The Sphingosine-1 Phosphate receptor agonist FTY720 dose dependently affected endothelial integrity in vitro and aggravated ventilator-induced lung injury in mice

AbstractVentilator-induced lung injury (VILI) is a serious acute injury to the lung tissue that can develop during mechanical ventilation of patients. Due to the mechanical strain of ventilation, damage can occur in the bronchiolar and alveolar epithelium resulting in a cascade of events that may be fatal to the patients. Patients requiring mechanical ventilation are often critically ill, which limits the possibility of obtaining patient samples, making VILI research challenging. In vitro models are very important for VILI research, but the complexity of the cellular interactions in multi-organ animals, necessitates in vivo studies where the mouse model is a common choice. However, the settings and duration of ventilation used to create VILI in mice vary greatly, causing uncertainty in interpretation and comparison of results. This review examines approaches to induce VILI in mouse models for the last 10 years, to our best knowledge, summarizing methods and key parameters presented across the studies. The results imply that a more standardized approach is warranted.

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Adipose-derived exosomes protect the pulmonary endothelial barrier in ventilator-induced lung injury by inhibiting the TRPV4/Ca2+ signaling pathway

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00255.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. L723-L741 ◽

Cited By ~ 6

Author(s):

Qian Yu ◽

Daoxin Wang ◽

Xiaoting Wen ◽

Xumao Tang ◽

Di Qi ◽

...

Keyword(s):

Lung Injury ◽

Inflammatory Response ◽

Transient Receptor Potential ◽

Inflammatory Responses ◽

Endothelial Barrier ◽

Mouse Serum ◽

Transient Receptor Potential Vanilloid ◽

Ventilator Induced Lung Injury

Mechanical ventilation (MV) is the main supportive treatment of acute respiratory distress syndrome (ARDS), but it may lead to ventilator-induced lung injury (VILI). Large epidemiological studies have found that obesity was associated with lower mortality in mechanically ventilated patients with acute lung injury, which is known as “obesity paradox.” However, the effects of obesity on VILI are unknown. In the present study, wild-type mice were fed a high-fat diet (HFD) and ventilated with high tidal volume to investigate the effects of obesity on VILI in vivo, and pulmonary microvascular endothelial cells (PMVECs) were subjected to 18% cyclic stretching (CS) to further investigate its underlying mechanism in vitro. We found that HFD protects mice from VILI by alleviating the pulmonary endothelial barrier injury and inflammatory responses in mice. Adipose-derived exosomes can regulate distant tissues as novel adipokines, providing a new mechanism for cell-cell interactions. We extracted three adipose-derived exosomes, including HFD mouse serum exosome (S-Exo), adipose tissue exosome (AT-Exo), and adipose-derived stem cell exosome (ADSC-Exo), and further explored their effects on MV or 18% CS-induced VILI in vivo and in vitro. Administration of three exosomes protected against VILI by suppressing pulmonary endothelial barrier hyperpermeability, repairing the expression of adherens junctions, and alleviating inflammatory response in vivo and in vitro, accompanied by transient receptor potential vanilloid 4 (TRPV4)/Ca2+ pathway inhibition. Collectively, these data indicated that HFD-induced obesity plays a protective role in VILI by alleviating the pulmonary endothelial barrier injury and inflammatory response via adipose-derived exosomes, at least partially, through inhibiting the TRPV4/Ca2+ pathway.

