scholarly journals miR-21-KO Alleviates Alveolar Structural Remodeling and Inflammatory Signaling in Acute Lung Injury

2020 ◽  
Vol 21 (3) ◽  
pp. 822 ◽  
Author(s):  
Johanna Christine Jansing ◽  
Jan Fiedler ◽  
Andreas Pich ◽  
Janika Viereck ◽  
Thomas Thum ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Structural Damage ◽  
Structural Changes ◽  
Elastic Fibers ◽  
Inflammatory Signaling ◽  
Knock Out ◽  
Tissue Resistance ◽  
Pulmonary Remodeling ◽  
Lps Treatment

Acute lung injury (ALI) is characterized by enhanced permeability of the air–blood barrier, pulmonary edema, and hypoxemia. MicroRNA-21 (miR-21) was shown to be involved in pulmonary remodeling and the pathology of ALI, and we hypothesized that miR-21 knock-out (KO) reduces injury and remodeling in ALI. ALI was induced in miR-21 KO and C57BL/6N (wildtype, WT) mice by an intranasal administration of 75 µg lipopolysaccharide (LPS) in saline (n = 10 per group). The control mice received saline alone (n = 7 per group). After 24 h, lung function was measured. The lungs were then excised for proteomics, cytokine, and stereological analysis to address inflammatory signaling and structural damage. LPS exposure induced ALI in both strains, however, only WT mice showed increased tissue resistance and septal thickening upon LPS treatment. Septal alterations due to LPS exposure in WT mice consisted of an increase in extracellular matrix (ECM), including collagen fibrils, elastic fibers, and amorphous ECM. Proteomics analysis revealed that the inflammatory response was dampened in miR-21 KO mice with reduced platelet and neutrophil activation compared with WT mice. The WT mice showed more functional and structural changes and inflammatory signaling in ALI than miR-21 KO mice, confirming the hypothesis that miR-21 KO reduces the development of pathological changes in ALI.

scholarly journals Determinants of surfactant function in acute lung injury and early recovery

2000 ◽  
Vol 279 (2) ◽  
pp. L342-L349 ◽  
Author(s):  
R. Mora ◽  
S. Arold ◽  
Y. Marzan ◽  
B. Suki ◽  
E. P. Ingenito
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Plasma Proteins ◽  
Surfactant Protein ◽  
Lung Mechanics ◽  
Phospholipid Content ◽  
Absolute Amount ◽  
Total Protein Content ◽  
Early Recovery ◽  
Tissue Resistance

Relationships between lung function and surfactant function and composition were examined during the evolution of acute lung injury in guinea pigs. Lung mechanics and gas exchange were assessed 12, 24, or 48 h after exposure to nebulized lipopolysaccharide (LPS). Bronchoalveolar lavage (BAL) fluid was processed for phospholipid and protein contents and surfactant protein (SP) A and SP-B levels; surfactant function was measured by pulsating bubble surfactometry. Lung elastance, tissue resistance, and arterial-alveolar gradient were moderately elevated by 12 h after LPS exposure and continued to increase over the first 24 h but began to recover between 24 and 48 h. Similarly, the absolute amount of 30,000 g pelleted SP-A and SP-B, the phospholipid content of BAL fluid, and surfactant function declined over the first 24 h after exposure, with recovery between 24 and 48 h. BAL fluid total protein content increased steadily over the first 48 h after LPS nebulization. In this model of acute lung injury, the intra-alveolar repletion of surfactant components in early recovery led to improved surfactant function despite the presence of potentially inhibitory plasma proteins.

scholarly journals Phagocytosis of microparticles by alveolar macrophages during acute lung injury requires MerTK

2018 ◽  
Vol 314 (1) ◽  
pp. L69-L82 ◽  
Author(s):  
Michael P. Mohning ◽  
Stacey M. Thomas ◽  
Lea Barthel ◽  
Kara J. Mould ◽  
Alexandria L. McCubbrey ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Primary Objective ◽  
Cytochalasin D ◽  
Inflammatory Signaling ◽  
Macrophage Population ◽  
Bronchoalveolar Fluid

