Cyclic stretch‐induced nuclear localization of transcription factors results in increased nuclear targeting of plasmids in alveolar epithelial cells

Lam, Anna; Dean, David A.

doi:10.1002/jgm.1187

Cited by 13 publications

(7 citation statements)

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“…3,8,66 More generally, the results alert us to the necessity of studying drug delivery in experimental models that adequately address the typical microenvironment of the target cell including biochemical and biomechanical factors such as flow and ischemia for endothelial cells, contraction for muscle cells, and stretch for alveolar epithelial cells. 67,68 …”

Section: Resultsmentioning

confidence: 99%

Acute and Chronic Shear Stress Differently Regulate Endothelial Internalization of Nanocarriers Targeted to Platelet-Endothelial Cell Adhesion Molecule-1

Han¹,

Zern²,

Shuvaev³

et al. 2012

ACS Nano

105

118

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Intracellular delivery of nanocarriers (NC) is controlled by their design and target cell phenotype, microenvironment, and functional status. Endothelial cells (EC) lining the vascular lumen represent an important target for drug delivery. Endothelium in vivo is constantly or intermittently (as, for example, during ischemia-reperfusion) exposed to blood flow, which influences NC–EC interactions by changing NC transport properties, and by direct mechanical effects upon EC mechanisms involved in NC binding and uptake. EC do not internalize antibodies to marker glycoprotein PECAM(CD31), yet internalize multivalent NC coated with PECAM antibodies (anti-PECAM/NC) via a noncanonical endocytic pathway distantly related to macropinocytosis. Here we studied the effects of flow on EC uptake of anti-PECAM/NC spheres (∼180 nm diameter). EC adaptation to chronic flow, manifested by cellular alignment with flow direction and formation of actin stress fibers, inhibited anti-PECAM/NC endocytosis consistent with lower rates of anti-PECAM/NC endocytosis in vivo in arterial compared to capillary vessels. Acute induction of actin stress fibers by thrombin also inhibited anti-PECAM/NC endocytosis, demonstrating that formation of actin stress fibers impedes EC endocytic machinery. In contrast, acute flow without stress fiber formation, stimulated anti-PECAM/NC endocytosis. Anti-PECAM/NC endocytosis did not correlate with the number of cell-bound particles under flow or static conditions. PECAM cytosolic tail deletion and disruption of cholesterol-rich plasmalemma domains abrogated anti-PECAM/NC endocytosis stimulation by acute flow, suggesting complex regulation of a flow-sensitive endocytic pathway in EC. The studies demonstrate the importance of the local flow microenvironment for NC uptake by the endothelium and suggest that cell culture models of nanoparticle uptake should reflect the microenvironment and phenotype of the target cells.

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Section: Resultsmentioning

confidence: 99%

Acute and Chronic Shear Stress Differently Regulate Endothelial Internalization of Nanocarriers Targeted to Platelet-Endothelial Cell Adhesion Molecule-1

Han¹,

Zern²,

Shuvaev³

et al. 2012

ACS Nano

105

118

View full text Add to dashboard Cite

show abstract

“…However, the mechanism by which hyperstretch induces miR-155 expression remain unclear. Recent studies suggest that expression of miR-155 in cancer growth and inflammation can be regulated by a variety of receptors and transcription factors, including TLR4 and AP-1 [58] and that IL-10 inhibits miR-155 by blocking the TLR4 signaling [59]. Mechanical stretch has been shown to modulate the activities of those molecules [60].…”

Section: Discussionmentioning

confidence: 99%

Human Mesenchymal Stem Cells Suppress the Stretch–Induced Inflammatory miR-155 and Cytokines in Bronchial Epithelial Cells