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Mechanisms of early pulmonary neutrophil sequestration in ventilator-induced lung injury in mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00187.2004 ◽

2004 ◽

Vol 287 (5) ◽

pp. L902-L910 ◽

Cited By ~ 52

Author(s):

Sharmila Choudhury ◽

Michael R. Wilson ◽

Michael E. Goddard ◽

Kieran P. O'Dea ◽

Masao Takata

Keyword(s):

Lung Injury ◽

Tidal Volume ◽

Molecular Mechanisms ◽

Control Ventilation ◽

Volume Control ◽

Neutrophil Sequestration ◽

Ventilator Induced Lung Injury ◽

Volume Control Ventilation

Polymorphonuclear leukocytes (PMN) play an important role in ventilator-induced lung injury (VILI), but the mechanisms of pulmonary PMN recruitment, particularly early intravascular PMN sequestration during VILI, have not been elucidated. We investigated the physiological and molecular mechanisms of pulmonary PMN sequestration in an in vivo mouse model of VILI. Anesthetized C57/BL6 mice were ventilated for 1 h with high tidal volume (injurious ventilation), low tidal volume and high positive end-expiratory pressure (protective ventilation), or normal tidal volume (control ventilation). Pulmonary PMN sequestration analyzed by flow cytometry of lung cell suspensions was substantially enhanced in injurious ventilation compared with protective and control ventilation, preceding development of physiological signs of lung injury. Anesthetized, spontaneously breathing mice with continuous positive airway pressure demonstrated that raised alveolar pressure alone does not induce PMN entrapment. In vitro leukocyte deformability assay indicated stiffening of circulating leukocytes in injurious ventilation compared with control ventilation. PMN sequestration in injurious ventilation was markedly inhibited by administration of anti-L-selectin antibody, but not by anti-CD18 antibody. These results suggest that mechanical ventilatory stress initiates pulmonary PMN sequestration early in the course of VILI, and this phenomenon is associated with stretch-induced inflammatory events leading to PMN stiffening and mediated by L-selectin-dependent but CD18-independent mechanisms.

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Rap1 mediates protective effects of iloprost against ventilator-induced lung injury

Journal of Applied Physiology ◽

10.1152/japplphysiol.00462.2009 ◽

2009 ◽

Vol 107 (6) ◽

pp. 1900-1910 ◽

Cited By ~ 36

Author(s):

Anna A. Birukova ◽

Panfeng Fu ◽

Junjie Xing ◽

Konstantin G. Birukov

Keyword(s):

Lung Injury ◽

Bronchoalveolar Lavage ◽

Tidal Volume ◽

Evans Blue ◽

High Tidal Volume ◽

Protective Effects ◽

Ventilator Induced Lung Injury ◽

High Tidal Volume Ventilation ◽

Volume Ventilation

Prostaglandin I2 (PGI2) has been shown to attenuate vascular constriction, hyperpermeability, inflammation, and acute lung injury. However, molecular mechanisms of PGI2 protective effects on pulmonary endothelial cells (EC) are not well understood. We tested a role of cAMP-activated Epac-Rap1 pathway in the barrier protective effects of PGI2 analog iloprost in the murine model of ventilator-induced lung injury. Mice were treated with iloprost (2 μg/kg) after onset of high tidal volume ventilation (30 ml/kg, 4 h). Bronchoalveolar lavage, histological analysis, and measurements of Evans blue accumulation were performed. In vitro, microvascular EC barrier function was assessed by morphological analysis of agonist-induced gap formation and monitoring of Rho pathway activation and EC permeability. Iloprost reduced bronchoalveolar lavage protein content, neutrophil accumulation, capillary filtration coefficient, and Evans blue albumin extravasation caused by high tidal volume ventilation. Small-interfering RNA-based Rap1 knockdown inhibited protective effects of iloprost. In vitro, iloprost increased barrier properties of lung microvascular endothelium and alleviated thrombin-induced EC barrier disruption. In line with in vivo results, Rap1 depletion attenuated protective effects of iloprost in the thrombin model of EC permeability. These data describe for the first time protective effects for Rap1-dependent signaling against ventilator-induced lung injury and pulmonary endothelial barrier dysfunction.

