Alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury

2006 ◽  
Vol 291 (6) ◽  
pp. L1191-L1198 ◽  
Author(s):  
James A. Frank ◽  
Charlie M. Wray ◽  
Danny F. McAuley ◽  
Reto Schwendener ◽  
Michael A. Matthay
Keyword(s):  
Mechanical Ventilation ◽  
Epithelial Cell ◽  
Lung Injury ◽  
Tidal Volume ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Macrophage Activation ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Ventilator Induced Lung Injury

In patients requiring mechanical ventilation for acute lung injury or acute respiratory distress syndrome (ARDS), tidal volume reduction decreases mortality, but the mechanisms of the protective effect have not been fully explored. To test the hypothesis that alveolar macrophage activation is an early and critical event in the initiation of ventilator-induced lung injury (VILI), rats were ventilated with high tidal volume (HVT) for 10 min to 4 h. Alveolar macrophage counts in bronchoalveolar lavage (BAL) fluid decreased 45% by 20 min of HVT( P < 0.05) consistent with activation-associated adhesion. Depletion of alveolar macrophages in vivo with liposomal clodronate significantly decreased permeability and pulmonary edema following 4 h of HVT( P < 0.05). BAL fluid from rats exposed to 20 min of HVTincreased nitric oxide synthase activity nearly threefold in naïve primary alveolar macrophages ( P < 0.05) indicating that soluble factors present in the air spaces contribute to macrophage activation in VILI. Media from cocultures of alveolar epithelial cell monolayers and alveolar macrophages exposed to 30 min of stretch in vitro also significantly increased nitrite production in naïve macrophages ( P < 0.05), but media from stretched alveolar epithelial cells or primary alveolar macrophages alone did not, suggesting alveolar epithelial cell-macrophage interaction was required for the subsequent macrophage activation observed. These data demonstrate that injurious mechanical ventilation rapidly activates alveolar macrophages and that alveolar macrophages play an important role in the initial pathogenesis of VILI.

Death-associated Protein Kinase 1 Mediates Ventilator-induced Lung Injury in Mice by Promoting Alveolar Epithelial Cell Apoptosis

2020 ◽  
Vol 133 (4) ◽  
pp. 905-918
Author(s):  
Yaxin Wang ◽  
Yiyi Yang ◽  
Lin Chen ◽  
Wei Xiong ◽  
Limin Song ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Lung Injury ◽  
Tidal Volume ◽  
Cell Apoptosis ◽  
Alveolar Epithelial Cell ◽  
B Cell Lymphoma ◽  
Cyclic Stretch ◽  
Alveolar Epithelial ◽  
Ventilator Induced Lung Injury ◽  
Epithelial Cell Apoptosis

Background Alveolar epithelial cell apoptosis is implicated in the onset of ventilator-induced lung injury. Death-associated protein kinase 1 (DAPK1) is associated with cell apoptosis. The hypothesis was that DAPK1 participates in ventilator-induced lung injury through promoting alveolar epithelial cell apoptosis. Methods Apoptosis of mouse alveolar epithelial cell was induced by cyclic stretch. DAPK1 expression was altered (knockdown or overexpressed) in vitro by using a small interfering RNA or a plasmid, respectively. C57/BL6 male mice (n = 6) received high tidal volume ventilation to establish a lung injury model. Adeno-associated virus transfection of short hairpin RNA and DAPK1 inhibitor repressed DAPK1 expression and activation in lungs, respectively. The primary outcomes were alveolar epithelial cell apoptosis and lung injury. Results Compared with the control group, the 24-h cyclic stretch group showed significantly higher alveolar epithelial cell apoptotic percentage (45 ± 4% fold vs. 6 ± 1% fold; P &lt; 0.0001) and relative DAPK1 expression, and this group also demonstrated a reduced apoptotic percentage after DAPK1 knockdown (27 ± 5% fold vs. 53 ± 8% fold; P &lt; 0.0001). A promoted apoptotic percentage in DAPK1 overexpression was observed without stretching (49 ± 6% fold vs. 14 ± 3% fold; P &lt; 0.0001). Alterations in B-cell lymphoma 2 and B-cell lymphoma 2–associated X are associated with DAPK1 expression. The mice subjected to high tidal volume had higher DAPK1 expression and alveolar epithelial cell apoptotic percentage in lungs compared with the low tidal volume group (43 ± 6% fold vs. 4 ± 2% fold; P &lt; 0.0001). Inhibition of DAPK1 through adeno-associated virus infection or DAPK1 inhibitor treatment appeared to be protective against lung injury with reduced lung injury score, resolved pulmonary inflammation, and repressed alveolar epithelial cell apoptotic percentage (47 ± 4% fold and 48 ± 6% fold; 35 ± 5% fold and 34 ± 4% fold; P &lt; 0.0001, respectively). Conclusions DAPK1 promotes the onset of ventilator-induced lung injury by triggering alveolar epithelial cell apoptosis through intrinsic apoptosis pathway in mice. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

