title: Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboli.
abstract: In patients with sickle cell disease (SCD), the polymerization of intraerythrocytic hemoglobin S promotes downstream vaso-occlusive events in the microvasculature. While vaso-occlusion is known to occur in the lung, often in the context of systemic vaso-occlusive crisis and the acute chest syndrome, the pathophysiological mechanisms that incite lung injury are unknown. We used intravital microscopy of the lung in transgenic humanized SCD mice to monitor acute vaso-occlusive events following an acute dose of systemic lipopolysaccharide sufficient to trigger events in SCD but not control mice. We observed cellular microembolism of precapillary pulmonary arteriolar bottlenecks by neutrophil-platelet aggregates. Blood from SCD patients was next studied under flow in an in vitro microfluidic system. Similar to the pulmonary circulation, circulating platelets nucleated around arrested neutrophils, translating to a greater number and duration of neutrophil-platelet interactions compared with normal human blood. Inhibition of platelet P-selectin with function-blocking antibody attenuated the neutrophil-platelet interactions in SCD patient blood in vitro and resolved pulmonary arteriole microembolism in SCD mice in vivo. These results establish the relevance of neutrophil-platelet aggregate formation in lung arterioles in promoting lung vaso-occlusion in SCD and highlight the therapeutic potential of targeting platelet adhesion molecules to prevent acute chest syndrome.
authors.affiliation: Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Bennewitz
authors.affiliation: Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Maritza A
authors.initials: MA
authors.lastname: Jimenez
authors.affiliation: Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vats
authors.affiliation: Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Egemen
authors.initials: E
authors.lastname: Tutuncuoglu
authors.affiliation: Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Division of Hematology and Oncology, and.
authors.forename: Jude
authors.initials: J
authors.lastname: Jonassaint
authors.affiliation: Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Division of Hematology and Oncology, and.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kato
authors.affiliation: Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.affiliation: Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Prithu
authors.initials: P
authors.lastname: Sundd
mesh_terms: D056586:Acute Chest Syndrome / Q000503:physiopathology / Q000517:prevention & control; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000503:physiopathology; D000818:Animals; D001160:Arterioles / Q000166:cytology / Q000473:pathology*; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D004617:Embolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D019007:P-Selectin / Q000187:drug effects* / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000187:drug effects* / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D019007:P-Selectin; C546937:SELP protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4