scholarly journals c-Fos is a mechanosensor that regulates inflammatory responses and lung barrier dysfunction during ventilator-induced acute lung injury

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Leilei Zhou ◽  
Chunju Xue ◽  
Zongyu Chen ◽  
Wenqing Jiang ◽  
Shuang He ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protein Expression ◽  
Tidal Volume ◽  
Lung Tissue ◽  
Inflammatory Reaction ◽  
Specific Inhibitor ◽  
Control Group ◽  
Fos Protein ◽  
Volume Group

Abstract Background As one of the basic treatments performed in the intensive care unit, mechanical ventilation can cause ventilator-induced acute lung injury (VILI). The typical features of VILI are an uncontrolled inflammatory response and impaired lung barrier function; however, its pathogenesis is not fully understood, and c-Fos protein is activated under mechanical stress. c-Fos/activating protein-1 (AP-1) plays a role by binding to AP-1 within the promoter region, which promotes inflammation and apoptosis. T-5224 is a specific inhibitor of c-Fos/AP-1, that controls the gene expression of many proinflammatory cytokines. This study investigated whether T-5224 attenuates VILI in rats by inhibiting inflammation and apoptosis. Methods The SD rats were divided into six groups: a control group, low tidal volume group, high tidal volume group, DMSO group, T-5224 group (low concentration), and T-5224 group (high concentration). After 3 h, the pathological damage, c-Fos protein expression, inflammatory reaction and apoptosis degree of lung tissue in each group were detected. Results c-Fos protein expression was increased within the lung tissue of VILI rats, and the pathological damage degree, inflammatory reaction and apoptosis in the lung tissue of VILI rats were significantly increased; T-5224 inhibited c-Fos protein expression in lung tissues, and T-5224 inhibit the inflammatory reaction and apoptosis of lung tissue by regulating the Fas/Fasl pathway. Conclusions c-Fos is a regulatory factor during ventilator-induced acute lung injury, and the inhibition of its expression has a protective effect. Which is associated with the antiinflammatory and antiapoptotic effects of T-5224.

scholarly journals Contribution of CFTR to Alveolar Fluid Clearance by Lipoxin A4via PI3K/Akt Pathway in LPS-Induced Acute Lung Injury

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Yi Yang ◽  
Yang Cheng ◽  
Qing-Quan Lian ◽  
Li Yang ◽  
Wei Qi ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protein Expression ◽  
Specific Inhibitor ◽  
Akt Pathway ◽  
Alveolar Type ◽  
Alveolar Fluid Clearance ◽  
Cftr Protein

The lipoxins are the first proresolution mediators to be recognized and described as the endogenous “braking signals” for inflammation. We evaluated the anti-inflammatory and proresolution bioactions of lipoxin A4in our lipopolysaccharide (LPS-)induced lung injury model. We demonstrated that lipoxin A4significantly improved histology of rat lungs and inhibited IL-6 and TNF-αin LPS-induced lung injury. In addition, lipoxin A4increased alveolar fluid clearance (AFC) and the effect of lipoxin A4on AFC was abolished byCFTRinh-172(a specific inhibitor of CFTR). Moreover, lipoxin A4could increase cystic fibrosis transmembrane conductance regulator (CFTR) protein expressionin vitroandin vivo. In rat primary alveolar type II (ATII) cells, LPS decreased CFTR protein expression via activation of PI3K/Akt, and lipoxin A4suppressed LPS-stimulated phosphorylation of Akt. These results showed that lipoxin A4enhanced CFTR protein expression and increased AFC via PI3K/Akt pathway. Thus, lipoxin A4may provide a potential therapeutic approach for acute lung injury.

scholarly journals HMGB1 and inflammatory cytokines in experimental acute lung injury induced in rabbits

2020 ◽  
Vol 72 (4) ◽  
pp. 1329-1338
Author(s):  
C.S. Kurokawa ◽  
J.P. Araújo Júnior ◽  
R.B. Pires ◽  
M.F. Carpi ◽  
M.A. Moraes ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Inflammatory Cytokines ◽  
Lung Tissue ◽  
Tnf Alpha ◽  
Control Group ◽  
Early Expression

