Endothelial mitochondria determine rapid barrier failure in chemical lung injury

Hough, Rebecca F.; Islam, Mohammad Naimul; Gusarova, Galina A.; Jin, Guangchun; Das, Shonit; Bhattacharya, Jahar

doi:10.1172/jci.insight.124329

Cited by 42 publications

(39 citation statements)

References 51 publications

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“…The rapid respiratory response to acid, as indicated by the difference in Vt at baseline within 30 minutes of acid instillation, is also consistent with the previous observations whereby the greatest impairment in pulmonary gas exchange occurs 20 minutes after acid aspiration [23]. This is probably linked to the rapid development of acid-induced pulmonary edema prior to subsequent recruitment of inflammatory cells including neutrophils [24]. We found that the low tidal volume ventilation strategy induced minimal changes in lung volume which is consistent with previous studies [10,25] and the clinical observation that low tidal volume plus moderate PEEP, minimises lung injury in the acute respiratory distress syndrome [26].…”

Section: Discussionsupporting

confidence: 89%

“…Reduction of MRC proteins may decrease ATP generation and energy supply, and lead to excessive reactive oxygen species, which can stimulate pathological processes including inflammation, cellular damage, mutations, and apoptosis [32]. Endothelial mitochondrial depolarization has been proposed as an important mechanism of global loss of endothelial barrier function and pulmonary edema in acidinduced lung injury [24]. In addition, evidence linking mitochondrial dysfunction with MV also exists.…”

Section: Discussionmentioning

confidence: 99%

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The proteomic response is linked to regional lung volumes in ventilator-induced lung injury

Yen

Song

Preissner

et al. 2020

Journal of Applied Physiology

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It is unclear how acid induced lung injury alters the regional lung volume response to mechanical ventilation (MV) and how this impacts protein expression. Using a mouse model, we investigated the separate and combined effects of acid aspiration and MV on regional lung volumes and how these were associated with the proteome. Adult BALB/c mice were divided into four groups: intratracheal saline, intratracheal acid, Saline/MV or Acid/MV. Specific tidal volume (sVt) and specific end-expiratory volume (sEEV) were measured at baseline and after 2 hours of ventilation using dynamic high-resolution four-dimensional computed tomography (4DCT) images. Lung tissue was dissected into 10 regions corresponding to the image segmentation for label-free quantitative proteomic analysis. Our data showed that acid aspiration significantly reduced sVt and caused further reductions in sVt and sEEV after 2 hours of ventilation. Proteomic analysis revealed 42 dysregulated proteins in both Saline/MV and Acid/MV groups, and 37 differentially expressed proteins in the Acid/MV group. Mapping of the overlapping proteins showed significant enrichment of complement/coagulation cascades (CCC). Analysis of 37 unique proteins in the Acid/MV group identified 6 additional CCC proteins and 7 down-regulated proteins involved in the mitochondrial respiratory chain (MRC). Regional MRC protein levels were positively correlated with sEEV, while the CCC protein levels were negatively associated with sVt. Therefore, this study showed that tidal volume was associated with the expression of CCC proteins while low end-expiratory lung volumes were associated with MRC protein expression, suggesting that tidal stretch and lung collapse activate different injury pathways.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

The proteomic response is linked to regional lung volumes in ventilator-induced lung injury

Yen

Song

Preissner

et al. 2020

Journal of Applied Physiology

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“…Interaction between Bcl-2 and Beclin-1 can inhibit apoptosis and autophagy (18), and α7nAchR protein of ALI cells can promote the interaction after being activated, thus playing a role in protecting cells and reducing apoptosis and autophagy (19). Hough et al (20) have confirmed that the activation of uncoupling protein-2 would increase vascular permeability, thus activating the calcineurin-cofilin-actin cascade reaction, disrupting protein-protein interaction related to endothelial barrier stability, leading to ALI. Zhang et al (21) have found that in lung injury, protein-protein interaction network mainly involves VEGF pathway, FoxO pathway, focal adhesion pathway and chemokine pathway.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of IL‑8‑induced acute lung injury through pulmonary surfactant proteins A and B

