The complement system constitutes a critical component of the innate immune response. The lectin pathway is one of the three activation pathways of the complement activation cascade that can recognise and respond to structures on oxygen deprived cells and contribute to ischaemia and reperfusion injury (IRI). Cerebral IRI mediated inflammation is known to be responsible for secondary damage in the penumbra region surrounding the initial area of infarct and the prevention of IRI-mediated secondary damage provides an attractive target for therapeutic intervention. Mannose binding lectin associated serine protease 2 (MASP-2) is the key effector enzyme of the lectin pathway, since depletion of this enzyme completely ablates lectin pathway function or activity. This study assessed the impact of MASP-2 deficiency on cerebral IRI and to what extent MASP-2 targeting can reduce the secondary inflammatory damage following an ischaemic insult. The 3 vessel occlusion (3-VO) model of stroke was found to be the most appropriate model to use in this study, as it was shown to have a lower degree of variability than the middle cerebral artery occlusion (MCAO) stroke model. TTC staining revealed that MASP-2 -/- mice were significantly protected from cerebral damage, showing statistically significant smaller infarct sizes when compared to age and sex matched wild type controls. MASP-2 deficient mice showed reduced C3 deposition and a lower degree of astrocytic activation in brain sections from mice undergoing 3-VO and showed higher mRNA abundance of anti-inflammatory mediators (such as IL-10) and lower abundance of pro-inflammatory mediators (such as MIP-2) when compared to wild type control mice. Subsequently, a recombinant inhibitory anti-MASP-2 antibody, AbD04211, a murine specific MASP-2 inhibitor, was assessed for the therapeutic utility of MASP-2 inhibition in the 3-VO cerebral IRI model of stroke. The results revealed that the use of MASP-2 inhibitors at a dose of 5mg/kg of body weight achieved a statistically significant protective effect, with infarct sizes reduced by up to 30% in the anti-MASP-2 treated animals.
|Contributors||Schwaeble, Wilhelm; Nicotera, Pierluigi|
|Publisher||University of Leicester|
|Source Sets||Ethos UK|
|Type||Electronic Thesis or Dissertation|
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