scholarly journals Gene transfer of MRCKα rescues lipopolysaccharide-induced acute lung injury by restoring alveolar capillary barrier function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jing Liu ◽  
David A. Dean
Keyword(s):  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Gene Transfer ◽  
Lung Injury ◽  
Tight Junction ◽  
Barrier Function ◽  
Alveolar Fluid Clearance ◽  
Capillary Barrier ◽  
Alveolar Epithelial ◽  
Alveolar Capillary

AbstractAcute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is characterized by alveolar edema accumulation with reduced alveolar fluid clearance (AFC), alveolar-capillary barrier disruption, and substantial inflammation, all leading to acute respiratory failure. Enhancing AFC has long been considered one of the primary therapeutic goals in gene therapy treatments for ARDS. We previously showed that electroporation-mediated gene delivery of the Na+, K+-ATPase β1 subunit not only increased AFC, but also restored alveolar barrier function through upregulation of tight junction proteins, leading to treatment of LPS-induced ALI in mice. We identified MRCKα as an interaction partner of β1 which mediates this upregulation in cultured alveolar epithelial cells. In this study, we investigate whether electroporation-mediated gene transfer of MRCKα to the lungs can attenuate LPS-induced acute lung injury in vivo. Compared to mice that received a non-expressing plasmid, those receiving the MRCKα plasmid showed attenuated LPS-increased pulmonary edema and lung leakage, restored tight junction protein expression, and improved overall outcomes. Interestingly, gene transfer of MRCKα did not alter AFC rates. Studies using both cultured microvascular endothelial cells and mice suggest that β1 and MRCKα upregulate junctional complexes in both alveolar epithelial and capillary endothelial cells, and that one or both barriers may be positively affected by our approach. Our data support a model of treatment for ALI/ARDS in which improvement of alveolar-capillary barrier function alone may be of more benefit than improvement of alveolar fluid clearance.

scholarly journals Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury

2009 ◽  
Vol 297 (2) ◽  
pp. L219-L227 ◽  
Author(s):  
Charlie Wray ◽  
Ying Mao ◽  
Jue Pan ◽  
Anita Chandrasena ◽  
Frank Piasta ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tight Junction ◽  
Pulmonary Edema ◽  
Barrier Function ◽  
Mapk Pathway ◽  
Paracellular Transport ◽  
Epithelial Barrier ◽  
Altered Expression ◽  
Alveolar Epithelial

Intact alveolar barrier function is associated with better outcomes in acute lung injury patients; however, the regulation of alveolar epithelial paracellular transport during lung injury has not been extensively investigated. This study was undertaken to determine whether changes in tight junction claudin expression affect alveolar epithelial barrier properties and to determine the mechanisms of altered expression. In anesthetized mice exposed to ventilator-induced lung injury, claudin-4 was specifically induced among tight junction structural proteins. Real-time PCR showed an eightfold increase in claudin-4 expression in the lung injury model. To examine the role of this protein in barrier regulation, claudin-4 function was inhibited with small interfering RNA (siRNA) and a blocking peptide derived from the binding domain of Clostridium perfringens enterotoxin (CPEBD). Inhibition of claudin-4 decreased transepithelial electrical resistance but did not alter macromolecule permeability in primary rat and human epithelial cells. In mice, CPEBD decreased air space fluid clearance >33% and resulted in pulmonary edema during moderate tidal volume ventilation that did not induce edema in control peptide-treated mice. In vitro phorbol ester induced a ninefold increase in claudin-4 expression that was dependent on PKC activation and the JNK MAPK pathway. These data establish that changes in alveolar epithelial claudin expression influence paracellular transport, alveolar fluid clearance rates, and susceptibility to pulmonary edema. We hypothesize that increased claudin-4 expression early in acute lung injury represents a mechanism to limit pulmonary edema and that the regulation of alveolar epithelial claudin expression may be a novel target for acute lung injury therapy.

scholarly journals Inflammation‐associated repression of vasodilator‐stimulated phosphoprotein (VASP) reduces alveolar‐capillary barrier function during acute lung injury

2009 ◽  
Vol 23 (12) ◽  
pp. 4244-4255 ◽  
Author(s):  
Janek Henes ◽  
Marthe A. Schmit ◽  
Julio C. Morote-Garcia ◽  
Valbona Mirakaj ◽  
David Köhler ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Barrier Function ◽  
Capillary Barrier ◽  
Alveolar Capillary

scholarly journals The severity of shock is associated with impaired rates of net alveolar fluid clearance in clinical acute lung injury

2012 ◽  
Vol 303 (6) ◽  
pp. L550-L555 ◽  
Author(s):  
Yosaf F. Zeyed ◽  
Julie A. Bastarache ◽  
Michael A. Matthay ◽  
Lorraine B. Ware
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Blood Cultures ◽  
Circulatory Shock ◽  
Alveolar Fluid Clearance ◽  
Capillary Barrier ◽  
Protein Ratio ◽  
Barrier Permeability ◽  
Edema Fluid ◽  
Alveolar Capillary