Yang

Tan

et al. 2019

Exp Ther Med

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This study explored how interleukin-8 (IL-8) causes acute lung injury (ALI) through pulmonary surfactant protein A (SP-A) and surfactant protein B (SP-B). Serum was collected from 53 ALI patients and further 56 healthy subjects who underwent physical examination. The IL-8, SP-A, and SP-B levels were determined using enzyme-linked immunosorbent assay (ELISA). An ALI model was constructed using lipopolysaccharide (LSP)-induced normal A549 cells. siRNA was employed to interfere with the expression of IL-8, SP-A and SP-B. Western blot analysis was carried out to determine the protein levels, and MTT assay to determine the cell activity. In addition, co-immunoprecipitation (Co-IP) assay was used to verify the interaction between IL-8, SP-A and SP-B. ALI patients showed high expression of serum IL-8, and low expression of SP-A and SP-B, and IL-8 was negatively correlated with SP-A and SP-B, respectively. LSP-induced normal A549 cells showed increased expression of IL-8 and decreased expression of SP-A and SP-B. Silencing IL-8 led to increased expression levels of SP-A, SP-B and Bcl2, decreased expression levels of caspase-9, caspase-3, Bax, TNF-α, IL-17 and IL-1β, reduced cell apoptosis rate, and enhanced cell viability. Silencing SP-A and SP-B resulted in increased expression of IL-8, caspase-9, caspase-3, Bax, TNF-α, IL-17 and IL-1β, and decreased expression of Bcl2. Co-IP assay revealed that IL-8 could interact with SP-A and SP-B, respectively. IL-8 induces apoptosis by inhibiting SP-A and SP-B, and intensifies cellular inflammatory reaction, leading eventually to ALI.

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“…One recent example of the power of this approach is the study by L i et al [ 89 ], in which both in situ and ex vivo imaging of murine fetal lungs was used to explore the link between mechanical and chemical cues in lung development. During the session, G usarova [ 90 , 91 ] (Columbia University, USA) highlighted recent technical advances for visualisation of acute lung injury and repair in ex vivo , blood-perfused mouse lungs using live confocal microscopy imaging. This setup allows for administration of drugs and other compounds during imaging; however, the system still lacks movements associated with normal breathing.…”

Section: Session X Visualising Lung Regenerationmentioning

confidence: 99%

Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Disease 2019

et al. 2020

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A workshop entitled “Stem Cells, Cell Therapies and Bioengineering in Lung Biology and Diseases” was hosted by the University of Vermont Larner College of Medicine in collaboration with the National Heart, Lung and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, the International Society for Cell and Gene Therapy and the Pulmonary Fibrosis Foundation. The event was held from July 15 to 18, 2019 at the University of Vermont, Burlington, Vermont. The objectives of the conference were to review and discuss the current status of the following active areas of research: 1) technological advancements in the analysis and visualisation of lung stem and progenitor cells; 2) evaluation of lung stem and progenitor cells in the context of their interactions with the niche; 3) progress toward the application and delivery of stem and progenitor cells for the treatment of lung diseases such as cystic fibrosis; 4) progress in induced pluripotent stem cell models and application for disease modelling; and 5) the emerging roles of cell therapy and extracellular vesicles in immunomodulation of the lung. This selection of topics represents some of the most dynamic research areas in which incredible progress continues to be made. The workshop also included active discussion on the regulation and commercialisation of regenerative medicine products and concluded with an open discussion to set priorities and recommendations for future research directions in basic and translation lung biology.

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Endothelial mitochondria determine rapid barrier failure in chemical lung injury

Cited by 42 publications

References 51 publications

The proteomic response is linked to regional lung volumes in ventilator-induced lung injury

The proteomic response is linked to regional lung volumes in ventilator-induced lung injury

Mechanism of IL‑8‑induced acute lung injury through pulmonary surfactant proteins A and B

Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Disease 2019

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