It is recommended that aspirin be avoided in the symptomatic management of Ebola. (1) However, the upregulation of heme oxygenase by cobalt protoporphyrin has been shown to have an attenuating effect on the viral replication and transcription rates of the Ebola virus. Aspirin also induces heme oxygenase. Therefore it may also slow Ebola replication.
Although there are a number of therapeutic agents under development, none have yet been approved for Ebola (EBOV), and at present treatment consists of IV fluids, maintenance of oxygen status and blood pressure and management of secondary infections. Once the disease is advanced prognosis is poor. If the progress of the disease could be slowed during early infection while arrangements to travel to hospital were being made, outcomes may be improved.
EBOV infection of macrophages and monocytes leads to hypercytokinaemia, which causes superoxide-mediated endothelial damage and the characteristic haemorrhaging, and activation of the coagulation cascade, which causes thrombosis.
Thus treatment of patients with EBOV depends not only on the inhibition of the virus but management of hypercytokinaemia. Heme oxygenase has been shown to have a mitigating effect in both these areas.
Heme oxygenase (HO-1) catalyses the degradation of heme to carbon monoxide, free iron and biliverdin. It can protect from septic shock and the oxidative injury experienced in hypercytokinaemia. (2). Upregulation of HO-1 with cobalt protoporphyrin has been shown to inhibit EBOV replication. This was shown to be an HO-1 dependent effect. Entry and budding were not affected, but viral replication and transcription were attenuated. (3) This may be due to the up-regulation of IFN-stimulated genes and the anti-oxidant effect of HO-1.
Other inducers of HO-1 include statins, rapamycin, paclitaxel, nitric oxide, probucol and aspirin.
Aspirin has been shown to produce significant dose-related increases in HO-1 in vivo (4), and in cultured human endothelial cells aspirin increased (HO-1) protein levels in a concentration-dependent fashion up to fivefold over basal levels. (5). Therefore viral replication and transcription of EBOV should be attenuated by aspirin.
Aspirin induces HO-1 by enhancing the production of 15-epi-lipoxin A4, (6), which stimulates NO production. This leads to an increase in HO-1 concentration. Other cyclooxygenase inhibitors such as indomethacin do not induce HO-1. (5). In vitro models show that aspirin is associated with an increase in O2 -scavenging, protecting endothelial cells from free radical-mediated toxicity. (5). Thus aspirin could mitigate the effects of hypercytokinaemia.
Conclusion
Although aspirin will not stop entry and budding of EBOV, it is likely to slow replication by the induction of HO-1, and could lessen cytokine-mediated endothelial damage by the scavenging of superoxide radicals. Therefore aspirin at the first onset of symptoms and in tandem with rehydration therapies may have a beneficial effect.
I declare no competing interests.
References
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4. Hennekens, CH, Schneider, WR, Pokov, A, Hetzel, S, David DeMets, D, Schröder, H, Victor Serebruany, V. (2009) Circulation 2009;120:S405.) “Usual Doses of Aspirin Markedly Increase Nitric Oxide Formation in Humans.”
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