The rate of alveolar fluid clearance (AFC) is associated with mortality in clinical acute lung injury (ALI). Patients with ALI often develop circulatory shock, but how shock affects the rate of AFC is unknown. To determine the effect of circulatory shock on the rate of AFC in patients with ALI, the rate of net AFC was measured in 116 patients with ALI by serial sampling of pulmonary edema fluid. The primary outcome was the rate of AFC in patients with shock compared with those without shock. We also tested the effects of shock severity and bacteremia. Patients with ALI and shock ( n = 86) had significantly slower rates of net AFC compared with those without shock ( n = 30, P = 0.03), and AFC decreased significantly as the number of vasopressors increased. Patients with positive blood cultures ( n = 21) had slower AFC compared with patients with negative blood cultures ( n = 96, P = 0.023). In addition, the edema fluid-to-plasma protein ratio, an index of alveolar-capillary barrier permeability, was highest in patients requiring the most vasopressors ( P < 0.05). Patients with ALI complicated by circulatory shock and bacteremia had slower rates of AFC compared with patients without shock or bacteremia. An impaired capacity to reabsorb alveolar edema fluid may contribute to high mortality among patients with sepsis-induced ALI. These findings also suggest that vasopressor use may be a marker of alveolar-capillary barrier permeability in ALI and provide justification for new therapies that enhance alveolar epithelial and endothelial barrier integrity in ALI, particularly in patients with shock.

scholarly journals TNF-α Mediated Increase of HIF-1α Inhibits VASP Expression, Which Reduces Alveolar-Capillary Barrier Function during Acute Lung Injury (ALI)

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e102967 ◽  
Author(s):  
Mengjie Tang ◽  
Yihao Tian ◽  
Doulin Li ◽  
Jiawei Lv ◽  
Qun Li ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Barrier Function ◽  
Capillary Barrier ◽  
Tnf Α ◽  
Alveolar Capillary

Tyrosol attenuates lipopolysaccharide-induced acute lung injury by inhibiting the inflammatory response and maintaining the alveolar capillary barrier

2017 ◽  
Vol 109 ◽  
pp. 526-533 ◽  
Author(s):  
Yeon-Yong Kim ◽  
Soyoung Lee ◽  
Min-Jong Kim ◽  
Byeong-Cheol Kang ◽  
Hima Dhakal ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Capillary Barrier ◽  
Alveolar Capillary

scholarly journals Cell-free hemoglobin: a novel mediator of acute lung injury

2016 ◽  
Vol 310 (6) ◽  
pp. L532-L541 ◽  
Author(s):  
Ciara M. Shaver ◽  
Cameron P. Upchurch ◽  
David R. Janz ◽  
Brandon S. Grove ◽  
Nathan D. Putz ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Proinflammatory Cytokine ◽  
Cytokine Expression ◽  
Mouse Lung ◽  
Capillary Barrier ◽  
Free Hemoglobin ◽  
Lung Epithelial ◽  
Air Space ◽  
Alveolar Capillary

Patients with the acute respiratory distress syndrome (ARDS) have elevated levels of cell-free hemoglobin (CFH) in the air space, but the contribution of CFH to the pathogenesis of acute lung injury is unknown. In the present study, we demonstrate that levels of CFH in the air space correlate with measures of alveolar-capillary barrier dysfunction in humans with ARDS ( r = 0.89, P < 0.001) and in mice with ventilator-induced acute lung injury ( r = 0.89, P < 0.001). To investigate the specific contribution of CFH to ARDS, we studied the impact of purified CFH in the mouse lung and on cultured mouse lung epithelial (MLE-12) cells. Intratracheal delivery of CFH in mice causes acute lung injury with air space inflammation and alveolar-capillary barrier disruption. Similarly, in MLE-12 cells, CFH increases proinflammatory cytokine expression and increases paracellular permeability as measured by electrical cell-substrate impedance sensing. Next, to determine whether these effects are mediated by the iron-containing heme moiety of CFH, we treated mice with intratracheal hemin, the chloride salt of heme, and found that hemin was sufficient to increase alveolar permeability but failed to induce proinflammatory cytokine expression or epithelial cell injury. Together, these data identify CFH in the air space as a previously unrecognized driver of lung epithelial injury in human and experimental ARDS and suggest that CFH and hemin may contribute to ARDS through different mechanisms. Interventions targeting CFH and heme in the air space could provide a new therapeutic approach for ARDS.

scholarly journals Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

2013 ◽  
Vol 305 (10) ◽  
pp. L665-L681 ◽  
Author(s):  
Susanne Herold ◽  
Nieves M. Gabrielli ◽  
István Vadász
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Capillary Barrier ◽  
Barrier Dysfunction ◽  
Signaling Events ◽  
Alveolar Capillary

In this review we summarize recent major advances in our understanding on the molecular mechanisms, mediators, and biomarkers of acute lung injury (ALI) and alveolar-capillary barrier dysfunction, highlighting the role of immune cells, inflammatory and noninflammatory signaling events, mechanical noxae, and the affected cellular and molecular entities and functions. Furthermore, we address novel aspects of resolution and repair of ALI, as well as putative candidates for treatment of ALI, including pharmacological and cellular therapeutic means.

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