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Syndecan-2–positive, Bone Marrow–derived Human Mesenchymal Stromal Cells Attenuate Bacterial-induced Acute Lung Injury and Enhance Resolution of Ventilator-induced Lung Injury in Rats

Anesthesiology ◽

10.1097/aln.0000000000002327 ◽

2018 ◽

Vol 129 (3) ◽

pp. 502-516 ◽

Cited By ~ 12

Author(s):

Claire Masterson ◽

James Devaney ◽

Shahd Horie ◽

Lisa O’Flynn ◽

Laura Deedigan ◽

...

Keyword(s):

Escherichia Coli ◽

Lung Injury ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Arterial Oxygenation ◽

Human Mesenchymal Stromal Cells ◽

Ventilator Induced Lung Injury ◽

Enhanced Resolution ◽

Macrophage Phagocytosis

Abstract What We Already Know about This Topic What This Article Tells Us That Is New Background Human mesenchymal stromal cells demonstrate promise for acute respiratory distress syndrome, but current studies use highly heterogenous cell populations. We hypothesized that a syndecan 2 (CD362)–expressing human mesenchymal stromal cell subpopulation would attenuate Escherichia coli–induced lung injury and enhance resolution after ventilator-induced lung injury. Methods In vitro studies determined whether CD362+ human mesenchymal stromal cells could modulate pulmonary epithelial inflammation, wound healing, and macrophage phagocytosis. Two in vivo rodent studies determined whether CD362+ human mesenchymal stromal cells attenuated Escherichia coli–induced lung injury (n = 10/group) and enhanced resolution of ventilation-induced injury (n = 10/group). Results CD362+ human mesenchymal stromal cells attenuated cytokine-induced epithelial nuclear factor kappa B activation, increased epithelial wound closure, and increased macrophage phagocytosis in vitro. CD362+ human mesenchymal stromal cells attenuated Escherichia coli–induced injury in rodents, improving arterial oxygenation (mean ± SD, 83 ± 9 vs. 60 ± 8 mmHg, P < 0.05), improving lung compliance (mean ± SD: 0.66 ± 0.08 vs. 0.53 ± 0.09 ml · cm H2O−1, P < 0.05), reducing bacterial load (median [interquartile range], 1,895 [100–3,300] vs. 8,195 [4,260–8,690] colony-forming units, P < 0.05), and decreasing structural injury compared with vehicle. CD362+ human mesenchymal stromal cells were more effective than CD362− human mesenchymal stromal cells and comparable to heterogenous human mesenchymal stromal cells. CD362+ human mesenchymal stromal cells enhanced resolution after ventilator-induced lung injury in rodents, restoring arterial oxygenation (mean ± SD: 113 ± 11 vs. 89 ± 11 mmHg, P < 0.05) and lung static compliance (mean ± SD: 0.74 ± 0.07 vs. 0.45 ± 0.07 ml · cm H2O−1, P < 0.05), resolving lung inflammation, and restoring histologic structure compared with vehicle. CD362+ human mesenchymal stromal cells efficacy was at least comparable to heterogenous human mesenchymal stromal cells. Conclusions A CD362+ human mesenchymal stromal cell population decreased Escherichia coli–induced pneumonia severity and enhanced recovery after ventilator-induced lung injury.

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Ventilator-induced lung injury: in vivo and in vitro mechanisms

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00154.2002 ◽

2002 ◽

Vol 283 (4) ◽

pp. L678-L682 ◽

Cited By ~ 75

Author(s):

Michael A. Matthay ◽

Sunita Bhattacharya ◽

Donald Gaver ◽

Lorraine B. Ware ◽

Lina H. K. Lim ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Barrier Properties ◽

Pulmonary Endothelium ◽

Ventilator Induced Lung Injury ◽

Proinflammatory Responses ◽

Substantial Progress ◽

Made In

A lung-protective ventilator strategy significantly reduces mortality in patients with acute lung injury. Substantial progress has been made in understanding how mechanical stress can injure the lung, both in terms of alterations in barrier properties of the pulmonary endothelium and epithelium as well as in stimulating proinflammatory responses of macrophages and neutrophils.

