Abstract SNACC-17

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The role of glycocalyx-dependant mechanotransduction in subarachnoid hemorrhage-induced neurogenic pulmonary edema

Changyaleket B, Dull R, Xu H
University of Illinois at Chicago, Chicago, IL, USA

Introduction:Neurogenic pulmonary edema (NPE) following subarachnoid hemorrhage (SAH) has a high morbidity and mortality rate. While the catecholamine storm following the acute increase in intracranial pressure is considered an inciting event in NPE, the precise mechanism(s) occurring at the level of the pulmonary vascular endothelium that lead to NPE are unknown. Our study uses an established model of SAH and the concept of glycocalyx-dependent mechanotransduction to investigate SAH-induced lung hyperpermeability and pulmonary inflammation that contribute to NPE.
Background:Endothelial glycocalyx (EG) is a complex layer of macromolecules that coats the luminal surface of vascular endothelium. EG participates in mechanotransduction by responding to changes in pressure and shear stress that, in turn, activate oxidative signaling pathways. Syndecan-1 (syn-1), a major heparan sulfate proteoglycan (HSPG) on EG, is believed to be a primary mechanotransducer that activates oxidative signaling. Shedding of syn-1 is a biomarker for both endothelial activation and EG degradation and may be a mechanism for increased permeability and attenuation of mechano-sensitive signaling. In NPE, the hyperadrenergic surge after SAH may trigger mechanotransduction in the pulmonary vasculature leading to lung hyperpermeability, inflammation, and edema.
Methods:SAH was induced in 4 rats by the injection of blood through the cisterna magna. At 12 hours post SAH, lungs in both sham and SAH groups were collected for histology and western blots (WB) performed to assess protein expression for syn-1 and HSPG. Catecholamine storm was also induced in normal rats by the infusion of norepinephrine (NE) for 2 hours to increase MAP from baseline (100 mm Hg) to 150 mm Hg with +/- a single bolus of L-NAME (an endothelial nitric oxide synthase and mechanotransduction inhibitor). The resulting decrease in PaO2, dynamic compliance and wet-to-dry weight (W/D) was used to assess lung edema. To investigate mechanotransduction in vitro, rat lung capillary endothelial cells were exposed to 30 cmH2O for 1 hour and then immunostained for VE-cadherin, an adherence junction molecule.
Results:Histology of the SAH group showed moderate to severe inflammatory cell infiltrate within the lung while sham lungs had mild inflammation consistent with mechanical ventilation and surgery. SAH resulted in 50-70% reduction of lung syn-1 and HSPG on WB analysis. In the hypertensive model, the animal group receiving NE infusion alone had a reduction in PaO2 of 50% while the group receiving both NE + L-NAME had a significantly less reduction in PaO2 (30%) conferring the protective effect of L-NAME. The in vitro study showed that pressure-treated cells had a significant loss of VE-Cadherin (whose loss is well described to cause hyperpermeability). Our data showed increased inflammation, syn-1 shedding, gas exchange impairment, and hyperpermeability in rats/rat lung capillary cells subjected to SAH, severe hypertension with uninhibited mechanotransduction, or pressure-induced mechanotransduction.
Conclusion:We report a first preliminary data suggesting an association between endothelial glycocalyx-induced mechanotransduction and lung hyperpermeability and inflammation seen in SAH-induced NPE.

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