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Poldip2 deficiency protects against lung edema and vascular inflammation in a model of acute respiratory distress syndrome.

ABSTRACT: Acute respiratory distress syndrome (ARDS) in a deadly disease that can be brought on by endotoxins such as lipopolysaccharide (LPS). ARDS is characterized by vascular permeability, a severe inflammatory response, lung leukocyte infiltration, and resultant lung edema. Polymerase ?-interacting protein 2 (Poldip2) is a novel regulator of blood-brain barrier permeability; however, its role in regulating lung permeability and vascular inflammation is unknown. Here, the role of Poldip2 in regulating vascular permeability and inflammation in a mouse model of ARDS was assessed. Heterozygous deletion of Poldip2 was found to reduce LPS-induced mortality within 20 h, lung inflammatory signaling, and leukocyte infiltration. Moreover, reduced Poldip2-suppressed LP-induced vascular cell adhesion molecule (VCAM)-1 induction, leukocyte recruitment, and mitochondrial reactive oxygen species (ROS) production in vitro These data indicate that Poldip2 is an important regulator of the debilitating consequences of ARDS, potentially through the regulation of mitochondrial ROS-induced inflammatory signaling. Consequently, inhibition of Poldip2 may be a viable option for therapeutic discovery moving forward.

SUBMITTER: Forrester SJ

PROVIDER: S-EPMC7954131 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Poldip2 deficiency protects against lung edema and vascular inflammation in a model of acute respiratory distress syndrome.

Forrester Steven J SJ Xu Qian Q Kikuchi Daniel S DS Okwan-Duodu Derick D Campos Ana Carolina AC Faidley Elizabeth A EA Zhang Guogang G Lassègue Bernard B Sadikot Ruxana T RT Griendling Kathy K KK Hernandes Marina S MS

Clinical science (London, England : 1979) 20190125 2

Acute respiratory distress syndrome (ARDS) in a deadly disease that can be brought on by endotoxins such as lipopolysaccharide (LPS). ARDS is characterized by vascular permeability, a severe inflammatory response, lung leukocyte infiltration, and resultant lung edema. Polymerase δ-interacting protein 2 (Poldip2) is a novel regulator of blood-brain barrier permeability; however, its role in regulating lung permeability and vascular inflammation is unknown. Here, the role of Poldip2 in regulating ...[more]

PMID: 30622219

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Project description:Background Lung injury, a severe adverse outcome of lipopolysaccharide-induced acute respiratory distress syndrome, is attributed to excessive neutrophil recruitment and effector response. Poldip2 (polymerase δ-interacting protein 2) plays a critical role in regulating endothelial permeability and leukocyte recruitment in acute inflammation. Thus, we hypothesized that myeloid Poldip2 is involved in neutrophil recruitment to inflamed lungs. Methods and Results After characterizing myeloid-specific Poldip2 knockout mice, we showed that at 18 hours post-lipopolysaccharide injection, bronchoalveolar lavage from myeloid Poldip2-deficient mice contained fewer inflammatory cells (8 [4-16] versus 29 [12-57]×104/mL in wild-type mice) and a smaller percentage of neutrophils (30% [28%-34%] versus 38% [33%-41%] in wild-type mice), while the main chemoattractants for neutrophils remained unaffected. In vitro, Poldip2-deficient neutrophils responded as well as wild-type neutrophils to inflammatory stimuli with respect to neutrophil extracellular trap formation, reactive oxygen species production, and induction of cytokines. However, neutrophil adherence to a tumor necrosis factor-α stimulated endothelial monolayer was inhibited by Poldip2 depletion (225 [115-272] wild-type [myePoldip2+/+] versus 133 [62-178] myeloid-specific Poldip2 knockout [myePoldip2-/-] neutrophils) as was transmigration (1.7 [1.3-2.1] versus 1.1 [1.0-1.4] relative to baseline transmigration). To determine the underlying mechanism, we examined the surface expression of β2-integrin, its binding to soluble intercellular adhesion molecule 1, and Pyk2 phosphorylation. Surface expression of β2-integrins was not affected by Poldip2 deletion, whereas β2-integrins and Pyk2 were less activated in Poldip2-deficient neutrophils. Conclusions These results suggest that myeloid Poldip2 is involved in β2-integrin activation during the inflammatory response, which in turn mediates neutrophil-to-endothelium adhesion in lipopolysaccharide-induced acute respiratory distress syndrome.

Dataset Information

Poldip2 deficiency protects against lung edema and vascular inflammation in a model of acute respiratory distress syndrome.

Publications

Poldip2 deficiency protects against lung edema and vascular inflammation in a model of acute respiratory distress syndrome.

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