Tandem P-Selectin Glycoprotein Ligand Immunoglobulin Prevents Lung Vaso-Occlusion in SCD Mice
| Autor: | Gray D. Shaw, Ravi Vats, Egemen Tutuncuoglu, Prithu Sundd, Jesús Tejero |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Liver injury
congenital hereditary and neonatal diseases and abnormalities Lung P-selectin business.industry Immunology Cell Biology Hematology Pharmacology Lung injury medicine.disease Biochemistry Acute chest syndrome Pathophysiology medicine.anatomical_structure hemic and lymphatic diseases Blocking antibody medicine business Vaso-occlusive crisis |
| Zdroj: | Blood. 132:2364-2364 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Introduction: Sickle cell disease (SCD) is an autosomal-recessive-genetic disorder, which leads to red blood cell sickling, hemolysis and vaso-occlusion. Acute systemic painful vaso-occlusive crisis (VOC) is the predominant pathophysiology requiring emergency medical care by SCD patients. 10-20% of SCD patients hospitalized with VOC tend to develop acute chest syndrome (ACS), a type of lung injury within next few days, suggesting a role for pulmonary vaso-occlusion in ACS. This epidemiology also provides a window for therapeutic intervention provided treatments to prevent vaso-occlusion are available. Earlier, we have shown that VOC involves entrapment of large neutrophil-platelet aggregates in lung arterioles of SCD mice, which is inhibited following intravenous administration of P-selectin function blocking antibody. Recently, a tandem-P-selectin-glycoprotein-ligand-immunoglobulin (TSGL-Ig) with two P-selectin binding sites in tandem, has been shown to prevent P-selectin-dependent liver injury in mice. Here, we test the ability of TSGL-Ig in attenuating P-selectin dependent lung vaso-occlusion in SCD mice. Materials and Methods: Townes knock-in humanized SS (hα/hα:βS/βS) mice were used as SCD mice. SCD mice were intravenously (IV) challenged with 10 µmole/kg Oxy-hemoglobin (Oxy-Hb) without or with 100 µg of TSGL-Ig to trigger lung vaso-occlusion. Fluorescent anti-mouse mAbs against CD49b and Ly6G, and FITC dextran were IV administered for in vivo staining of platelets, neutrophils, and visualizing lung microvasculature, respectively. Presence or absence of lung vaso-occlusion was assessed using multi-photon excitation enabled quantitative fluorescence intravital lung microscopy (qFILM). Results and Discussion: IV administration of Oxy-Hb led to occlusion of pulmonary arterioles by large neutrophil-platelet aggregates. Remarkably, IV administration of TSGL-Ig significantly attenuated lung vaso-occlusion in SCD mice by reducing the number as well as size of neutrophil-platelet aggregates in the pulmonary arterioles of SCD mice. Conclusion: Systemic challenge with Oxy-Hb promotes lung vaso-occlusion in SCD mice. TSGL-Ig significantly reduced oxy-Hb induced lung vaso-occlusion in SCD mice, highlighting the potential of TSGL-Ig to prevent ACS. Disclosures No relevant conflicts of interest to declare. |
| Databáze: | OpenAIRE |
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