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

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.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00190.2012 ◽

2012 ◽

Vol 303 (6) ◽

pp. L550-L555 ◽

Cited By ~ 16

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.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00232.2013 ◽

2013 ◽

Vol 305 (10) ◽

pp. L665-L681 ◽

Cited By ~ 84

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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Adenosine and ATPγS protect against bacterial pneumonia-induced acute lung injury

Scientific Reports ◽

10.1038/s41598-020-75224-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Christine M. Gross ◽

Anita Kovacs-Kasa ◽

Mary Louise Meadows ◽

Mary Cherian-Shaw ◽

David J. Fulton ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Function ◽

Lung Injury ◽

Inflammatory Responses ◽

Gram Negative Bacteria ◽

Capillary Barrier ◽

E Coli ◽

Downstream Effector ◽

Extracellular Purines ◽

Alveolar Capillary

Abstract Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, disrupts the alveolar-capillary barrier, triggering pulmonary vascular leak thus inducing acute lung injury (ALI). Extracellular purines, adenosine and ATP, protected against ALI induced by purified LPS. In this study, we investigated whether these purines can impact vascular injury in more clinically-relevant E.coli (non-sterile LPS) murine ALI model. Mice were inoculated with live E. coli intratracheally (i.t.) with or without adenosine or a non-hydrolyzable ATP analog, adenosine 5′-(γ-thio)-triphosphate (ATPγS) added intravenously (i.v.). After 24 h of E. coli treatment, we found that injections of either adenosine or ATPγS 15 min prior or adenosine 3 h after E.coli insult significantly attenuated the E.coli-mediated increase in inflammatory responses. Furthermore, adenosine prevented weight loss, tachycardia, and compromised lung function in E. coli-exposed mice. Accordingly, treatment with adenosine or ATPγS increased oxygen saturation and reduced histopathological signs of lung injury in mice exposed to E. coli. Lastly, lung-targeting gene delivery of adenosine or ATPγS downstream effector, myosin phosphatase, significantly attenuated the E. coli-induced compromise of lung function. Collectively, our study has demonstrated that adenosine or ATPγS mitigates E. coli-induced ALI in mice and may be useful as an adjuvant therapy in future pre-clinical studies.

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Regulation and Repair of the Alveolar-Capillary Barrier in Acute Lung Injury

Annual Review of Physiology ◽

10.1146/annurev-physiol-030212-183756 ◽

2013 ◽

Vol 75 (1) ◽

pp. 593-615 ◽

Cited By ~ 157

Author(s):

Jahar Bhattacharya ◽

Michael A. Matthay

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Capillary Barrier ◽

Alveolar Capillary

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Gene Delivery of MRCKα Repairs the Alveolar‐Capillary Barrier and Rescues the Experimental Lipopolysaccharide‐Induced Acute Lung Injury

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.04261 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Jing Liu ◽

Michael Barravecchia ◽

David Dean

Keyword(s):

Acute Lung Injury ◽

Gene Delivery ◽

Lung Injury ◽

Capillary Barrier ◽

Alveolar Capillary

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

Scientific Reports ◽

10.1038/s41598-021-99897-3 ◽

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.

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Seabuckthorn Berries Attenuate Pulmonary Vascular Hyperpermeability in Lipopolysaccharide-induced Acute Lung Injury in Mice

10.21203/rs.3.rs-20308/v1 ◽

2020 ◽

Author(s):

Leilei Du ◽

Ying Liu ◽

Li Wan ◽

Chu Chen ◽

Gang Fan

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Mice Model ◽

Key Factors ◽

Capillary Barrier ◽

Endotoxin Challenge ◽

Tnf Α ◽

Short Term Mortality ◽

Sparse Methods ◽

Alveolar Capillary

Abstract Background Acute lung injury is featured by pulmonary vascular hyperpermeability, resulting in high short-term mortality. Currently pharmacological therapies are still sparse. Methods In the mice model of acute lung injury induced by Lipopolysaccharide, the effect of seabuckthorn berries extract on pulmonary vascular hyperpermeability was evaluated by histopathologic observation and transvascular leakage determination. The key factors involved in alveolar-capillary barrier lesion were assessed. Results The findings indicated that treatment of seabuckthorn berries alleviated morphological lesion as well as water, Evans blue and total proteins leakage in lung tissue, suppressed the release of TNF-α and IL-6, decreased accumulation of neutrophils, inhibited the activation of NF-κB and down-regulated the expression of ICAM-1 and CD62E. Conclusions These results demonstrated seabuckthorn berries help maintaining alveolar-capillary barrier integrity under endotoxin challenge in mice by suppressing the key factors in the pathogenesis of acute lung injury.

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