Kuo

Zhou

et al. 2013

PLoS ONE

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Current research in pulmonary pathology has focused on inflammatory reactions initiated by immunological responses to allergens and irritants. In addition to these biochemical stimuli, physical forces also play an important role in regulating the structure, function, and metabolism of the lung. Hyperstretch of lung tissues can contribute to the inflammatory responses in asthma, but the mechanisms of mechanically induced inflammation in the lung remain unclear. Our results demonstrate that excessive stretch increased the secretion of inflammatory cytokines by human bronchial epithelial cells (hBECs), including IL-8. This increase of IL-8 secretion was due to an elevated microRNA-155 (miR-155) expression, which caused the suppression of Src homology 2 domain–containing inositol 5-phosphatase 1 (SHIP1) production and the subsequent activation of JNK signaling. In vivo studies in our asthmatic mouse model also showed such changes in miR-155, IL-8, and SHIP1 expressions that reflect inflammatory responses. Co-culture with human mesenchymal stem cells (hMSCs) reversed the stretch-induced hBEC inflammatory responses as a result of IL-10 secretion by hMSCs to down-regulate miR-155 expression in hBECs. In summary, we have demonstrated that mechanical stretch modulates the homeostasis of the hBEC secretome involving miR-155 and that hMSCs can be used as a potential therapeutic approach to reverse bronchial epithelial inflammation in asthma.

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“…Several recent studies have addressed signaling mechanisms that contribute to VILI [ 5 ]. Mechanical forces arising from MV has been shown to directly stretch cell membrane, and rapidly induce phosphorylation and activation of receptors [ 6 ], cation channels [ 7 ], phospholipases [ 8 ], and signaling pathways such as protein kinase C, mitogen-activated protein kinases, and transcriptional factors that regulate lung inflammation and injury [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Sphingolipids in Ventilator Induced Lung Injury: Role of Sphingosine-1-Phosphate Lyase

Suryadevara

Ebenezer

et al. 2018

IJMS

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Mechanical ventilation (MV) performed in respiratory failure patients to maintain lung function leads to ventilator-induced lung injury (VILI). This study investigates the role of sphingolipids and sphingolipid metabolizing enzymes in VILI using a rodent model of VILI and alveolar epithelial cells subjected to cyclic stretch (CS). MV (0 PEEP (Positive End Expiratory Pressure), 30 mL/kg, 4 h) in mice enhanced sphingosine-1-phosphate lyase (S1PL) expression, and ceramide levels, and decreased S1P levels in lung tissue, thereby leading to lung inflammation, injury and apoptosis. Accumulation of S1P in cells is a balance between its synthesis catalyzed by sphingosine kinase (SphK) 1 and 2 and catabolism mediated by S1P phosphatases and S1PL. Thus, the role of S1PL and SphK1 in VILI was investigated using Sgpl1+/− and Sphk1−/− mice. Partial genetic deletion of Sgpl1 protected mice against VILI, whereas deletion of SphK1 accentuated VILI in mice. Alveolar epithelial MLE-12 cells subjected to pathophysiological 18% cyclic stretch (CS) exhibited increased S1PL protein expression and dysregulation of sphingoid bases levels as compared to physiological 5% CS. Pre-treatment of MLE-12 cells with S1PL inhibitor, 4-deoxypyridoxine, attenuated 18% CS-induced barrier dysfunction, minimized cell apoptosis and cytokine secretion. These results suggest that inhibition of S1PL that increases S1P levels may offer protection against VILI.

show abstract

Cyclic stretch‐induced nuclear localization of transcription factors results in increased nuclear targeting of plasmids in alveolar epithelial cells

Cited by 13 publications

References 50 publications

Acute and Chronic Shear Stress Differently Regulate Endothelial Internalization of Nanocarriers Targeted to Platelet-Endothelial Cell Adhesion Molecule-1

Acute and Chronic Shear Stress Differently Regulate Endothelial Internalization of Nanocarriers Targeted to Platelet-Endothelial Cell Adhesion Molecule-1

Human Mesenchymal Stem Cells Suppress the Stretch–Induced Inflammatory miR-155 and Cytokines in Bronchial Epithelial Cells

Sphingolipids in Ventilator Induced Lung Injury: Role of Sphingosine-1-Phosphate Lyase

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