Degree
Master of Science
Program
Physiology and Pharmacology
Supervisor
Dr. Sean Gill
Abstract
Acute respiratory distress syndrome (ARDS) is a lung disease involving profound inflammation. Origins of persistent inflammation in select cases of ARDS are poorly understood, and we propose persistent inflammatory macrophages may be one of its mechanisms. Macrophages polarize to either promote inflammation, or suppress inflammation. Tissue inhibitor of metalloproteinases 3 (TIMP3) reduces the pro-inflammatory polarization in macrophages. Additionally, studies have shown TIMP3 promotes apoptosis, and its absence delays recovery from bleomycin-induced lung injury.
We hypothesize that TIMP3 promotes apoptosis of murine macrophages through inhibition of metalloproteinase activity and stabilization of FAS on the cell surface. Pro-inflammatory Timp3-/- bone marrow-derived macrophages (BMDMs) have significantly higher metalloproteinase activity, and significantly lower sFASL-induced apoptosis compared to WT BMDMs measured with FLICA and Annexin V. rTIMP3 treatment rescued both metalloproteinase activity and apoptosis.
In conclusion, excessive metalloproteinase activity in Timp3-/- BMDMs is associated with sFASL-induced apoptosis potentially due to metalloproteinase dependent death receptor processing.
Recommended Citation
Brock, Michael S., "TIMP3 Regulation of Macrophage Activation and Apoptosis" (2015). Electronic Thesis and Dissertation Repository. 2740.
https://ir.lib.uwo.ca/etd/2740
Included in
Circulatory and Respiratory Physiology Commons, Medical Cell Biology Commons, Medical Physiology Commons