TLR4 is required for macrophage efferocytosis during resolution of ventilator-induced lung injury

2021 ◽  
Vol 321 (4) ◽  
pp. L787-L801
Author(s):  
Kai Su ◽  
Lulong Bo ◽  
Chunling Jiang ◽  
Xiaoming Deng ◽  
You-Yang Zhao ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Lung Damage ◽  
Lung Edema ◽  
Apoptotic Cells ◽  
Ventilator Induced Lung Injury

Mechanical ventilation is a life-sustaining therapy for patients with respiratory failure but can cause further lung damage known as ventilator-induced lung injury (VILI). However, the intrinsic molecular mechanisms underlying recovery of VILI remain unknown. Phagocytosis of apoptotic cells (also known as efferocytosis) is a key mechanism orchestrating successful resolution of inflammation. Here we show the positive regulation of macrophage Toll-like receptor (TLR) 4 in efferocytosis and resolution of VILI. Mice were depleted of alveolar macrophages and then subjected to injurious ventilation (tidal volume, 20 mL/kg) for 4 h. On day 1 after mechanical ventilation, Tlr4+/+ or Tlr4−/− bone marrow-derived macrophages (BMDMs) were intratracheally administered to alveolar macrophage-depleted mice. We observed that mice depleted of alveolar macrophages exhibited defective resolution of neutrophilic inflammation, exuded protein, lung edema, and lung tissue injury after ventilation, whereas these delayed responses were reversed by administration of Tlr4+/+ BMDMs. Importantly, these proresolving effects by Tlr4+/+ BMDMs were abolished in mice receiving Tlr4−/− BMDMs. The number of macrophages containing apoptotic cells or bodies in bronchoalveolar lavage fluid was much less in mice receiving Tlr4−/− BMDMs than that in those receiving Tlr4+/+ BMDMs. Macrophage TLR4 deletion facilitated a disintegrin and metalloprotease 17 maturation and enhanced Mer cleavage in response to mechanical ventilation. Heat shock protein 70 dramatically increased Mer tyrosine kinase surface expression, phagocytosis of apoptotic neutrophils, and rescued the inflammatory phenotype in alveolar macrophage-depleted mice receiving Tlr4+/+ BMDMs, but not Tlr4−/− BMDMs. Our results suggest that macrophage TLR4 promotes resolution of VILI via modulation of Mer-mediated efferocytosis.

scholarly journals Preexposure to hyperoxia causes increased lung injury and epithelial apoptosis in mice ventilated with high tidal volumes

2010 ◽  
Vol 299 (5) ◽  
pp. L711-L719 ◽  
Author(s):  
Patrudu S. Makena ◽  
Charlean L. Luellen ◽  
Louisa Balazs ◽  
Manik C. Ghosh ◽  
Kaushik Parthasarathi ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Tidal Volume ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Lower Tidal Volume ◽  
Caspase Cleavage ◽  
Alveolar Epithelial ◽  
Severe Lung

Both high tidal volume mechanical ventilation (HV) and hyperoxia (HO) have been implicated in ventilator-induced lung injury. However, patients with acute lung injury are often exposed to HO before the application of mechanical ventilation. The potential priming of the lungs for subsequent injury by exposure to HO has not been extensively studied. We provide evidence that HO (90%) for 12 h followed by HV (25 μl/g) combined with HO for 2 or 4 h (HO-12h+HVHO-2h or -4h) induced severe lung injury in mice. Analysis of lung homogenates showed that lung injury was associated with cleavage of executioner caspases, caspases-3 and -7, and their downstream substrate poly(ADP-ribose) polymerase-1 (PARP-1). No significant lung injury or caspase cleavage was seen with either HO for 16 h or HV for up to 4 h. Ventilation for 4 h with HO (HVHO) did not cause significant lung injury without preexposure to HO. Twelve-hour HO followed by lower tidal volume (6 μl/g) mechanical ventilation failed to produce significant injury or caspase cleavage. We also evaluated the initiator caspases, caspases-8 and -9, to determine whether the death receptor or mitochondrial-mediated pathways were involved. Caspase-9 cleavage was observed in HO-12h+HVHO-2h and -4h as well as HO for 16 h. Caspase-8 activation was observed only in HO-12h+HVHO-4h, indicating the involvement of both pathways. Immunohistochemistry and in vitro stretch studies showed caspase cleavage in alveolar epithelial cells. In conclusion, preexposure to HO followed by HV produced severe lung injury associated with alveolar epithelial cell apoptosis.

