Tandem P-selectin glycoprotein ligand immunoglobulin prevents lung vaso-occlusion in sickle cell disease mice

Vats, Ravi; Tutuncuoglu, Egemen; Pradhan‐Sundd, Tirthadipa; Tejero, Jesús; Shaw, Gray D.; Sundd, Prithu

doi:10.1016/j.exphem.2020.03.002

Cited by 7 publications

(8 citation statements)

References 23 publications

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“…15 TSGL-Ig was previously shown to prevent ischemiareperfusion injury of orthotopic liver transplants in mice by attenuating leukocyte sequestration in the liver microcirculation, 15 and significantly attenuated intravenous oxy-hemoglobin triggered lung vasoocclusion in sickle cell disease mice. 16 We demonstrated that SELPLG promoter activity increases with LPS and mechanical stretch. Through serial progressive 5′ to 3′ unidirectional deletions and promoter activity assays, we identified possible SELPLG promoter regions that might affect basic and LPSinduced enhanced SELPLG transcription activities.…”

Section: Discussionmentioning

confidence: 75%

“…Spontaneously breathing (SB) control mice received intratracheal PBS instead of LPS and following 18 h period, allowed to breathe spontaneously on room air (SB) for 4 h before harvesting. TSGL-Ig (1 mg/Kg), a novel recombinant tandem PSGL1 immunoglobulin fusion molecule which is a competitive inhibitor of PSGL1/P-selectin interactions 15,16 was delivered intravenously concomitantly with LPS challenge before initiation of VILI.…”

Section: Lps/vili "Two-hit" Preclinical Ards Mouse Model and Delivery...mentioning

confidence: 99%

“…TSGL-Ig was shown to prevent ischemia-reperfusion injury, 15 and lung vasoocclusion in sickle cell disease mice. 16 However, the functions of TSGL-Ig in sepsis-induced ARDS and VILI are unknown. In addition to novel studies utilizing the novel, immunoglobulin fusion molecule, TSGL-Ig, we examined the transcriptional regulation of SELPLG promoter in response to ARDS stimuli (LPS, 18% cyclic stretch [CS]), and genetic and epigenetic regulation of SELPLG by ARDS relevant transcription factors.…”

Section: Introductionmentioning

confidence: 99%

“…11 Consistent with this observation, the infusion of a FDA-approved P-selectinbinding humanized monoclonal antibody, Crizanlizumab, 12 dramatically reduced lung injury in a rat model of ARDS 13 and significantly reduced the rate of vasoocclusive crises in sickle cell diseases. 14 In the current study, we employed Tandem P-selectin glycoprotein ligand-1 immunoglobulin (TSGL-Ig), a novel recombinant tandem PSGL1 immunoglobulin fusion molecule and competitive inhibitor of PSGL1/P-selectin interactions, 15,16 to further investigate the role of PSGL1 in preclinical ARDS models of LPS combined with VILI. TSGL-Ig carries two P-selectin sulfated-glycopeptidebinding domains resulting in a dimer with 4 P-selectin binding sites per molecule of TSGL-Ig compared to 2 sites for regular monoclonal antibody.…”

Section: Introductionmentioning

confidence: 99%

“…TSGL‐Ig carries two P‐selectin sulfated‐glycopeptide‐binding domains resulting in a dimer with 4 P‐selectin binding sites per molecule of TSGL‐Ig compared to 2 sites for regular monoclonal antibody. TSGL‐Ig was shown to prevent ischemia‐reperfusion injury, 15 and lung vaso‐occlusion in sickle cell disease mice 16 . However, the functions of TSGL‐Ig in sepsis‐induced ARDS and VILI are unknown.…”

Section: Introductionmentioning

confidence: 99%

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Targeting SELPLG/P‐selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter

et al. 2023

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We previously identified a missense single nucleotide polymorphism rs2228315 (G>A, Met62Ile) in the selectin-P-ligand gene (SELPLG), encoding P-selectin glycoprotein ligand 1 (PSGL-1), to be associated with increased susceptibility to acute respiratory distress syndrome (ARDS). These earlier studies demonstrated that SELPLG lung tissue expression was increased in mice exposed to lipopolysaccharide (LPS)-and ventilator-induced lung injury (VILI) suggesting that inflammatory and epigenetic factors regulate SELPLG promoter activity and transcription. In this report, we used a novel recombinant tandem PSGL1 immunoglobulin fusion molecule (TSGL-Ig), a competitive inhibitor of PSGL1/P-selectin interactions, to demonstrate significant TSGL-Ig-mediated decreases in SELPLG lung tissue expression as well as highly significant protection from LPS-and VILI-induced lung injury.In vitro studies examined the effects of key ARDS stimuli (LPS, 18% cyclic stretch to simulate VILI) on SELPLG promoter activity and showed LPSmediated increases in SELPLG promoter activity and identified putative promoter regions associated with increased SELPLG expression. SELPLG promoter activity was strongly regulated by the key hypoxia-inducible transcription factors, HIF-1α, and HIF-2α as well as NRF2. Finally, the transcriptional regulation of SELPLG promoter by ARDS stimuli and the effect of DNA methylation on SELPLG expression in endothelial cell was confirmed.These findings indicate SELPLG transcriptional regulation by clinicallyrelevant inflammatory factors with the significant TSGL-Ig-mediated attenuation of LPS and VILI highly consistent with PSGL1/P-selectin as therapeutic targets in ARDS.

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Section: Discussionmentioning

confidence: 75%

Section: Lps/vili "Two-hit" Preclinical Ards Mouse Model and Delivery...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting SELPLG/P‐selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter

et al. 2023

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Live Imaging of the Lung

et al. 2020

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Live imaging is critical to determining the dynamics and spatial interactions of cells within the tissue environment. In the lung, this has proven to be difficult due to the motion brought about by ventilation and cardiac contractions. A previous version of this Current Protocols in Cytometry article reported protocols for imaging ex vivo live lung slices and the intact mouse lung. Here, we update those protocols by adding new methodologies, new approaches for quantitative image analysis, and new areas of potential application.

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