Vital organ blood flow can be compromised by microvascular gas embolism that occurs during surgery, endoscopic procedures, and in decompression sickness. The associated morbidity and mortality carry considerable human and economic impact. The pathophysiology of gas lesion disease has been studied little and is poorly understood. The initiating events involve bubble lodging within the vasculature. The molecular mechanical basis of bubble adhesion to the vessel wall causing blood flow obstruction is unknown. Our preliminary experiments suggest that blood flow obstruction is caused by adhesion of the bubble surface to the endothelial glycocalyx. Our global hypothesis is that surface-surface adhesion interactions between the endothelial glycocalyx and the bubble interface control bubble lodging, and thus determine microcirculatory blood flow and resultant organ injury. We will test this hypothesis via four Specific Aims. To identify determinants of bubble adhesion to the vessel wall, we will use in vivo and in vitro methods and biomimetic glycocalyx constructs. Once the molecular basis of adhesion is identified, we predict that modulation of adhesion by administration of (1) surfactants (a polydimethylsiloxane, a nonionic polyol, and a perfluorocarbon) targeted to bubble-blood interfaces and (2) compounds that modify the endothelial surface layer (air stripping, degradation by Ox-LDL and Heparinase), will alter obstruction of blood flow and development of injury in embolized tissue and organs. Experimental methods will include neurobehavioral assessment, brain microdialysis, histopathology, and transcript profiling in a rat model of middle cerebral artery gas embolism, intravital microscopy in rat cremaster muscle, and measurement of bubble adhesion force in excised microvessels and in microcapillary tubes lined with synthetic endothelial surface layers. The use of preclinical novel pharmacological interventions in the proposed research will enable identification of potential therapeutic targets to reduce bubble adhesion and treat gas embolism. The only clinical alternative is hyperbaric therapy, which requires patient transport to a chamber for post- embolism treatment, and is therefore generally used only in catastrophic cases.