ABSTRACT The aim of this work was to measure HMGB1, TNF-alpha, and IL-8 in bronchoalveolar lavage (BAL), serum and TLR2 and TLR4mRNA expression in lung tissue of rabbits with two grades of acute lung injury (ALI). The animals were randomly assigned to groups with severe (S) and mild/moderate (MM) ALI, induced with warm saline, and a control group. HMGB1, TNF-alpha, IL-8, TLR2mRNA and TLR4mRNA were measured after ALI induction. The results showed increased levels of IL-8, TNF-alpha, HMGB1 and TLR4mRNA in the ALI groups. HMGB1, IL-8 and TNF-alpha concentrations in BAL were higher in S compared MM. Increased TLR4mRNA was observed in S and MM versus control. The results suggest an early participation of HMGB1 in ALI together with IL-8 and TNF-alpha and association with severity. TLR4 has early expression and role in ALI pathophysiology but is not associated with severity.

scholarly journals Suppression of Endoplasmic Reticulum Stress by 4-PBA Protects Against Hyperoxia-Induced Acute Lung Injury via Up-Regulating Claudin-4 Expression

2021 ◽  
Vol 12 ◽  
Author(s):  
Hsin-Ping Pao ◽  
Wen-I. Liao ◽  
Shih-En Tang ◽  
Shu-Yu Wu ◽  
Kun-Lun Huang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Protein Expression ◽  
Er Stress ◽  
Lung Tissue ◽  
Lung Epithelial Cells ◽  
Stress Factors ◽  
Mouse Lung ◽  
Lung Edema

Endoplasmic reticulum (ER) stress that disrupts ER function can occur in response to a wide variety of cellular stress factors leads to the accumulation of unfolded and misfolded proteins in the ER. Many studies have shown that ER stress amplified inflammatory reactions and was involved in various inflammatory diseases. However, little is known regarding the role of ER stress in hyperoxia-induced acute lung injury (HALI). This study investigated the influence of ER stress inhibitor, 4-phenyl butyric acid (4-PBA), in mice with HALI. Treatment with 4-PBA in the hyperoxia groups significantly prolonged the survival, decreased lung edema, and reduced the levels of inflammatory mediators, lactate dehydrogenase, and protein in bronchoalveolar lavage fluid, and increased claudin-4 protein expression in lung tissue. Moreover, 4-PBA reduced the ER stress-related protein expression, NF-κB activation, and apoptosis in the lung tissue. In in vitro study, 4-PBA also exerted a similar effect in hyperoxia-exposed mouse lung epithelial cells (MLE-12). However, when claudin-4 siRNA was administrated in mice and MLE-12 cells, the protective effect of 4-PBA was abrogated. These results suggested that 4-PBA protected against hyperoxia-induced ALI via enhancing claudin-4 expression.

scholarly journals Keratinocyte Growth Factor-2 Reduces Inflammatory Response to Acute Lung Injury Induced by Oleic Acid in Rats by Regulating Key Proteins of the Wnt/β-Catenin Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Shao Tenghao ◽  
Chen Ning ◽  
Wang Shenghai ◽  
Sun Qinlong ◽  
Wu Jiaqian ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Oleic Acid ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Lung Tissue ◽  
Blood Cells ◽  
Keratinocyte Growth Factor ◽  
White Blood Cells ◽  
Inflammatory Factors ◽  
Control Group

