The role of mitochondrial DAMPs on the inflammatory response in an <i>in vitro</i> model of canine SIRS

SIRS and sepsis are common systemic inflammatory conditions that affect both dogs and humans. Despite advances in optimizing supportive care, case fatality levels for these syndromes unfortunately remain high in a large subset of patients. Novel therapies are desperately needed in an attempt to mitigate the inflammatory response and improve patient outcomes in these all-too-common conditions.Endogenous danger signals from damaged cells trigger inflammatory responses in sepsis and conditions leading to SIRS. Much work has recently been performed that demonstrates the importance of signals from mitochondrial fragments – termed damage-associated molecular patterns or DAMPs – in helping to initiate and perpetuate this inflammatory response. These findings have yet to be investigated in a large animal model such as dogs. Given the similarities between dogs and humans, and questions regarding the usefulness of rodent models in modeling human disease, we have developed a preliminary <i>in vitro</i> model system to investigate the effects of mitochondrial DAMPs (as well as other DAMPs) in dogs.Our model system relies primarily on the use of splenocytes, which constitute a mixed population of inflammatory cells that is likely to mimic <i>in vivo</i> conditions and has been used by others to assess responses in models of SIRS and sepsis. Additionally, we employed dendritic cells in our model, as these antigen presenting cells are first responders to inflammatory stimuli and comprise an important subset of the splenocyte population.This study demonstrates the pro-inflammatory nature of mitochondrial DAMPs in dogs. Specifically, this work shows that mitochondrial DAMPs increase the production of the cytokine TNF-a while having little effect on IL-1ß, IL-6, IFN-a, or the expression of cell surface receptors MHC class II or CD80. Highly purified recombinant HMGB1 had no effects in our model systems. This study also validates the utility of an <i>in vitro</i> splenocyte assay to evaluate DAMP-induced inflammation in dogs. Both ELISA and qRT-PCR were useful screening methods for assessing the inflammatory response.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Veterinary Clinical Sciences

Grantor dc:publisher

The Ohio State University

Year dc:date

2013

Author dc:creator

• Friedenberg, Steven Gene

Contributors dc:contributor

• Papenfuss, Tracey

• Animal Sciences
• Animals
• Animal Diseases
• Immunology

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=osu1365174635

OAI identifier oai:identifier

oai:etd.ohiolink.edu:osu1365174635