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Effect Of Brain Death On Microvasculature, S-nitroso-hemoglobin (sno-hb) And Sings Of Ischemia: Implications For Vascular Composite Allografts In Brain Dead Donors
Mohamed Awad, MD, Cristin Coquillard, MD, Arvin Smith, MS, James Reyonlds, PhD, Anand Kumar, MD.
Case Western Reserve University, Cleveland, OH, USA.

Effect of Brain Death on Microvasculature, S-Nitroso-Hemoglobin (SNO-Hb) and Sings of Ischemia: Implications for Vascular Composite Allografts in Brain Dead Donors.
Introduction: Brain death (BD) results in intense sympathetic stimulation that results in organ and extremity hypoperfusion and hypoxia. The effects of BD pathophysiology on muscle tissue in VCA transplants have not been well studied. Our lab has demonstrated that decreased S-nitroso-hemoglobin (SNO-Hb) after BD correlates with tissue ischemia and hypoxia. We hypothesized that BD would significantly decrease (SNO-Hb) mediated microcirculation and upregulate HIF-1 alpha in VCA muscle tissue found in hand and face transplants.
Methods In prospective cohort study of 63 adult Death by Neurological Criteria (DNC) organ donors. Serial measurements of arterial S-nitroso-hemoglobin (SNO-Hb) were collected and tissue oxygenation (StO2) were continuously measured by a tissue oxygen monitor (T-Stat) during donor support phase. Muscle samples(n=29) were harvested from the donor during organ recovery surgery, and analyzed by western blot for Hypoxia induced factor 1 alpha (HIF-1 alpha) expression as a sign of ischemia/ hypoxia, inducible NOS (iNOS/NOS2) as a sign of inflammation and endothelial NOS (p-eNOS/eNOS) as a sign of vascular activity in tissue samples. statistical analysis was performed using R software
Sign of vascular activity
Sign of inflammation
Sign of tissue hypoxia
Results: 90% of brain dead donors muscle tissue analyzed showed increased expression of HIF-1 alpha. High SNO-Hb was protective of hypoxia and negatively correlated with HIF-1 alpha (P=0.0012) (R=-0.6), H High SNO-Hb was associated with increased endothelial vasodilatory p-eNOS/eNOS (P<0.05) (R=-0.39) and tissue oxygenation (StO2) (P<0.05) (R=-0.8). All the tissue samples showed evidence of hypoxia by expression of iNOS (NOS2) with a strong positive correlation of iNOS (NOS2) and HIF-1 alpha expression (P=0.001) (R=0.75).
Conclusion: Brain Death has a negative impact on target VCA transplant muscle tissue and is mediated by a decreased level of SNO-Hb in BD donor tissue. This is associated with decreased micro circulation, increase inflammatory markers such as HIF-1 alpha and iNOS/NOS2 . S-nitrosylating modification agents are possible novel therapeutic targets to mitigate the effects of BD pathophysiology.
INOS/NOS2
P-eNOS
eNOS
HIF-1 alpha
GAPDH


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