Reducing inflammation can effectively relieve acute lung injury (ALI). Objective. To test whether keratinocyte growth factor-2 (KGF-2) can reduce oleic acid-induced inflammation in ALI of rats and explore its possible mechanism. Methods. 45 Sprague-Dawley rats were randomly divided into control group, ALI group, and ALI + KGF-2 group. The animal model of acute lung injury was established by injecting 0.1 mL/kg oleic acid into the tail vein of rats. Rats in the control group were injected with equal volume of normal saline (NS). Each group needs pretreatment 72 hours before the preparation of the acute lung injury model. The control group and ALI group were instilled with 5 ml/kg NS through the airway, and the same amount of KGF-2 was instilled in the ALI + KGF-2 group. It takes 8 hours to successfully prepare the ALI model. Observe the pathological changes of lung tissue through light microscopy, ultrastructural changes through electron microscopy, and the lung wettability/dry weight (w/d) ratio and lung permeability index (LPI). By detecting changes in inflammatory factors in lung tissue and changes in the number of BALF cells, the changes in inflammation in each group were observed. The expressions of Wnt5a, β-catenin, and APC in lung tissue were detected by immunohistochemistry and Western blot. The changes of key proteins in Wnt/β-catenin signaling pathway in the lung tissue of each group were observed. Result. Compared with the ALI group, after KGF-2 pretreatment, the degree of lung injury was reduced, the expression of inflammatory factors was reduced, and the number of red blood cells and white blood cells in BALF was reduced. It can also be observed that the expression of Wnt5a, β-catenin, and APC, a key protein in the Wnt/β-catenin signaling pathway, is reduced. The analysis showed that the number of inflammatory factors, red blood cells, and white blood cells in BALF was positively correlated with the expression of Wnt5a, β-catenin, and APC. Conclusion. KGF-2 may reduce the inflammatory response in ALI induced by oleic acid by regulating key proteins in the Wnt/β-catenin signaling pathway.

scholarly journals Metformin Activates the Protective Effects of the AMPK Pathway in Acute Lung Injury Caused by Paraquat Poisoning

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Liaozhang Wu ◽  
Yifang Cen ◽  
Menglong Feng ◽  
Yanna Zhou ◽  
Hui Tang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protein Expression ◽  
Lung Tissue ◽  
Tissue Homogenate ◽  
Rat Lung ◽  
Pathological Changes ◽  
Expression Levels ◽  
Oxidation Index ◽  
Paraquat Poisoning

Objective. To observe whether metformin (MET) plays a protective role in acute lung injury (ALI) induced by paraquat (PQ) poisoning in rats by activating the AMPK/NF-κB signaling pathway. Methods. PQ exposure was used to construct a rat model of ALI and a model of acute type II alveolar epithelial cell (RLE-6TN) injury, and MET intervention was performed. Rat lung tissue samples were collected to evaluate pathological changes in rat lung tissue, the oxidation index, and inflammatory factors; cell viability was detected by CCK-8 assays, and the protein expression levels of phospho-AMPK and phospho-NF-κBp65 in rat lung tissue and RLE-6TN cells were observed by Western blotting. Results. Compared with the PQ group, the MET treatment group showed significantly (1) reduced lung wet/dry ratio (W/D: 4.67±0.31 vs. 5.45±0.40, P<0.001), (2) reduced pathological changes in lung tissue, (3) decreased MDA levels (nmol/mg prot: 2.70±0.19 vs. 3.08±0.15, P<0.001) and increased SOD and GSH-Px activities (U/mg prot: 76.17±5.22 vs. 45.23±6.58, 30.40±2.84 vs. 21.00±3.20; all P<0.001) in lung tissue homogenate, (4) reduced levels of IL-1β, IL-6, and TNF-α in lung tissue homogenates (pg/mL: 47.87±5.06 vs. 66.77±6.55; 93.03±7.41 vs. 107.39±9.81; 75.73±6.08 vs. 89.12±8.94; all P<0.001), (5) increased activity of RLE-6TN cells (%: 0.69±0.09, 0.76±0.06, and 0.58±0.03 vs. 0.50±0.05; all P<0.05), (6) decreased protein levels of phospho-NF-κBp65 in lung homogenates and RLE-6TN cells (p-NF-κB/NF-κB: 0.47±0.09 vs. 0.81±0.13; 0.26±0.07 vs. 0.79±0.13; all P<0.01), and (7) upregulated protein expression of phospho-AMPK in lung homogenates and RLE-6TN cells (p-AMPK/AMPK: 0.88±0.05 vs. 0.36±0.12; 0.93±0.03 vs. 0.56±0.15; all P<0.01). After the addition of the AMPK inhibitor Compound C (Com C), the protein expression levels of phospho-AMPK and phospho-NF-κBp65 returned to baseline. Conclusion. MET can effectively alleviate ALI induced by paraquat poisoning and increase the viability of cells exposed to paraquat. The mechanism may be related to the activation of the AMPK/NF-κB pathway, downregulation of inflammatory mediators such as IL-6 and TNF-α, and upregulation of the SOD and GSH-Px oxidation index, and these effects can be inhibited by the AMPK inhibitor Com C.

