Mechanisms Linking Chronic Obstructive Pulmonary Disease and Stroke

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Recent studies have shown that chronic obstructive pulmonary disease (COPD) is associated with an increased stroke risk2 and mortality3. Cigarette smoke is a shared risk factor for COPD and stroke. Therefore it is conceivable that the link between COPD and stroke may relate, at least in part, to cigarette smoke. During stroke, excess reactive oxygen species (ROS) or oxidative stress disrupts the blood‐brain barrier (BBB), which in turn can accentuate brain injury. Importantly, cigarette smoke increases ROS production by endothelial cells. Therefore, we tested the hypothesis that COPD/smoking worsens stroke severity by exacerbating oxidative‐induced BBB disruption after stroke. Monolayers of mouse cerebral microvascular endothelial cells (bEnd.3 cells) were pre‐treated with either vehicle, 5, 10, 20 or 40% CSE (1 h) prior to exposure to oxygen glucose deprivation (OGD) (4 h) and reoxygenation (RO) (23 h). Cells cultured under normoxic conditions (27 h) were used as controls. We assessed BBB disruption by measuring paracellular permeability (FITC‐dextran), tight junction protein expression (Western blotting), and cell viability (MTS assay). Furthermore, we measured superoxide (L‐012‐enhanced chemiluminescence) and hydrogen peroxide (H2O2) production (Amplex Red fluorescence). 10% CSE increased the paracellular permeability of bEnd.3 cells cultured under normoxic conditions, indicating BBB disruption. Furthermore, 10% CSE exacerbated (~2‐fold) the hyperpermeability of bEnd.3 cells exposed to OGD + RO (10% CSE, 5±0.9 vs. vehicle, 2.8±0.7; fold‐change relative to normoxic controls, n=8, P<0.05), indicating a worsening of BBB disruption after ischaemic‐like conditions. However, this was found to be independent of increased tight junction protein degradation (occludin or ZO‐1) or cell death (n=6, P>0.05). Contrary to our hypothesis, CSE (10% or 20%) significantly attenuated OGD/RO‐induced elevations in superoxide production (10% CSE, 97±6.3, 20% CSE 75±5 vs. vehicle, 147±16; % normoxic, n=5, P<0.05), but had no significant effect on H2O2 production (n=5, P>0.05). Thus, CSE worsens BBB disruption in an in vitro model of stroke; however, this appears to be unrelated to increased oxidative stress. Although, much more research is needed, these tantalizing findings raise the possibility that such an effect may play a role in the link between COPD and stroke.Support or Funding InformationSupported by NHMRC funding