scholarly journals Core genes involved in the regulation of acute lung injury and their association with COVID-19 and tumor progression: A bioinformatics and experimental study

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260450
Author(s):  
Aleksandra V. Sen’kova ◽  
Innokenty A. Savin ◽  
Evgenyi V. Brenner ◽  
Marina A. Zenkova ◽  
Andrey V. Markov
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
The Cancer Genome Atlas ◽  
Lung Damage ◽  
Lps Challenge ◽  
Key Genes ◽  
Anti Inflammatory

Acute lung injury (ALI) is a specific form of lung damage caused by different infectious and non-infectious agents, including SARS-CoV-2, leading to severe respiratory and systemic inflammation. To gain deeper insight into the molecular mechanisms behind ALI and to identify core elements of the regulatory network associated with this pathology, key genes involved in the regulation of the acute lung inflammatory response (Il6, Ccl2, Cat, Serpine1, Eln, Timp1, Ptx3, Socs3) were revealed using comprehensive bioinformatics analysis of whole-genome microarray datasets, functional annotation of differentially expressed genes (DEGs), reconstruction of protein-protein interaction networks and text mining. The bioinformatics data were validated using a murine model of LPS-induced ALI; changes in the gene expression patterns were assessed during ALI progression and prevention by anti-inflammatory therapy with dexamethasone and the semisynthetic triterpenoid soloxolone methyl (SM), two agents with different mechanisms of action. Analysis showed that 7 of 8 revealed ALI-related genes were susceptible to LPS challenge (up-regulation: Il6, Ccl2, Cat, Serpine1, Eln, Timp1, Socs3; down-regulation: Cat) and their expression was reversed by the pre-treatment of mice with both anti-inflammatory agents. Furthermore, ALI-associated nodal genes were analysed with respect to SARS-CoV-2 infection and lung cancers. The overlap with DEGs identified in postmortem lung tissues from COVID-19 patients revealed genes (Saa1, Rsad2, Ifi44, Rtp4, Mmp8) that (a) showed a high degree centrality in the COVID-19-related regulatory network, (b) were up-regulated in murine lungs after LPS administration, and (c) were susceptible to anti-inflammatory therapy. Analysis of ALI-associated key genes using The Cancer Genome Atlas showed their correlation with poor survival in patients with lung neoplasias (Ptx3, Timp1, Serpine1, Plaur). Taken together, a number of key genes playing a core function in the regulation of lung inflammation were found, which can serve both as promising therapeutic targets and molecular markers to control lung ailments, including COVID-19-associated ALI.

Class B Scavenger Receptors BI and BII Protect Against LPS-induced Acute Lung Injury in Mice by Mediating LPS Clearance

2021 ◽  
Author(s):  
Irina N. Baranova ◽  
Alexander V. Bocharov ◽  
Tatyana G. Vishnyakova ◽  
Zhigang Chen ◽  
Anna A. Birukova ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Transgenic Mice ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Protective Role ◽  
Lung Damage ◽  
Wild Type ◽  
Class B ◽  
Anti Inflammatory

Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an alternative role of SR-BI, facilitating bacterial and endotoxin uptake, and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates understanding SR-BI’s role in endotoxemia/sepsis, calling for use of alternative models. In this study, using hSR-BI and hSR-BII transgenic mice, we found that SR-BI and to a lesser extent its splicing variant SR-BII, protects against LPS-induced lung damage. At 20 hours after intratracheal LPS instillation the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice compared to wild type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content as well as lung tissue neutrophil infiltration found in wild type mice was associated with markedly (2-3 times) increased pro-inflammatory cytokine production as compared to transgenic mice following LPS administration. Markedly lower endotoxin levels detected in BALF of transgenic vs. wild type mice along with the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 hours after the IT LPS injection suggest that hSR-BI and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.

scholarly journals Cissus subtetragona Planch. Ameliorates Inflammatory Responses in LPS-induced Macrophages, HCl/EtOH-induced Gastritis, and LPS-induced Lung Injury via Attenuation of Src and TAK1

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6073
Author(s):  
Laily Rahmawati ◽  
Nur Aziz ◽  
Jieun Oh ◽  
Yo Han Hong ◽  
Byoung Young Woo ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Raw264.7 Cells ◽  
Acute Gastritis ◽  
Anti Inflammatory

