title: Intramicroparticle nitrogen dioxide is a bubble nucleation site leading to decompression-induced neutrophil activation and vascular injury.
abstract: Inert gases diffuse into tissues in proportion to ambient pressure, and when pressure is reduced, gas efflux forms bubbles due to the presence of gas cavitation nuclei that are predicted based on theory but have never been characterized. Decompression stress triggers elevations in number and diameter of circulating annexin V-coated microparticles (MPs) derived from vascular cells. Here we show that ∼10% MPs from wild-type (WT) but not inflammatory nitric oxide synthase-2 (iNOS) knockout (KO) mice increase in size when exposed to elevated air pressure ex vivo. This response is abrogated by a preceding exposure to hydrostatic pressure, demonstrating the presence of a preformed gas phase. These MPs have lower density than most particles, 10-fold enrichment in iNOS, and generate commensurately more reactive nitrogen species (RNS). Surprisingly, RNS only slowly diffuse from within MPs unless particles are subjected to osmotic stress or membrane cholesterol is removed. WT mice treated with iNOS inhibitor and KO mice exhibit less decompression-induced neutrophil activation and vascular leak. Contrary to injecting naïve mice with MPs from wild-type decompressed mice, injecting KO MPs triggers fewer proinflammatory events. We conclude that nitrogen dioxide is a nascent gas nucleation site synthesized in some MPs and is responsible for initiating postdecompression inflammatory injuries.
authors.affiliation: Institute for Environmental Medicine, Univ. of Pennsylvania, Philadelphia, PA 19104-6068, USA. sthom@mail.med.upenn.edu
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Thom
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Veena M
authors.initials: VM
authors.lastname: Bhopale
authors.forename: Tatyana N
authors.initials: TN
authors.lastname: Milovanova
authors.forename: Marina
authors.initials: M
authors.lastname: Bogush
authors.forename: Donald G
authors.initials: DG
authors.lastname: Buerk
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000235:genetics / Q000502:physiology; D055252:Cell-Derived Microparticles / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D003665:Decompression Sickness / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000235:genetics / Q000502:physiology*; D009504:Neutrophils / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009585:Nitrogen Dioxide / Q000378:metabolism*; D009997:Osmotic Pressure / Q000502:physiology; D026361:Reactive Nitrogen Species / Q000235:genetics / Q000378:metabolism; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism*
chemical_list: D017304:Annexin A5; D026361:Reactive Nitrogen Species; D002784:Cholesterol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D009585:Nitrogen Dioxide