scholarly journals Nebulized Heparin Attenuates Pulmonary Coagulopathy and Inflammation through Alveolar Macrophages in a Rat Model of Acute Lung Injury

2017 ◽  
Vol 117 (11) ◽  
pp. 2125-2134 ◽  
Author(s):  
Laura Chimenti ◽  
Marta Camprubí-Rimblas ◽  
Raquel Guillamat-Prats ◽  
Maria Gomez ◽  
Jessica Tijero ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Lung Tissue ◽  
Alveolar Macrophages ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Coagulation Cascade ◽  
Control Group ◽  
Proinflammatory Mediators

Objective Alveolar macrophages play a key role in the development and resolution of acute respiratory distress syndrome (ARDS), modulating the inflammatory response and the coagulation cascade in lungs. Anti-coagulants may be helpful in the treatment of ARDS. This study investigated the effects of nebulized heparin on the role of alveolar macrophages in limiting lung coagulation and inflammatory response in an animal model of acute lung injury (ALI). Methods Rats were randomized to four experimental groups. In three groups, ALI was induced by intratracheal instillation of lipopolysaccharide (LPS) and heparin was nebulized at constant oxygen flow: the LPS/Hep group received nebulized heparin 4 and 8 hours after injury; the Hep/LPS/Hep group received nebulized heparin 30 minutes before and 4 and 8 hours after LPS-induced injury; the LPS/Sal group received nebulized saline 4 and 8 hours after injury. The control group received only saline. Animals were exsanguinated 24 hours after LPS instillation. Lung tissue, bronchoalveolar lavage fluid (BALF) and alveolar macrophages isolated from BALF were analysed. Results LPS increased protein concentration, oedema and neutrophils in BALF as well as procoagulant and proinflammatory mediators in lung tissue and alveolar macrophages. In lung tissue, nebulized heparin attenuated ALI through decreasing procoagulant (tissue factor, thrombin–anti-thrombin complexes, fibrin degradation products) and proinflammatory (interleukin 6, tumour necrosis factor alpha) pathways. In alveolar macrophages, nebulized heparin reduced expression of procoagulant genes and the effectors of transforming growth factor beta (Smad 2, Smad 3) and nuclear factor kappa B (p-selectin, CCL-2). Pre-treatment resulted in more pronounced attenuation. Conclusion Nebulized heparin reduced pulmonary coagulopathy and inflammation without producing systemic bleeding, partly by modulating alveolar macrophages.

scholarly journals Influence of Low Tidal Volume Ventilation on Time to Extubation in Cardiac Surgical Patients

2011 ◽  
Vol 114 (5) ◽  
pp. 1102-1110 ◽  
Author(s):  
Sugantha Sundar ◽  
Victor Novack ◽  
Karinne Jervis ◽  
S. Patrick Bender ◽  
Adam Lerner ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Lung Injury ◽  
Tidal Volume ◽  
Lung Mechanics ◽  
Control Group ◽  
Elective Cardiac Surgery ◽  
Low Tidal Volume ◽  
Low Tidal Volume Ventilation ◽  
Volume Ventilation ◽  
Volume Group

Background Low tidal volumes have been associated with improved outcomes in patients with established acute lung injury. The role of low tidal volume ventilation in patients without lung injury is still unresolved. We hypothesized that such a strategy in patients undergoing elective surgery would reduce ventilator-associated lung injury and that this improvement would lead to a shortened time to extubation Methods A single-center randomized controlled trial was undertaken in 149 patients undergoing elective cardiac surgery. Ventilation with 6 versus 10 ml/kg tidal volume was compared. Ventilator settings were applied immediately after anesthesia induction and continued throughout surgery and the subsequent intensive care unit stay. The primary endpoint of the study was time to extubation. Secondary endpoints included the proportion of patients extubated at 6 h and indices of lung mechanics and gas exchange as well as patient clinical outcomes. Results Median ventilation time was not significantly different in the low tidal volume group; a median (interquartile range) of 450 (264-1,044) min was achieved compared with 643 (417-1,032) min in the control group (P = 0.10). However, a higher proportion of patients in the low tidal volume group was free of any ventilation at 6 h: 37.3% compared with 20.3% in the control group (P = 0.02). In addition, fewer patients in the low tidal volume group required reintubation (1.3 vs. 9.5%; P = 0.03). Conclusions Although reduction of tidal volume in mechanically ventilated patients undergoing elective cardiac surgery did not significantly shorten time to extubation, several improvements were observed in secondary outcomes. When these data are combined with a lack of observed complications, a strategy of reduced tidal volume could still be beneficial in this patient population.

