A novel role for matrix metalloproteinase-8 in sepsis*

Abstract

Objectives Matrix metalloproteinase-8 (MMP-8) mRNA expression was previously found to be increased in whole blood of children with septic shock. The impact of this finding on the severity and inflammatory response to sepsis is unknown. Here, we investigate the relationship between MMP-8 and disease severity in a children with septic shock. We further corroborate the role of MMP-8 in sepsis in a murine model. Design Retrospective observational clinical study and randomized controlled laboratory experiments. Setting Pediatric intensive care units and an animal research facility at an academic children’s hospital. Patients/Subjects Patients age ≤ 10 years admitted to the intensive care unit with a diagnosis of septic shock. For laboratory studies, we utilized male mice deficient for MMP-8 and male wild type C57/Bl6 mice. Interventions Blood from children with septic shock was analyzed for MMP-8 mRNA expression and MMP-8 activity, and correlated with disease severity based on mortality and degree of organ failure. A murine model of sepsis was used to explore the effect of genetic and pharmacologic inhibition of MMP-8 on the inflammatory response to sepsis. Finally, activation of nuclear factor-κB (NF-κB) was assessed both in vitro and in vivo. Measurements and Main Results Increased MMP-8 mRNA expression and activity in septic shock correlates with decreased survival and increased organ failure in pediatric patients. Genetic and pharmacologic inhibition of MMP-8 leads to improved survival and a blunted inflammatory profile in a murine model of sepsis. We also identify MMP-8 as a direct in vitro activator of the pro-inflammatory transcription factor, NF-κB. Conclusions MMP-8 is a novel modulator of inflammation during sepsis and a potential therapeutic target.

Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis

“…IL-1R2 is a decoy receptor for IL-1 and highlights the tightly regulated activity of IL-1 in neonates (21). Several innate immunityrelated genes with biology significance were represented among the top 10 in three of the four infected groups, including MMP-8 (metalloproteinase-8, a neutrophil-derived collagenase involved in the degradation of type I collagen [22]), olfactomedin 4 (OLFM4; present in neutrophil granules [23] and potentially important in neutrophil extracellular trap [NET] formation [24]), membranespanning 4-domains, subfamily A, member 4A (MS4A4A; tetraspanin; important for cell migration [25]) and IL-18R1 (receptor for proinflammatory cytokine IL-18 [21] and also ranked eleventh in the early sepsis group). Top downregulated genes were far more varied among groups compared with those that were upregulated.…”

Matrix Metalloprotease 8-Dependent Extracellular Matrix Cleavage at the Blood-CSF Barrier Contributes to Lethality during Systemic Inflammatory Diseases

“…Solan et al (2012) reported that MMP8 inhibition can improve outcome in experimental sepsis. Moreover, serum MMP8 levels at admission to intensive care unit were high among sepsis patients with fatal outcome (Lauhio et al, 2011).…”

“…Consequently, they are involved in several inflammatory diseases (Wielockx et al, 2001;Vanlaere and Libert, 2009;Dejonckheere et al, 2011b;Vandenbroucke et al, 2011). Solan et al (2012) recently reported that MMP8 inhibition can improve outcome in experimental sepsis. Moreover, serum MMP8 levels at admission to intensive care units were high among sepsis patients with fatal outcome (Lauhio et al, 2011).…”

Genome-Wide Expression Profiles in Very Low Birth Weight Infants With Neonatal Sepsis

“…14,36 Furthermore, in a murine model of sepsis, either genetic or pharmacologic inhibition of MMP8 activity significantly increased survival rates. 37 MMPs play an important role in the remodeling of a number of tissues. These enzymes are the only ones capable of degrading the components of the extracellular matrix.…”