsis. Crit. Care Med. 40, 379–387 (2012). [Abstract]

Navigate This Article