scholarly journals Tumor necrosis factor-α small interfering RNA alveolar epithelial cell-targeting nanoparticles reduce lung injury in C57BL/6J mice with sepsis

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098465
Author(s):  
Like Qian ◽  
Xi Yin ◽  
Jiahao Ji ◽  
Zhengli Chen ◽  
He Fang ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Epithelial Cell ◽  
Lung Injury ◽  
Tumor Necrosis ◽  
Alveolar Epithelial Cell ◽  
Weight Ratio ◽  
B Cell Lymphoma ◽  
Alveolar Epithelial ◽  
Tnf Α ◽  
Necrosis Factor

Background The role of tumor necrosis factor (TNF)-α small interfering (si)RNA alveolar epithelial cell (AEC)-targeting nanoparticles in lung injury is unclear. Methods Sixty C57BL/6J mice with sepsis were divided into normal, control, sham, 25 mg/kg, 50 mg/kg, and 100 mg/kg siRNA AEC-targeting nanoparticles groups (n = 10 per group). The wet:dry lung weight ratio, and hematoxylin and eosin staining, western blotting, and enzyme-linked immunosorbent assays for inflammatory factors were conducted to compare differences among groups. Results The wet:dry ratio was significantly lower in control and sham groups than other groups. TNF-α siRNA AEC-targeting nanoparticles significantly reduced the number of eosinophils, with significantly lower numbers in the 50 mg/kg group than in 25 mg/kg and 100 mg/kg groups. The nanoparticles also significantly reduced the expression of TNF-α, B-cell lymphoma-2, caspase 3, interleukin (IL)-1β, and IL-6, with TNF-α expression being significantly lower in the 50 mg/kg group than in 25 mg/kg and 100 mg/kg groups. Conclusion TNF-α siRNA AEC-targeting nanoparticles appear to be effective at improving lung injury-related sepsis, and 50 mg/kg may be a preferred dose option for administration.

Effect of stretch on structural integrity and micromechanics of human alveolar epithelial cell monolayers exposed to thrombin

2006 ◽  
Vol 290 (6) ◽  
pp. L1104-L1110 ◽  
Author(s):  
Xavier Trepat ◽  
Ferranda Puig ◽  
Nuria Gavara ◽  
Jeffrey J. Fredberg ◽  
Ramon Farre ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Epithelial Cell ◽  
Structural Integrity ◽  
Alveolar Epithelial Cell ◽  
Compressive Strain ◽  
Cell Junctions ◽  
Cell Monolayers ◽  
Alveolar Epithelial ◽  
Epithelial Cell Monolayers ◽  
Human Alveolar Epithelial Cell

Alveolar epithelial cells in patients with acute lung injury subjected to mechanical ventilation are exposed to increased procoagulant activity and mechanical strain. Thrombin induces epithelial cell stiffening, contraction, and cytoskeletal remodeling, potentially compromising the balance of forces at the alveolar epithelium during cell stretching. This balance can be further compromised by the loss of integrity of cell-cell junctions in the injured epithelium. The aim of this work was to study the effect of stretch on the structural integrity and micromechanics of human alveolar epithelial cell monolayers exposed to thrombin. Confluent and subconfluent cells (A549) were cultured on collagen-coated elastic substrates. After exposure to thrombin (0.5 U/ml), a stepwise cell stretch (20%) was applied with a vacuum-driven system mounted on an inverted microscope. The structural integrity of the cell monolayers was assessed by comparing intercellular and intracellular strains within the monolayer. Strain was measured by tracking beads tightly bound to the cell surface. Simultaneously, cell viscoelasticity was measured using optical magnetic twisting cytometry. In confluent cells, thrombin did not induce significant changes in transmission of strain from the substrate to overlying cells. By contrast, thrombin dramatically impaired the ability of subconfluent cells to follow imposed substrate deformation. Upon substrate unstretching, thrombin-treated subconfluent cells exhibited compressive strain (9%). Stretch increased stiffness (56–62%) and decreased cell hysteresivity (13–22%) of vehicle cells. By contrast, stretch did not increase stiffness of thrombin-treated cells, suggesting disruption of cytoskeletal structures. Our findings suggest that thrombin could exacerbate epithelial barrier dysfunction in injured lungs subjected to mechanical ventilation.

scholarly journals Inhibition of Poly(Adenosine Diphosphate–Ribose) Polymerase Attenuates Ventilator-induced Lung Injury

