scholarly journals Bletinib ameliorates neutrophilic inflammation and lung injury by inhibiting Src family kinase phosphorylation and activity

2021 ◽  
Author(s):  
Ting‐I Kao ◽  
Po‐Jen Chen ◽  
Yi‐Hsuan Wang ◽  
Hsin‐Hui Tseng ◽  
Shih‐Hsin Chang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Src Family Kinase ◽  
Neutrophilic Inflammation ◽  
Kinase Phosphorylation

Bletinib ameliorates neutrophilic inflammation and lung injury by inhibiting Src family kinase phosphorylation and activity

Authorea ◽  
2020 ◽  
Author(s):  
Ting I Kao ◽  
Hsin Hui Tseng ◽  
Shih Hsin Chang ◽  
Tian Shung Wu ◽  
Sien Hung Yang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Src Family Kinase ◽  
Neutrophilic Inflammation ◽  
Kinase Phosphorylation

Inhibition of matrix metalloproteinase-9 prevents neutrophilic inflammation in ventilator-induced lung injury

2006 ◽  
Vol 291 (4) ◽  
pp. L580-L587 ◽  
Author(s):  
Je Hyeong Kim ◽  
Min Hyun Suk ◽  
Dae Wui Yoon ◽  
Seung Heon Lee ◽  
Gyu Young Hur ◽  
...  
Keyword(s):  
Lung Injury ◽  
Matrix Metalloproteinase ◽  
Tidal Volume ◽  
Weight Ratio ◽  
Dry Weight ◽  
Neutrophil Infiltration ◽  
Neutrophilic Inflammation ◽  
Ventilator Induced Lung Injury ◽  
Metalloproteinase 9 ◽  
Expression And Activity

Neutrophils are considered to play a central role in ventilator-induced lung injury (VILI). However, the pulmonary consequences of neutrophil accumulation have not been fully elucidated. Matrix metalloproteinase-9 (MMP-9) had been postulated to participate in neutrophil transmigration. The purpose of this study was to investigate the role of MMP-9 in the neutrophilic inflammation of VILI. Male Sprague-Dawley rats were divided into three groups: 1) low tidal volume (LVT), 7 ml/kg of tidal volume (VT); 2) high tidal volume (HVT), 30 ml/kg of VT; and 3) HVT with MMP inhibitor (HVT+MMPI). As a MMPI, CMT-3 was administered daily from 3 days before mechanical ventilation. Degree of VILI was assessed by wet-to-dry weight ratio and acute lung injury (ALI) scores. Neutrophilic inflammation was determined from the neutrophil count in the lung tissue and myeloperoxidase (MPO) activity in the bronchoalveolar lavage fluid (BALF). MMP-9 expression and activity were examined by immunohistochemical staining and gelatinase zymography, respectively. The wet-to-dry weight ratio, ALI score, neutrophil infiltration, and MPO activity were increased significantly in the HVT group. However, in the HVT+MMPI group, pretreatment with MMPI decreased significantly the degree of VILI, as well as neutrophil infiltration and MPO activity. These changes correlated significantly with MMP-9 immunoreactivity and MMP-9 activity. Most outcomes were significantly worse in the HVT+MMPI group compared with the LVT group. In conclusion, VILI mediated by neutrophilic inflammation is closely related to MMP-9 expression and activity. The inhibition of MMP-9 protects against the development of VILI through the downregulation of neutrophil-mediated inflammation.

scholarly journals Targeting redox regulatory site of protein kinase B impedes neutrophilic inflammation in lung injury

2018 ◽  
Author(s):  
Po-Jen Chen ◽  
I-Ling Ko ◽  
Chia-Lin Lee ◽  
Hao-Chun Hu ◽  
Fang-Rong Chang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Protein Kinase B ◽  
Reduced Form ◽  
Human Neutrophils ◽  
Akt Inhibitor ◽  
Neutrophilic Inflammation

