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PARP15 promotes vascular barrier integrity in inflammation

ABSTRACT: The vascular endothelial barrier, which supports balanced plasma solute and macromolecule composition, controls hemostasis, and limits leukocyte extravasation at homeostasis, is frequently disrupted in inflammation associated with sepsis and other critical illness. Monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS, Clarkson disease) is a rare and devastating disorder characterized by relapsing-remitting episodes of spontaneous, profound microvascular hyper-permeability. A loss of function (LOF) mutation (G628R) in the mono ADP-ribosyltransferase PARP15, a protein of unknown function that is absent in mice, is associated with ISCLS and correlates with clinical markers of severe vascular leakage. In vascular endothelial cells, PARP15 suppresses cytokine-induced barrier disruption by ADP-ribosylating the scaffold protein JNK-interacting protein 3 (JIP3) and inhibiting p38 MAP kinase activation. Mice expressing human wild type (WT) PARP15 have curtailed inflammation-associated vascular leakage compared to mice expressing PARP15(G628R) in a p38-dependent fashion. Thus, PARP15 is essential for vascular endothelial barrier function under inflammatory stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236167 | GEO | 2024/06/29

REPOSITORIES: GEO

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Project description:Background: Microvascular injury and increased vascular leakage are prominent features of the radiation-induced lung injury (RILI) which follows cancerâ??associated thoracic irradiation. The mechanisms of RILI are incompletely understood and therapeutic strategies to limit RILI are currently unavailable. We established a murine model of radiation pneumonitis in order to assess mechanism-based therapies for RILI-induced inflammation and vascular barrier dysfunction. Based on prior studies, we investigated the therapeutic potential of simvastatin as a vascular barrier protective agent in RILI. Methods: C57BL6/J mice receiving single dose exposure to 18, 20, 22, or 25 Gy, (n=10/group) were temporally assessed (4-12 weeks) for cellular and biochemical indices of injury present in both bronchoalveolar lavage (BAL) and lung tissues (cytokines, tyrosine nitrosylated proteins, leukocytes, extravasation of Evans blue dye or EBD, BAL albumin, histology). In specific experiments, irradiated mice (25Gy) received simvastatin (10 mg/kg) via intraperitoneal injection three times a week (pre and post irradiation) for 2- 6 weeks post irradiation. Results. Acute RILI evolved in a dose- and time-dependent fashion. Mice irradiated with 25Gy exhibited modest increases in BAL leukocytes but significant increases in BAL IL-6 (p=0.03) and TNF-a (p=0.01) at 4 weeks compared to controls. Increases in BAL nitrotyrosine content peaked at 6 weeks (p=0.03) and was accompanied by marked nitrotyrosine immunostaining in lung tissues. Indices of increase lung vascular permeability such as EBD extravasation, BAL protein and BAL albumin significantly increased over time beginning at 6 weeks (p>0.002 all) with histological evidence of severe edema formation and airway inflammation. Simvastatin- treated irradiated mice were noted to exhibit marked attenuation of vascular leak with significantly decreased BAL protein (p=0.01) and inflammatory cell infiltration (50% reduction). Conclusion: Simvastatin is a potentially important therapeutic strategy to limit RILI and may influence radiation associated morbidity and mortality. We used microarrays to detail the global programme of gene expression induced by radiation in Wild type and the protection of SIMVA Experiment Overall Design: animals were treated by Vehical, Radiation (25Gy), SIMVA(10mg/kg), or both.

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PARP15 promotes vascular barrier integrity in inflammation

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