Septic shock is a major public health problem in both adults and children, and consequently there is a need to develop novel targets and therapeutic strategies. Based on microarray-centered clinical studies and follow up animal-centered experiments, we have indentified matrix metallopeptidase-8 (MMP-8) as a candidate target in sepsis pathology. MMP-8 is best known as a neutrophil product that cleaves collagen type 1 during extra-cellular matrix turnover. However, it has now become evident that MMP-8 also modulates acute inflammation and may play a role in sepsis pathology. The overarching hypothesis of this proposal is that MMP-8 expression and activity play a major role in sepsis pathology. We are now proposing to test this hypothesis via four complementary Specific Aims.
In Specific Aim 1 we will test the hypothesis that inhibition of MMP-8 activity improves multiple endpoints relevant to sepsis pathology.
This Aim will use MMP-8 null animals and a pharmacologic inhibitor of MMP-8 activity.
In Specific Aim 2 we will test the hypothesis that developmental age influences the role of MMP-8 in sepsis.
This Aim will use a sepsis model adaptable to 1 week old mouse pups, and will also make use of MMP-8 null mice and a pharmacologic inhibitor of MMP-8 activity.
In Specific Aim 3 we will test the hypothesis that bone marrow-derived cells are the main source of MMP-8 gene regulation in sepsis. The in vivo experiments for this Aim will involve adoptive transfer of MMP-8 null bone marrow to wild-type mice, and vice versa. The in vitro experiments for this Aim will systematically elucidate the signaling mechanisms that lead to de novo MMP-8 gene expression in neutrophils and monocytes.
In Specific Aim 4 we will test the hypothesis that collagen type 1 degradation products are involved in the mechanism by which MMP-8 regulates inflammation. The in vitro experiments for this Aim will test the ability of conditioned media, derived from collagen type 1 coated tissue culture plates treated with activated MMP-8, to activate macrophages. The in vivo experiments for this Aim will measure the response to sepsis in mice having a mutation of collagen type 1, which renders it resistant to cleavage by MMP-8. The major deliverables of this proposal include the establishment of MMP-8 as a novel therapeutic target in sepsis, the elucidation of how development influences the role of MMP-8 in sepsis, the elucidation of the major cellular source of MMP-8 in sepsis, a comprehensive understanding of the signaling mechanisms involved in MMP-8 expression during inflammation, and the establishment of MMP-8-dependent collagen type 1 degradation products as danger associated molecular patterns for the innate immune system.

Public Health Relevance

The deliverable of this program will be the elucidation of a major role for MMP-8 expression and activity in sepsis pathology. Public health will be positively impacted by providing the foundation for the development of a novel therapeutic strategy for clinical sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM096994-04
Application #
8634800
Study Section
Special Emphasis Panel (ZRG1-SBIB-E (02))
Program Officer
Dunsmore, Sarah
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$290,700
Indirect Cost
$100,700
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Atkinson, Sarah J; Nolan, Meghan; Klingbeil, Lindsey et al. (2016) Intestine-Derived Matrix Metalloproteinase-8 Is a Critical Mediator of Polymicrobial Peritonitis. Crit Care Med 44:e200-6
Wheeler, Derek S; Wong, Hector R (2016) Sepsis in Pediatric Cardiac Intensive Care. Pediatr Crit Care Med 17:S266-71
Daly, Meghan C; Atkinson, Sarah J; Varisco, Brian M et al. (2016) Role of matrix metalloproteinase-8 as a mediator of injury in intestinal ischemia and reperfusion. FASEB J 30:3453-3460
Sweeney, Timothy E; Wong, Hector R (2016) Risk Stratification and Prognosis in Sepsis: What Have We Learned from Microarrays? Clin Chest Med 37:209-18
Weitkamp, Jörn-Hendrik; Guthrie, Scott O; Wong, Hector R et al. (2016) Histological chorioamnionitis shapes the neonatal transcriptomic immune response. Early Hum Dev 98:1-6
Basu, Rajit K; Donaworth, Emily; Siroky, Brian et al. (2015) Loss of matrix metalloproteinase-8 is associated with worsened recovery after ischemic kidney injury. Ren Fail 37:469-75
Wynn, James L; Guthrie, Scott O; Wong, Hector R et al. (2015) Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis. Mol Med 21:496-504
Slinko, Siarhei; Piraino, Giovanna; Hake, Paul W et al. (2014) Combined zinc supplementation with proinsulin C-peptide treatment decreases the inflammatory response and mortality in murine polymicrobial sepsis. Shock 41:292-300
Wynn, James L; Wong, Hector R; Shanley, Thomas P et al. (2014) Time for a neonatal-specific consensus definition for sepsis. Pediatr Crit Care Med 15:523-8
Atkinson, Sarah J; Wong, Hector R (2014) Identifying critically ill patients who may benefit from adjunctive corticosteroids: not as easy as we thought. Pediatr Crit Care Med 15:769-71

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