2008 ◽  
Vol 108 (2) ◽  
pp. 261-268 ◽  
Author(s):  
Rosanna Vaschetto ◽  
Jan W. Kuiper ◽  
Shyh Ren Chiang ◽  
Jack J. Haitsma ◽  
Jonathan W. Juco ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Tidal Volume ◽  
Interleukin 6 ◽  
Inflammatory Responses ◽  
Adenosine Diphosphate ◽  
High Tidal Volume ◽  
Positive End Expiratory Pressure ◽  
Ventilator Induced Lung Injury ◽  
Pharmacologic Inhibition

Background Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. Methods Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. Results The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney. Conclusion The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

scholarly journals Mesenchymal Stem Cells Attenuate Acute Lung Injury in Mice Partly by Suppressing Alveolar Macrophage Activation in a PGE2-dependent Manner

2021 ◽  
Author(s):  
Gaojian Wang ◽  
Yaping Zhang ◽  
Nianqiang Hu ◽  
Qinxue Liu ◽  
Fengjie Ma ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Macrophage Activation ◽  
Rna Seq ◽  
Ep4 Receptor ◽  
Pge2 Receptor ◽  
Cox2 Inhibitor

Abstract Background: Mesenchymal stem cell have shown therapeutic effect on acute lung injury, MSC could be activated when added to inflammatory environment and in turn suppress inflammation, yet the mechanism is complex and not understood. Methods: To determine the effect of MSC on ALI and alveolar macrophage activation, MSCs were administered to ALI mice and co-cultured with activated MH-S cells (alveolar macrophage cell line). To find the genes critical for MSC’s immunosuppressive effects, rest and activated MSCs induced by inflammatory MH-S cells were harvested for RNA-seq. To prove that PGE2 participates in the immunosuppressive effects of MSC, COX2 inhibitor and PGE2 receptor antagonist were added to the co-culture system and administrated to ALI mice. Results: The intratracheal administration of MSCs attenuated ALI and suppressed alveolar macrophages activation in vivo, the activation of MH-S cells was also significantly reduced after co-culturing with MSCs in vitro. The RNA-seq data of rest and activated MSCs suggested that the Ptgs2 gene may play an important role in MSC exerting immunosuppressive effects. Correspondingly, we found that the COX2 protein and PGE2 released by activated MSCs were increased dramatically after co-culturing with MH-S. The use of COX2 inhibitor NS-398 restrained the secretion of PGE2 and reversed the suppressive effect on macrophages activation of MSCs in vitro. Furthermore, GW627368X, a selective antagonist of PGE2 receptor (EP4 receptor), also reversed the inhibitory effects of MSCs on alveolar macrophages and their protective effects on ALI mice.Conclusions: MSC attenuate ALI partly through suppressing alveolar macrophage activation via PGE2 binding to EP4 receptor.

scholarly journals Mechanosensitive cation channel Piezo1 contributes to ventilator-induced lung injury by activating RhoA/ROCK1 in rats

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yang Zhang ◽  
Lulu Jiang ◽  
Tianfeng Huang ◽  
Dahao Lu ◽  
Yue Song ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Tidal Volume ◽  
Cyclic Stretch ◽  
High Tidal Volume ◽  
Enzyme Linked Immunosorbent Assay ◽  
Sprague Dawley ◽  
Ventilator Induced Lung Injury ◽  
Enhanced Expression ◽  
Underlying Mechanisms

Abstract Background Mechanical ventilation can induce or aggravate lung injury, which is termed ventilator-induced lung injury (VILI). Piezo1 is a key element of the mechanotransduction process and can transduce mechanical signals into biological signals by mediating Ca2+ influx, which in turn regulates cytoskeletal remodeling and stress alterations. We hypothesized that it plays an important role in the occurrence of VILI, and investigated the underlying mechanisms. Methods High tidal volume mechanical ventilation and high magnitude cyclic stretch were performed on Sprague–Dawley rats, and A549 and human pulmonary microvascular endothelial cells, respectively, to establish VILI models. Immunohistochemical staining, flow cytometry, histological examination, enzyme-linked immunosorbent assay, western blotting, quantitative real-time polymerase chain reaction and survival curves were used to assess the effect of Piezo1 on induction of lung injury, as well as the signaling pathways involved. Results We observed that Piezo1 expression increased in the lungs after high tidal volume mechanical ventilation and in cyclic stretch-treated cells. Mechanistically, we observed the enhanced expression of RhoA/ROCK1 in both cyclic stretch and Yoda1-treated cells, while the deficiency or inhibition of Piezo1 dramatically antagonized RhoA/ROCK1 expression. Furthermore, blockade of RhoA/ROCK1 signaling using an inhibitor did not affect Piezo1 expression. GSMTx4 was used to inhibit Piezo1, which alleviated VILI-induced pathologic changes, water content and protein leakage in the lungs, and the induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats. Conclusions These findings indicate that Piezo1 affects the development and progression of VILI through promotion of RhoA/ROCK1 signaling.

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