Abstract 20051: Divergent Actions of Circulating Angiopoietin-2 on Vascular Inflammation and Leak in a Mouse Model of Acute Lung Injury

Introduction: Angiopoietin-2 (Angpt2) is a partial agonist/antagonist of the vascular-stabilizing endothelial Tie2 receptor. In both animal models and patients with acute lung injury (ALI), Angpt2 circulating levels are elevated; however, it remains unclear whether these elevated levels contribute to, or protect against, the lung inflammation and vascular leak associated with ALI. Objective: To evaluate the biological consequences of elevated circulating Angpt2 levels in a mouse model of endotoxin-induced ALI. Methods and Results: Transgenic mice (Angpt2OVR) with elevated circulating levels of human (h)Angpt2, via conditional hepatocyte-specific overexpression, were examined at several timepoints (from 3 h to 72 h) following lipopolysaccharide (LPS)-induced ALI (n=7-14 mice/genotype group/timepoint). Bronchoalveolar lavage (BAL) neutrophil and inflammatory cytokine levels were significantly higher (P<0.05) in Angpt2OVR versus littermate controls at 48 h and 6 h post LPS, respectively. In contrast, vascular leak, evidenced by decreased BAL IgM and albumin levels at 24 and 48 h, was attenuated in Angpt2OVR mice. Systemic Angpt2 overexpression showed no net detriment or benefit for survival following LPS-induced injury (n=37-38 mice/group). Tail vein injection of an anti-hAngpt2-neutralizing aptamer (versus non-functional scrambled-sequence control; n=12-13 mice/group), reversed the pro-inflammatory and anti-leak effects observed at 48 h in LPS-injured Angpt2OVR mice. Transcript profiling, via PCR array, was also conducted to probe the effects of Angpt2 neutralization on the lung tissue expression of 84 genes involved in vascular biology. Angpt2 neutralization via aptamer caused alterations in multiple genes linked to angiogenesis, vascular tone, inflammation, apoptosis, cell adhesion, coagulation, and platelet activation (P<0.05 versus scrambled control, n=4/group). Conclusions: Angpt2 exerts differential effects on lung inflammation and permeability under pathological conditions in vivo. These data establish novel context-dependent actions of Angpt2, and suggest elevated circulating levels may help regulate multiple pathways necessary to fine-tune the vascular response to lung injury.

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miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS-induced acute lung injury mouse model by targeting progranulin

Journal of Cellular Physiology ◽

10.1002/jcp.26274 ◽

2018 ◽

Vol 233 (9) ◽

pp. 6615-6631 ◽

Cited By ~ 34

Author(s):

Wang Xie ◽

Qingchun Lu ◽

Kailing Wang ◽

Jingjing Lu ◽

Xia Gu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Mouse Model ◽

Lung Inflammation

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The Crucial Role of PPARγ-Egr-1-Pro-Inflammatory Mediators Axis in IgG Immune Complex-Induced Acute Lung Injury

Frontiers in Immunology ◽

10.3389/fimmu.2021.634889 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chunguang Yan ◽

Jing Chen ◽

Yue Ding ◽

Zetian Zhou ◽

Bingyu Li ◽

...

Keyword(s):

