Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Dr Gediminas Cepinskas

Abstract

Acute limb compartment syndrome (CS), a devastating complication of musculoskeletal trauma, develops in response to elevation of the pressure within a closed osseofascial compartment, producing muscle- and limb-threatening ischemia. Full decompression of all involved compartments by fasciotomy is the current gold-standard therapy, but it must be performed within a surgical window of 6-8 hours, before tissue damage becomes permanent.

Carbon monoxide (CO), a byproduct of heme metabolism, has been shown protective in ischemia. While inhalation of CO leads to elevation of carboxyhemoglobin (COHb), recent development of transitional metal carbonyls, CO-releasing molecules (CO-RMs), particularly the water-soluble CORM-3, delivers CO in a controlled manner without COHb formation, making it well suited to clinical applications.

The purpose of this thesis was to examine the effects of CORM-3-derived CO on microvascular dysfunction due to elevated compartment pressure within skeletal muscle, using clinically relevant models of CS. The efficacy of both CO and CORM-3 was tested in the rat, demonstrating that CORM-3, just like inhaled CO, was able to prevent the CS-associated microvascular perfusion deficits, tissue injury and inflammation, all without the CO-generated elevation of COHb.

The effects of CORM-3 were then tested in a preclinical large animal model of CS (pig), demonstrating the abolition of CS-induced systemic leukocyte activation correlated with the inhibition of systemic TNF-α release, improved tissue microvascular perfusion, diminished tissue injury and apoptosis.

To lay the foundation for translation of animal CS research to humans, CS was modelled in vitro, employing tissue culture of human vascular endothelial cells and serum of CS patients. CORM-3 was able to prevent free-radical formation, breakdown of endothelial barrier, apoptosis, leukocyte activation and transendothelial migration in response to CS stimulus.

Thus, CORM-3 appears to have an enormous clinical potential; it might be capable of at least prolonging the surgical window, if not significantly reducing the need for fasciotomy