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Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00323.2014 ◽

2015 ◽

Vol 308 (3) ◽

pp. L259-L269 ◽

Cited By ~ 26

Author(s):

E. Letsiou ◽

A. N. Rizzo ◽

S. Sammani ◽

P. Naureckas ◽

J. R. Jacobson ◽

...

Keyword(s):

Lung Injury ◽

Experimental Models ◽

Cyclic Stretch ◽

Cell Junctions ◽

Ventilator Induced Lung Injury ◽

Abl Kinases ◽

Vitro Model ◽

Opposing Effects ◽

Pharmaceutical Agents

Endothelial dysfunction underlies the pathophysiology of vascular disorders such as acute lung injury (ALI) syndromes. Recent work has identified the Abl family kinases (c-Abl and Arg) as important regulators of endothelial cell (EC) barrier function and suggests that their inhibition by currently available pharmaceutical agents such as imatinib may be EC protective. Here we describe novel and differential effects of imatinib in regulating lung pathophysiology in two clinically relevant experimental models of ALI. Imatinib attenuates endotoxin (LPS)-induced vascular leak and lung inflammation in mice but exacerbates these features in a mouse model of ventilator-induced lung injury (VILI). We next explored these discrepant observations in vitro through investigation of the roles for Abl kinases in cultured lung EC. Imatinib attenuates LPS-induced lung EC permeability, restores VE-cadherin junctions, and reduces inflammation by suppressing VCAM-1 expression and inflammatory cytokine (IL-8 and IL-6) secretion. Conversely, in EC exposed to pathological 18% cyclic stretch (CS) (in vitro model of VILI), imatinib decreases VE-cadherin expression, disrupts cell-cell junctions, and increases IL-8 levels. Downregulation of c-Abl expression with siRNA attenuates LPS-induced VCAM-1 expression, whereas specific reduction of Arg reduces VE-cadherin expression in 18% CS-challenged ECs to mimic the imatinib effects. In summary, imatinib exhibits pulmonary barrier-protective and anti-inflammatory effects in LPS-injured mice and lung EC; however, imatinib exacerbates VILI as well as dysfunction in 18% CS-EC. These findings identify the Abl family kinases as important modulators of EC function and potential therapeutic targets in lung injury syndromes.

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Sphingolipids as a Novel Therapeutic Target in Radiation-Induced Lung Injury

Cell Biochemistry and Biophysics ◽

10.1007/s12013-021-01022-8 ◽

2021 ◽

Author(s):

Jeffrey R. Jacobson

Keyword(s):

Lung Injury ◽

Cell Injury ◽

Inflammatory Responses ◽

Small Animal ◽

Protective Effects ◽

Sphingosine 1 Phosphate ◽

Radiation Induced ◽

Injury Models

AbstractRadiation-induced lung injury (RILI) is a potential complication of thoracic radiotherapy that can result in pneumonitis or pulmonary fibrosis and is associated with significant morbidity and mortality. The pathobiology of RILI is complex and includes the generation of free radicals and DNA damage that precipitate oxidative stress, endothelial cell (EC), and epithelial cell injury and inflammation. While the cellular events involved continue to be elucidated and characterized, targeted and effective therapies for RILI remain elusive. Sphingolipids are known to mediate EC function including many of the cell signaling events associated with the elaboration of RILI. Sphingosine-1-phosphate (S1P) and S1P analogs enhance EC barrier function in vitro and have demonstrated significant protective effects in vivo in a variety of acute lung injury models including RILI. Similarly, statin drugs that have pleiotropic effects that include upregulation of EC S1P receptor 1 (S1PR1) have been found to be strongly protective in a small animal RILI model. Thus, targeting of EC sphingosine signaling, either directly or indirectly, to augment EC function and thereby attenuate EC permeability and inflammatory responses, represents a novel and promising therapeutic strategy for the prevention or treatment of RILI.

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