scholarly journals Effects of Bacterial Translocation and Autophagy on Acute Lung Injury Induced by Severe Acute Pancreatitis

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Hanlin Wang ◽  
Chang Li ◽  
Yingjian Jiang ◽  
Hongbo Li ◽  
Dianliang Zhang
Keyword(s):  
Oxidative Stress ◽  
Acute Pancreatitis ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Severe Acute Pancreatitis ◽  
Lung Tissue ◽  
Bacterial Translocation ◽  
Control Group ◽  
Sham Operation ◽  
Rdna Sequencing

Aim. To reveal the role of bacterial translocation (BT) and autophagy in severe acute pancreatitis-induced acute lung injury (SAP-ALI). Methods. Rats were separated into a control (sham-operation) group (n=10) and a SAP group (n=30). Sodium taurocholate (5%) was retrogradely injected into the cholangiopancreatic duct to induce SAP-ALI in rats. Then, 16S rDNA sequencing was used to detect bacterial translocation (BT). Hematoxylin eosin staining (HE) was used to detect morphological changes to the pancreas, intestine, and lung. And lung tissue wet/dry weight ratio (W/D ratio) was used to assess the extent of pulmonary edema. The expressions of LC3II and Beclin1 proteins were analyzed by western blot and immunofluorescence. Glutathione peroxidase (GPx), malondialdehyde (MDA), and superoxide dismutase (SOD) were used to assess oxidative stress in lung tissue. Results. Levels of TNF-α, IL-6, lipase, and amylase in the SAP group were significantly higher than those in the control group (P<0.01). Histopathological score and W/D ratio of the lung in the SAP-BT(+) group were significantly higher than that in the SAP-BT(-) group (P<0.01). LC3II expression was higher in the SAP-BT(-) group than that in the SAP-BT(+) group (P<0.01). The results were consistent with those of LC3II immunofluorescence assay. The expression of Beclin1 was similar to that of LC3II (P<0.01). MDA content in the SAP-BT(+) group was significantly higher than that in the SAP-BT(-) group (P<0.01), whereas SOD and GPX activities were opposite (P<0.01). Conclusions. BT can aggravate SAP-ALI with the increasing oxidative stress level, which may be related to the decrease of autophagy level.

scholarly journals Phillygenin attenuates LPS-induced acute lung injury of newborn mice in infantile pneumonia

2021 ◽  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Tissue ◽  
Control Group ◽  
Western Blot Assay ◽  
Newborn Mice ◽  
Cell Counts ◽  
Tnf Α ◽  
Underlying Mechanisms ◽  
And Control

Purpose: The aim of this study was to assess the effect of phillygenin (PHI) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and understand its underlying mechanisms. Methods: Mice were separated into four different groups at random, including LPS, LPS+ PHI (5 mg/kg), LPS + PHI (50 mg/kg) and control group. The two LPS + PHI groups were intraperitoneally administered with PHI after LPS intratracheal administered for 1 h. Subsequently, the lung tissues of different groups were collected and evaluated by H&E staining and W/D (W/D) ratio. The inflammatory cytokines in BALF or lung tissue were also assessed. Western blot assay was applied to examine the expressions of TLR4, MyD88, and NF-κB. Results: The ameliorated pathological changes and lung W/D ratio demonstrated that PHI dramatically suppressed the lung injury levels. PHI strikingly reduced the number of inflammatory cell counts and total protein concentration in BALF. In addition, PHI attenuated expression of IL-1β and TNF-α in BALF and lung tissue. Furthermore, it was confirmed that PHI alleviated LPS-induced ALI via TLR4/MyD88/NF-κB pathway. Conclusions: Together the above results show that PHI attenuates LPS-induced ALI via inactivation of TLR4/MyD88/NF-κB pathway in newborn mice.

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