Transcription Factor ◽

Acute Lung Injury ◽

Lung Injury ◽

Immune Complex ◽

Inflammatory Mediators ◽

Lung Inflammation ◽

Acute Lung Inflammation ◽

Pparγ Agonist

BackgroundThe ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR) γ plays crucial roles in diverse biological processes including cellular metabolism, differentiation, development, and immune response. However, during IgG immune complex (IgG-IC)-induced acute lung inflammation, its expression and function in the pulmonary tissue remains unknown.ObjectivesThe study is designed to determine the effect of PPARγ on IgG-IC-triggered acute lung inflammation, and the underlying mechanisms, which might provide theoretical basis for therapy of acute lung inflammation.SettingDepartment of Pathogenic Biology and Immunology, Medical School of Southeast UniversitySubjectsMice with down-regulated/up-regulated PPARγ activity or down-regulation of Early growth response protein 1 (Egr-1) expression, and the corresponding controls.InterventionsAcute lung inflammation is induced in the mice by airway deposition of IgG-IC. Activation of PPARγ is achieved by using its agonist Rosiglitazone or adenoviral vectors that could mediate overexpression of PPARγ. PPARγ activity is suppressed by application of its antagonist GW9662 or shRNA. Egr-1 expression is down-regulated by using the gene specific shRNA.Measures and Main ResultsWe find that during IgG-IC-induced acute lung inflammation, PPARγ expression at both RNA and protein levels is repressed, which is consistent with the results obtained from macrophages treated with IgG-IC. Furthermore, both in vivo and in vitro data show that PPARγ activation reduces IgG-IC-mediated pro-inflammatory mediators’ production, thereby alleviating lung injury. In terms of mechanism, we observe that the generation of Egr-1 elicited by IgG-IC is inhibited by PPARγ. As an important transcription factor, Egr-1 transcription is substantially increased by IgG-IC in both in vivo and in vitro studies, leading to augmented protein expression, thus amplifying IgG-IC-triggered expressions of inflammatory factors via association with their promoters.ConclusionDuring IgG-IC-stimulated acute lung inflammation, PPARγ activation can relieve the inflammatory response by suppressing the expression of its downstream target Egr-1 that directly binds to the promoter regions of several inflammation-associated genes. Therefore, regulation of PPARγ-Egr-1-pro-inflammatory mediators axis by PPARγ agonist Rosiglitazone may represent a novel strategy for blockade of acute lung injury.

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Oxycodone attenuates vascular leak and lung inflammation in a clinically relevant two-hit rat model of acute lung injury

Cytokine ◽

10.1016/j.cyto.2020.155346 ◽

2020 ◽

pp. 155346

Author(s):

Xinyi Li ◽

Rui Li ◽

Qing Fang ◽

Muhammad Jamal ◽

Chengyao Wang ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Rat Model ◽

Lung Inflammation ◽

Vascular Leak

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Supernatant of stored platelets causes lung inflammation and coagulopathy in a novel in vivo transfusion model

Blood ◽

10.1182/blood-2009-10-248732 ◽

2010 ◽

Vol 116 (8) ◽

pp. 1360-1368 ◽

Cited By ~ 74

Author(s):

Alexander P. J. Vlaar ◽

Jorrit J. Hofstra ◽

Wim Kulik ◽

Henk van Lenthe ◽

Rienk Nieuwland ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Lung Inflammation ◽

Pulmonary Injury ◽

Blood Products ◽

Platelet Concentrates ◽

Priming Activity ◽

Neutrophil Priming

Abstract Transfusion-related acute lung injury is suggested to be a “2-hit” event resulting from priming and activation of pulmonary neutrophils. Activation may result from infusion of lysophosphatidylcholines (LysoPCs), which accumulate during storage of blood products. In the present study, we developed a syngeneic in vivo transfusion model to test whether storage of platelet concentrates (PLTs) results in lung injury in healthy rats as well as in a “2-hit” model using lipopolysaccharide-pretreated rats. In addition, the effect of washing of platelets was studied. In healthy rats, transfusion of aged PLTs caused mild lung inflammation. In LPS-pretreated rats, transfusion of aged PLTs, but not fresh PLTs, augmented pulmonary systemic coagulopathy. When PLTs components were transfused separately, supernatant of aged PLTs, but not washed aged platelets, induced pulmonary injury in the “2-hit” model. Supernatants of aged PLTs contained increased concentrations of LysoPCs compared with fresh PLTs, which enhanced neutrophil priming activity in vitro. We conclude that transfusion of aged PLTs induces lung inflammation in healthy rats. In a “2-hit” model, aged PLTs contribute to pulmonary and systemic coagulopathy, which may be mediated by LysoPCs, which accumulate in the supernatant of PLTs during storage.

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