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MMP-8 is best known as neutrophil collagenase given its neutrophil source and its ability to degrade collagen in the extracellular matrix. However, MMP-8 also appears to play a role in the inflammatory response. We have found that MMP-8 is consistently the highest expressed gene in children with septic shock, and the degree of MMP-8 expression and activity correlate with disease severity. Accordingly, we have tested the role of MMP-8 in experimental models of sepsis and have found that genetic absence of MMP-8 or pharmacological inhibition of MMP-8 confers a significant survival advantage. We are further pursuing the role of MMP-8 in sepsis via a recently funded grant from the National Institute of General Medical Science and are interested in developing collaborations with the pharmaceutical industry to further explore MMP-8 inhibition in sepsis.
In several of our gene expression studies we have reported that pediatric septic shock is characterized by early and persistent repression of gene programs that either directly participate in zinc homeostasis, or depend on zinc homeostasis for normal function. Given the established role of normal zinc homeostasis for normal functioning of the immune system, these observations have raised the possibility of zinc supplementation in sepsis. Several studies have documented a beneficial effect of zinc supplementation in animal models of sepsis. We are currently collaborating in a Phase 1 clinical trial of zinc supplementation in critical illness (NCT01062009). Natalie Cvijanovich, MD, from Children’s Hospital & Research Center Oakland is the principal investigator for this Phase 1 trial, and Alexander Vinks, PharmD, PhD, from the Division of Clinical Pharmacology at Cincinnati Children’s is providing expertise in the area of pharmacokinetics and pharmacodynamics.
Wong, H.R., Shanley, T.P., Cvijanovich, N., Allen, G.L., Lin, R., Anas, N., Meyer, K., Freishtat, R.J., Monaco, M., Odoms, K. and Sakthivel, B. Genome-wide expression profiling across the pediatric SIRS, sepsis, and septic shock spectrum. Crit Care Med. 37:1558-1566, 2009.
Shanley, T.P., Cvijanovich, N., Lin, R., Allen, G.L., Thomas, N.J., Doctor, A., Kalyanaraman, M., Tofil, N.M., Penfil, S., Monaco, M., Odoms, K., Barnes, M., Sakthivel, B., Aronow, B.J. and Wong, H.R. Genome-level longitudinal expression of signaling pathways and gene networks in pediatric septic shock. Mol Med. 13:496-508, 2007.
Wong, H.R., Shanley, T.P., Sakthivel, B., Cvijanovich, N., Lin, R., Allen, G.L., Thomas, N.J., Doctor, A., Kalyanaraman, M., Tofil, N.M., Penfil, S., Monaco, M., Tagavilla, M.A., Odoms, K., Dunsmore, K., Barnes, M. and Aronow, B.J., for the Genomics of Pediatric SIRS Investigators. Genome level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome. Physiol Genomics. 30:146-155, 2007.
PPARα belongs to a family of nuclear receptors involved in metabolism and inflammation. Repression of multiple genes corresponding to the PPARα signaling pathway is a prominent characteristic of a subclass of children with septic shock having a high level of illness severity. Consistent with this observation, we recently demonstrated that mutant mice deficient for the PPARα gene have a survival disadvantage in an experimental model of sepsis. The role of PPARα in sepsis is being further pursued by Stephen Standage, MD, a former fellow in the Wong laboratory and now a faculty member in the Division of Critical Care Medicine at Seattle Children’s Hospital.
Wong, H.R., Cvijanovich, N., Lin, R., Allen, G.L., Thomas, N.J., Willson, D.F., Freishtat, R.J., Anas, N., Meyer, K., Checchia, P.A., Monaco, M., Odoms, K. and Shanley, T.P. Identification of pediatric septic shock classes based on genome-wide expression profiling. BMC Medicine. 7:34, 2009.
We recently interrogated our expression database to determine the influence of developmental age on genome-wide expression patterns of septic shock. We compared four distinct developmental age groups (neonates, infants, toddlers and school-age) and found that neonates have the most unique gene expression pattern among the four groups. In particular, the neonate group has decreased expression of a number of key inflammation- and immune-related signaling pathway genes, thus demonstrating that developmental age greatly influences the host response to sepsis and that these differences must be taken into account when developing novel sepsis therapeutic strategies targeting the inflammatory / immune response.
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