The influence of tissue-specific heme oxygenase-1 (HO-1) deficiency on neuronal damage induced by subarachnoid hemorrhage in mice: the role of carbon monoxide (CO)
Final Report Abstract
In this project, we define a novel role for the enzyme heme oxygenase 1 (HO-1) in microglia in response to subarachnoid hemorrhage (SAH). Our experimental study with mice, isolated primary microglia and human CSF samples shows that microglial expression of HO-1, which catalyzes the degradation of heme to bilirubin, is essential in the response to SAH by mediating clearance of blood, eliminating the pro-oxidant heme burden, but also via the generation of the gas carbon monoxide (CO) that in turn regulates erythrophagocytosis. Deficiency in microglial HO-1 was responsible for increased neuronal injury and worsened functional outcome measured by spatial memory function in a mouse model of SAH and in turn could be compensated by exogenous application of CO. Interestingly, deficiency of HO-1 in astrocytes and neurons did not influence neuronal injury or functional outcome. Experiments with isolated primary microglia demonstrated that the lack of HO-1 strongly impairs eryhtrophagocytic activity of microglia, which in turn increased neuronal cell death. Additional clinical data showed the importance of HO-1 expression and activity following SAH in humans, as cisternal hematoma volume was directly linked to the extent of HO-1 expression and activity. This study is the first to provide evidence of the potential clinical utility of HO-1 in SAH and underscores the role of HO-1 and CO in erythrophagocytosis and ultimately for the amelioration of neuronal injury following SAH. Our data do not allow us to draw any conclusion regarding HO-1 and clinical outcome after SAH due to the small sample size. However, based on the potent effects of CO in our mouse model of SAH, further clinical investigation is warranted. Indeed with inhaled CO in multiple clinical trials consideration of its use in patients diagnosed with SAH is possible.
Publications
- Circadian Rhythm in Stroke – The Influence of Our Internal Cellular Clock on Cerebrovascular Events. J Clin Exp Pathol. 2014, 4:163
Schallner N, LeBlanc R, Otterbein LE, Hanafy KA
(See online at https://dx.doi.org/10.4172/2161-0681.1000163) - Friend or Foe? Carbon Monoxide and the Mitochondria. Front Physiol. 2015, 6:17
Schallner N, Otterbein LE
(See online at https://doi.org/10.3389/fphys.2015.00017) - Microglia Regulate Blood Clearance in Subarachnoid Hemorrhage by Heme Oxygenase-1. J Clin Invest. 2015;125(7):2609–2625
Schallner N, Pandit R, LeBlanc R, Thomas A, Ogilvy C, Zuckerbraun B, Gallo D, Otterbein LE, Hanafy KA
(See online at https://doi.org/10.1172/JCI78443)