Several Cissus species have been used and reported to possess medicinal benefits. However, the anti-inflammatory mechanisms of Cissus subtetragona have not been described. In this study, we examined the potential anti-inflammatory effects of C. subtetragona ethanol extract (Cs-EE) in vitro and in vivo, and investigated its molecular mechanism as well as its flavonoid content. Lipopolysaccharide (LPS)-induced macrophage-like RAW264.7 cells and primary macrophages as well as LPS-induced acute lung injury (ALI) and HCl/EtOH-induced acute gastritis mouse models were utilized. Luciferase assays, immunoblotting analyses, overexpression strategies, and cellular thermal shift assay (CETSA) were performed to identify the molecular mechanisms and targets of Cs-EE. Cs-EE concentration-dependently reduced the secretion of NO and PGE2, inhibited the expression of inflammation-related cytokines in LPS-induced RAW264.7 cells, and decreased NF-κB- and AP-1-luciferase activity. Subsequently, we determined that Cs-EE decreased the phosphorylation events of NF-κB and AP-1 pathways. Cs-EE treatment also significantly ameliorated the inflammatory symptoms of HCl/EtOH-induced acute gastritis and LPS-induced ALI mouse models. Overexpression of HA-Src and HA-TAK1 along with CETSA experiments validated that inhibited inflammatory responses are the outcome of attenuation of Src and TAK1 activation. Taken together, these findings suggest that Cs-EE could be utilized as an anti-inflammatory remedy especially targeting against gastritis and acute lung injury by attenuating the activities of Src and TAK1.

scholarly journals Euphorbia cuneata Represses LPS-Induced Acute Lung Injury in Mice via Its Antioxidative and Anti-Inflammatory Activities

Plants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1620
Author(s):  
Hossam M. Abdallah ◽  
Dina S. El-Agamy ◽  
Sabrin R. M. Ibrahim ◽  
Gamal A. Mohamed ◽  
Wael M. Elsaed ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protective Effect ◽  
Lung Tissue ◽  
Histopathological Examination ◽  
Total Protein Content ◽  
Lps Challenge ◽  
Cell Counts ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Euphorbia cuneata (EC; Euphorbiaceae), which widely grows in Saudi Arabia and Yemen, is used traditionally to treat pain and inflammation. This study aimed to evaluate the protective anti-inflammatory effect of a standardized extract of EC against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible underlying mechanism(s) of this pharmacologic activity. ALI was induced in male Balb/c mice using intraperitoneal injection of LPS. A standardized total methanol extract of EC or dexamethasone was administered 5 days prior to LPS challenge. Bronchoalveolar fluid (BALF) and lung samples were collected for analysis. The results demonstrated the protective anti-inflammatory effect of EC against LPS-induced ALI in mice. Standardized EC contained 2R-naringenin-7-O-β-glucoside (1), kaempferol-7-O-β-glucoside (2), cuneatannin (3), quercetin (4), and 2R-naringenin (5) in concentrations of 6.16, 4.80, 51.05, 13.20, and 50.00 mg/g of extract, respectively. EC showed a protective effect against LPS-induced pulmonary damage. EC reduced lung wet/dry weight (W/D) ratio and total protein content in BALF, indicating attenuation of the pulmonary edema. Total and differential cell counts were decreased in EC-treated animals. Histopathological examination confirmed the protective effect of EC, as indicated by an amelioration of LPS-induced lesions in lung tissue. EC also showed a potent anti-oxidative property as it decreased lipid peroxidation and increased the antioxidants in lung tissue. Finally, the anti-inflammatory activity of EC was obvious through its ability to suppress the activation of nuclear factor-κB (NF-κB), and hence its reduction of the levels of downstream inflammatory mediators. In conclusion, these results demonstrate the protective effects of EC against LPS-induced lung injury in mice, which may be due to its antioxidative and anti-inflammatory activities.

scholarly journals Alveolar Type II Cells or Mesenchymal Stem Cells: Comparison of Two Different Cell Therapies for the Treatment of Acute Lung Injury in Rats

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1816
Author(s):  
Raquel Guillamat-Prats ◽  
Marta Camprubí-Rimblas ◽  
Ferranda Puig ◽  
Raquel Herrero ◽  
Neus Tantinyà ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Molecular Mechanisms ◽  
Lung Damage ◽  
Alveolar Type ◽  
Therapeutic Effects ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Type Ii Cells ◽  
Cell Therapies