Microparticles are a newly recognized class of mediators in the pathophysiology of lung inflammation and injury, but little is known about the factors that regulate their accumulation and clearance. The primary objective of our study was to determine whether alveolar macrophages engulf microparticles and to elucidate the mechanisms by which this occurs. Alveolar microparticles were quantified in bronchoalveolar fluid of mice with lung injury induced by LPS and hydrochloric acid. Microparticle numbers were greatest at the peak of inflammation and declined as inflammation resolved. Isolated, fluorescently labeled particles were placed in culture with macrophages to evaluate ingestion in the presence of endocytosis inhibitors. Ingestion was blocked with cytochalasin D and wortmannin, consistent with a phagocytic process. In separate experiments, mice were treated intratracheally with labeled microparticles, and their uptake was assessed though microscopy and flow cytometry. Resident alveolar macrophages, not recruited macrophages, were the primary cell-ingesting microparticles in the alveolus during lung injury. In vitro, microparticles promoted inflammatory signaling in LPS primed epithelial cells, signifying the importance of microparticle clearance in resolving lung injury. Microparticles were found to have phosphatidylserine exposed on their surfaces. Accordingly, we measured expression of phosphatidylserine receptors on macrophages and found high expression of MerTK and Axl in the resident macrophage population. Endocytosis of microparticles was markedly reduced in MerTK-deficient macrophages in vitro and in vivo. In conclusion, microparticles are released during acute lung injury and peak in number at the height of inflammation. Resident alveolar macrophages efficiently clear these microparticles through MerTK-mediated phagocytosis.

scholarly journals Bcl-2 Proteins Regulate Mitophagy in Lipopolysaccharide-Induced Acute Lung Injury via PINK1/Parkin Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Zhihao Zhang ◽  
Zhugui Chen ◽  
Ruimeng Liu ◽  
Qingchun Liang ◽  
Zhiyong Peng ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Protein Interactions ◽  
Cell Apoptosis ◽  
A549 Cells ◽  
Therapeutic Strategies ◽  
Protein Protein Interactions ◽  
Mitochondrial Homeostasis ◽  
Lps Treatment

Mitophagy is involved in sepsis-induced acute lung injury (ALI). Bcl-2 family proteins play an important role in mitochondrial homeostasis. However, whether targeting Bcl-2 proteins (Bcl-2 and Bad) could influence mitophagy in ALI remains unclear. In this study, lipopolysaccharide (LPS) was used to induce injury in A549 cells and ALI in mice. LPS treatment resulted in elevated cell apoptosis, enhanced mitophagy, decreased Bcl-2 expression, increased Bad expression, and activation of PINK1/Parkin signaling in cells and lung tissues. Both Bcl-2 overexpression and Bad knockdown attenuated LPS-induced injury, inhibited cell apoptosis and mitophagy, and improved survival. Atg5 knockout (KO) inhibited LPS-induced cell apoptosis. Furthermore, Bcl-2 proteins regulated mitophagy by modulating the recruitment of Parkin from the cytoplasm to mitochondria via direct protein-protein interactions. These results were further confirmed in Park2 KO cells and Park2-/- mice. This is the first study to demonstrate that Bcl-2 proteins regulated mitophagy in LPS-induced ALI via modulating the PINK1/Parkin signaling pathway, promoting new insights into the mechanisms and investigation of therapeutic strategies for a septic patient with ALI.

scholarly journals The Activation of Macrophage and Upregulation of CD40 Costimulatory Molecule in Lipopolysaccharide-Induced Acute Lung Injury

2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Liang Dong ◽  
Shujuan Wang ◽  
Ming Chen ◽  
Hongjia Li ◽  
Wenxiang Bi
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Costimulatory Molecule ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Vital Role ◽  
Control Group ◽  
Toll Like Receptor 4 ◽  
Activated Macrophage ◽  
Lps Treatment

To study the activation of macrophage and upregulation of costimulatory molecule of CD40 in lipopolysaccharide- (LPS-) induced acute lung injury (ALI) model, and to investigate the pathogenecy of ALI, mice were randomly divided into two groups. ALI model was created by injecting 0.2 mg/kg LPS in phosphate saline (PBS) in trachea. The pathologic changes of mice lungs were observed by HE staining at 24 and 48 hours after LPS treatment, then the alveolar septum damage, abnormal contraction, alveolar space hyperemia, and neutrophils or other inflammatory cells infiltration in the LPS group, but not in the control group, were observed. The expression of CD40 mRNA and CD40 protein molecules were higher in LPS group as compared to the control group by Northern blot and flow cytometry, respectively. Expression of Toll-like receptor-4 (TLR4) in activated macrophage (AM) was higher in LPS group as compared to the control group by RT-PCR. The activation of NF-B binding to NF-B consensus oligos increased in LPS group by EMSA in macrophage. The concentrations of TNF-, MIP-2, and IL-1 cytokines from bronchoalveolar lavage fluid (BALF) were increased significantly in LPS group as compared to the control group by ELISA. The activation of AM and upregulation of costimulatory molecule CD40 induced all kinds of inflammatory cytokines releasing, then led to ALI. Therefore, both of them played vital role in the process of development of ALI.