AbstractNeutrophil activation has a pathogenic effect in inflammatory diseases. Protein kinase B (PKB)/AKT regulates diverse cellular responses. However, the significance of AKT in neutrophilic inflammation is still not well understood. Here, we identified CLLV-1 as a novel AKT inhibitor. CLLV-1 inhibited respiratory burst, degranulation, chemotaxis, and AKT phosphorylation in activated human neutrophils and dHL-60 cells. Significantly, CLLV-1 blocked AKT activity and covalently reacted with AKT Cys310 in vitro. The AKT309-313 peptide-CLLV-1 adducts were determined by NMR or mass spectrometry assay. The alkylation agent-conjugated AKT (reduced form) level was also inhibited by CLLV-1. Additionally, CLLV-1 ameliorated lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. CLLV-1 acts as a covalent allosteric AKT inhibitor by targeting AKT Cys310 to restrain inflammatory responses in human neutrophils and LPS-induced ALI in vivo. Our findings provide a mechanistic framework for redox modification of AKT that may serve as a novel pharmacological target to alleviate neutrophilic inflammation.

scholarly journals Mechanical Power Correlates With Lung Inflammation Assessed by Positron-Emission Tomography in Experimental Acute Lung Injury in Pigs

2021 ◽  
Vol 12 ◽  
Author(s):  
Martin Scharffenberg ◽  
Jakob Wittenstein ◽  
Xi Ran ◽  
Yingying Zhang ◽  
Anja Braune ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Uptake Rate ◽  
Emission Tomography ◽  
Mechanical Power ◽  
Relative Mass ◽  
Neutrophilic Inflammation ◽  
Positron Emission ◽  
Pet Ct

Background: Mechanical ventilation (MV) may initiate or worsen lung injury, so-called ventilator-induced lung injury (VILI). Although different mechanisms of VILI have been identified, research mainly focused on single ventilator parameters. The mechanical power (MP) summarizes the potentially damaging effects of different parameters in one single variable and has been shown to be associated with lung damage. However, to date, the association of MP with pulmonary neutrophilic inflammation, as assessed by positron-emission tomography (PET), has not been prospectively investigated in a model of clinically relevant ventilation settings yet. We hypothesized that the degree of neutrophilic inflammation correlates with MP.Methods: Eight female juvenile pigs were anesthetized and mechanically ventilated. Lung injury was induced by repetitive lung lavages followed by initial PET and computed tomography (CT) scans. Animals were then ventilated according to the acute respiratory distress syndrome (ARDS) network recommendations, using the lowest combinations of positive end-expiratory pressure and inspiratory oxygen fraction that allowed adequate oxygenation. Ventilator settings were checked and adjusted hourly. Physiological measurements were conducted every 6 h. Lung imaging was repeated 24 h after first PET/CT before animals were killed. Pulmonary neutrophilic inflammation was assessed by normalized uptake rate of 2-deoxy-2-[18F]fluoro-D-glucose (KiS), and its difference between the two PET/CT was calculated (ΔKiS). Lung aeration was assessed by lung CT scan. MP was calculated from the recorded pressure–volume curve. Statistics included the Wilcoxon tests and non-parametric Spearman correlation.Results: Normalized 18F-FDG uptake rate increased significantly from first to second PET/CT (p = 0.012). ΔKiS significantly correlated with median MP (ρ = 0.738, p = 0.037) and its elastic and resistive components, but neither with median peak, plateau, end-expiratory, driving, and transpulmonary driving pressures, nor respiratory rate (RR), elastance, or resistance. Lung mass and volume significantly decreased, whereas relative mass of hyper-aerated lung compartment increased after 24 h (p = 0.012, p = 0.036, and p = 0.025, respectively). Resistance and PaCO2 were significantly higher (p = 0.012 and p = 0.017, respectively), whereas RR, end-expiratory pressure, and MP were lower at 18 h compared to start of intervention.Conclusions: In this model of experimental acute lung injury in pigs, pulmonary neutrophilic inflammation evaluated by PET/CT increased after 24 h of MV, and correlated with MP.

scholarly journals Regulation of neutrophilic inflammation in lung injury induced by community-acquired pneumonia

The Lancet ◽  
2015 ◽  
Vol 385 ◽  
pp. S52 ◽  
Author(s):  
Ricardo José ◽  
Andrew Williams ◽  
Michal Sulikowski ◽  
David Brealey ◽  
Jeremy Brown ◽  
...  
Keyword(s):  
Lung Injury ◽  
Community Acquired Pneumonia ◽  
Neutrophilic Inflammation
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