The use of cell therapies has recently increased for the treatment of pulmonary diseases. Mesenchymal stem/stromal cells (MSCs) and alveolar type II cells (ATII) are the main cell-based therapies used for the treatment of acute respiratory distress syndrome (ARDS). Many pre-clinical studies have shown that both therapies generate positive outcomes; however, the differences in the efficiency of MSCs or ATII for reducing lung damage remains to be studied. We compared the potential of both cell therapies, administering them using the same route and dose and equal time points in a sustained acute lung injury (ALI) model. We found that the MSCs and ATII cells have similar therapeutic effects when we tested them in a hydrochloric acid and lipopolysaccharide (HCl-LPS) two-hit ALI model. Both therapies were able to reduce proinflammatory cytokines, decrease neutrophil infiltration, reduce permeability, and moderate hemorrhage and interstitial edema. Although MSCs and ATII cells have been described as targeting different cellular and molecular mechanisms, our data indicates that both cell therapies are successful for the treatment of ALI, with similar beneficial results. Understanding direct cell crosstalk and the factors released from each cell will open the door to more accurate drugs being able to target specific pathways and offer new curative options for ARDS.

scholarly journals Early Local Inhibition of Club Cell Protein 16 Following Chest Trauma Reduces Late Sepsis-Induced Acute Lung Injury

2019 ◽  
Vol 8 (6) ◽  
pp. 896 ◽  
Author(s):  
Philipp Störmann ◽  
Nils Becker ◽  
Jan Tilmann Vollrath ◽  
Kernt Köhler ◽  
Andrea Janicova ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cecal Ligation ◽  
Lung Damage ◽  
Cell Protein ◽  
Neutrophilic Infiltration ◽  
Local Inflammatory Response ◽  
Club Cell ◽  
Double Hit ◽  
Anti Inflammatory

Blunt thoracic trauma (TxT) deteriorates clinical post-injury outcomes. Ongoing inflammatory changes promote the development of post-traumatic complications, frequently causing Acute Lung Injury (ALI). Club Cell Protein (CC)16, a pulmonary anti-inflammatory protein, correlates with lung damage following TxT. Whether CC16-neutralization influences the inflammatory course during ALI is elusive. Ninety-six male CL57BL/6N mice underwent a double hit model of TxT and cecal ligation puncture (CLP, 24 h post-TxT). Shams underwent surgical procedures. CC16 was neutralized by the intratracheal application of an anti-CC16-antibody, either after TxT (early) or following CLP (late). Euthanasia was performed at 6 or 24 h post-CLP. Systemic and pulmonary levels of IL-6, IL-1β, and CXCL5 were determined, the neutrophils were quantified in the bronchoalveolar lavage fluid, and histomorphological lung damage was assessed. ALI induced a significant systemic IL-6 increase among all groups, while the local inflammatory response was most prominent after 24 h in the double-hit groups as compared to the shams. Significantly increased neutrophilic infiltration upon double hit was paralleled with the enhanced lung damage in all groups as compared to the sham, after 6 and 24 h. Neutralization of CC16 did not change the systemic inflammation. However, early CC16-neutralization increased the neutrophilic infiltration and lung injury at 6 h post-CLP, while 24 h later, the lung injury was reduced. Late CC16-neutralization increased neutrophilic infiltration, 24 h post-CLP, and was concurrent with an enhanced lung injury. The data confirmed the anti-inflammatory potential of endogenous CC16 in the murine double-hit model of ALI.

Ethanolic extract of Achillea wilhelmsii C. Koch improves pulmonary function and inflammation in LPS-induced acute lung injury mice

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Niloofar Honari ◽  
Parastoo Shaban ◽  
Saeed Nasseri ◽  
Mehran Hosseini
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Cell ◽  
Ethanolic Extract ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Lps Challenge ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Achillea Wilhelmsii