The effect of aminoguanidine on acute lung injury induced by influenza A/H1N1/PDM09

2020 ◽  
Vol 20 (2) ◽  
pp. 33-44
Author(s):  
Andrei G. Aleksandrov ◽  
Tatiana N. Savateeva-Lyubimova ◽  
Kira I. Stosman ◽  
Arman A. Muzhikyan ◽  
Konstantin V. Sivak
Keyword(s):  
Influenza Virus ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Influenza A ◽  
Structural Changes ◽  
Saturation Index ◽  
Influenza Infection ◽  
Proinflammatory Response ◽  
Influenza Virus A ◽  
Influenza A H1n1

Background. Acute lung injury is one of severe course of influenza infection with mortality up to 40% of patients, despite on etiological and pathogenetic therapy. The aim of the article to study of the effects of aminoguanidine on correcting on acute lung injury induced by influenza virus A/California/7/09MA (mouse-adapted) (H1N1)pdm09, collection Smorodintsev Research Institute of Influenza. Materials and methods. The study was performed on 95 outbred female mice. The mouse-adapted pandemic influenza virus A/California/7/09MA (H1N1)pdm09 was used for modeling viral infection at a dose of 1 LD50. The mortality was analysed. Levels of advanced glycation end-products (AGEs), proinflammatory cytokines in lung; saturation index and leukocytes marker parameters in blood; pathological and histological studies of lung were performed on 4 and 7 days post infection. Results. Aminoguanidine led to 2-fold decrease in mortality in mice with virus-induced acute lung injury; significantly suppressed the growth of AGEs and proinflammatory cytokine levels in lung; reduced decrease of saturation index and hematological inflammatory markers; decreased level of inflammatory injury in lung tissue. Conclusion. Aminoguanidine relieved virus-induced acute lung injury in mice. These AGEs inhibitor reduced the proinflammatory response and structural changes in respiratory tract epithelial cells induced by reactive carbonyl compounds on cell membrane.

HDAC6 inhibition blocks inflammatory signaling and caspase-1 activation in LPS-induced acute lung injury

2019 ◽  
Vol 370 ◽  
pp. 178-183 ◽  
Author(s):  
Li Liu ◽  
Xiaoming Zhou ◽  
Sreerama Shetty ◽  
Gang Hou ◽  
Qiuyue Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Signaling ◽  
Caspase 1

scholarly journals Nrf2 attenuates ferroptosis-mediated IIR-ALI by modulating TERT and SLC7A11

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Hui Dong ◽  
Yangyang Xia ◽  
Shanliang Jin ◽  
Chaofan Xue ◽  
Yanjun Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Structural Changes ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Alveolar Epithelial Cells ◽  
Related Factor ◽  
Alveolar Epithelial ◽  
Scanning Transmission ◽  
Intestinal Ischemia Reperfusion

AbstractAcute lung injury (ALI) carries a mortality rate of ~50% and is a hot topic in the world of critical illness research. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical modulator of intracellular oxidative homeostasis and serves as an antioxidant. The Nrf2-related anti-oxidative stress is strongly associated with ferroptosis suppression. Meanwhile, telomerase reverse transcriptase (TERT), the catalytic portion of the telomerase protein, is reported to travel to the mitochondria to alleviate ROS. In our study, we found that TERT was significantly reduced in lung tissue of Nrf2−/− mice in the model of intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI). In addition, MDA levels showed marked increase, whereas GSH and GPX4 levels fell drastically in ALI models. Moreover, typical-related structural changes were observed in the type II alveolar epithelial cells in the IIR model. We further employed the scanning transmission X-ray microscopy (STXM) to examine Fe levels and distribution within cells. Based on our observations, massive aggregates of Fe were found in the MLE-12 cells upon OGD/R (oxygen and glucose deprivation/reperfusion) induction. Additionally, Nrf2 silencing dramatically reduced TERT and SLC7A11 levels, and further exacerbated cellular injuries. In contrast, TERT-overexpressing cells exhibited marked elevation in SLC7A11 levels and thereby inhibited ferroptosis. Collectively, these data suggest that Nrf2 can negatively regulate ferroptosis via modulation of TERT and SLC7A11 levels. The conclusion from this study brings insight into new candidates that can be targeted in future IIR-ALI therapy.

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