Abstract
The systemic inflammatory response syndrome (SIRS) is a life-threatening condition that arises secondary to massive immune system activation or dysregulation. Damage associated molecular patterns (DAMPs) are endogenous danger signals released after trauma or sepsis that trigger these potent immune responses. DAMPS derived from mitochondrial fractions have been shown to be pro-inflammatory in mouse models and play a role in human disease. However, the role of mitochondrial DAMPs as a trigger of SIRS in dogs has not been explored. In this study we characterized the response of canine splenocytes to mitochondrial DAMPs and developed an in vitro model system to study SIRS-induced immune dysregulation in dogs. We demonstrated that splenocytes respond to crude fractionated mitochondrial and soluble protein fractions by upregulating TNF-alpha, a described biomarker for SIRS. We further studied the effects of these DAMPs on splenocyte myeloid cell subpopulations (i.e. dendritic cell and macrophage) and found similar upregulation of TNF-alpha. Our findings mimic studies in mouse splenocyte models where mitochondrial DAMPs were shown to promote TNF-alpha release, suggesting that the in vitro model employed here is useful to study the impact of mitochondrial DAMPs in dogs. Given that dogs are increasingly being used to model and optimize therapy for human disease, these results have direct applications in understanding the role of mitochondrial DAMPs in both canine and human SIRS.
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