Abstract Objectives Acute lung injury (ALI) is a life-threatening pulmonary dysfunction associated with severe inflammation. There are still no effective pharmacological therapies for the treatment of ALI. In this concern, several anti-inflammatory agents could be used as add-on therapy to inhibit inflammation. Achillea wilhelmsii (AW) C. Koch is a well-known medicinal plant in the Iranian ethnomedical practices with anti-inflammatory activity. This study was aimed to evaluate the efficacy of ethanolic extract of AW on lipopolysaccharide (LPS)-induced ALI in mice. Methods The ALI model was established via the intra-tracheal (i.t.) administration of LPS (2 mg/kg) to male BALB/c mice. The ALI mice were divided into four groups (n=8 each) which intra-peritoneally (i.p.) treated with repeated doses of saline (model), dexamethasone (2 mg/kg), and AW (150–300 mg/kg) 1, 11 and 23 h post LPS administration. Twenty-four hours after the LPS challenge, bronchoalveolar lavage fluid (BALF) and lung tissue were evaluated for inflammatory cell influx, level of tumor necrosis factor-α (TNF-α) and histopathological changes. Results The AW (150–300 mg/kg) treated mice showed lower inflammatory cells infiltration in BALF and TNF-α level when compared to the model group. In addition, LPS induced several pathological alterations such as edema, alveolar hemorrhage and inflammatory cell infiltration into the interstitium and alveolar spaces. Treatment with AW significantly reduced LPS-induced pathological injury. Conclusions Taken together, the data here indicated that AW may be considered as a promising add-on therapy for ALI.

Bilobalide, a bioactive compound on sepsis-induced acute lung injury through its anti-inflammatory and antioxidative activity

2021 ◽  
Vol 17 (73) ◽  
pp. 163
Author(s):  
Yi Zhu ◽  
Feng Wang ◽  
Jian Huang ◽  
Jun Li ◽  
Kang Chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Antioxidative Activity ◽  
Bioactive Compound ◽  
Anti Inflammatory

scholarly journals Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury

2018 ◽  
Vol 51 (6) ◽  
pp. 2776-2793 ◽  
Author(s):  
Yung-Fong Tsai ◽  
Shun-Chin Yang ◽  
Wen-Yi Chang ◽  
Jih-Jung Chen ◽  
Chun-Yu Chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Superoxide Anion ◽  
Calcium Influx ◽  
Neutrophil Activation ◽  
Lung Damage ◽  
Hek293 Cells ◽  
Human Neutrophils ◽  
Therapeutic Effects

Background/Aims: Formyl peptide receptors (FPRs) recognize different endogenous and exogenous molecular stimuli and mediate neutrophil activation. Dysregulation of excessive neutrophil activation and the resulting immune responses can induce acute lung injury (ALI) in the host. Accordingly, one promising approach to the treatment of neutrophil-dominated inflammatory diseases involves therapeutic FPR1 inhibition. Methods: We extracted a potent FPR1 antagonist from Garcinia multiflora Champ. (GMC). The inhibitory effects of GMC on superoxide anion release and elastase degranulation from activated human neutrophils were determined with spectrophotometric analysis. Reactive oxygen species (ROS) production and the FPR1 binding ability of neutrophils were assayed by flow cytometry. Signaling transduction mediated by GMC in response to chemoattractants was assessed with a calcium influx assay and western blotting. A lipopolysaccharide (LPS)-induced ALI mouse model was used to determine the therapeutic effects of GMC in vivo. Results: GMC significantly reduced superoxide anion release, the reactive oxidants derived therefrom, and elastase degranulation mediated through selective, competitive FPR1 blocking in N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF)-stimulated human neutrophils. In cell-free systems, GMC was unable to scavenge superoxide anions or suppress elastase activity. GMC produced a right shift in fMLF-activated concentration-response curves and was confirmed to be a competitive FPR1 antagonist. GMC binds to FPR1 not only in neutrophils, but also FPR1 in neutrophil-like THP-1 and hFPR1-transfected HEK293 cells. Furthermore, the mobilization of calcium and phosphorylation of mitogen-activated protein kinases and Akt, which are involved in FPR1-mediated downstream signaling, was competitively blocked by GMC. In an in vivo study, GMC significantly reduced pulmonary edema, neutrophil infiltration, and alveolar damage in LPS-induced ALI mice. Conclusion: Our findings demonstrate that GMC is a natural competitive FPR1 inhibitor, which makes it a possible anti-inflammatory treatment option for patients critically inflicted with FPR1-mediated neutrophilic lung damage.

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