Local tissue expression of the cell death ligand, FasL, plays a central role in the development of acute lung injury

ABSTRACT Due to the limitations of effective treatments, avian influenza A H5N1 virus is the most lethal influenza virus strain that causes severe acute lung injury (ALI). To develop effective drugs ameliorating H5N1-induced ALI, we explore an RNA interference (RNAi) screening method to monitor changes in cell death induced by H5N1 infection. We performed RNAi screening on 19,424 genes in A549 lung epithelial cells and examined cell death induced by H5N1 infection. These screens identified 1,137 host genes for which knockdown altered cell viability by over 20%. DrugBank searches of these 1,137 host genes identified 146 validated druggable target genes with 372 drug candidates. We obtained 104 commercially available drugs with 65 validated target genes and examined their improvement of cell viability following H5N1 infection. We identified 28 drugs that could significantly recover cell viability following H5N1 infection and tested 10 in an H5N1-induced-ALI mouse model. The neurological drug ifenprodil and the anticancer drug flavopiridol markedly decreased leukocyte infiltration and lung injury scores in infected mouse lungs, significantly ameliorated edema in infected mouse lung tissues, and significantly improved the survival of H5N1-infected mice. Ifenprodil is an antagonist of the N-methyl-d-aspartate (NMDA) receptor, which is linked to inflammation and lung injury. Flavopiridol is an inhibitor of cyclin-dependent kinase 4 (CDK4), which is linked to leukocyte migration and lung injury. These results suggest that ifenprodil and flavopiridol represent novel remedies against potential H5N1 epidemics in addition to their proven indications. Furthermore, our strategy for identifying repurposable drugs could be a general approach for other diseases. IMPORTANCE Drug repurposing is a quick and economical strategy for developing new therapies with approved drugs. H5N1 is a highly pathogenic avian influenza virus subtype that can cause severe acute lung injury (ALI) and a high mortality rate due to limited treatments. The use of RNA interference (RNAi) is a reliable approach to identify essential genes in diseases. In most genomewide RNAi screenings, virus replication is the readout of interference. Since H5N1 virus infection could induce significant cell death and the percentage of cell death is associated with virus lethality, we designed a genomewide RNAi screening method to identify repurposable drugs against H5N1 virus with cell death as the readout. We discovered that the neurological drug ifenprodil and the anticancer drug flavopiridol could effectively ameliorate murine ALI after influenza A H5N1 virus infection, suggesting that they might be novel remedies for H5N1 virus-induced ALI in addition to the traditional indications.

Download Full-text

Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis

Respiratory Research ◽

10.1186/s12931-020-01500-2 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Yu-bao Qiu ◽

Bin-bin Wan ◽

Gang Liu ◽

Ya-xian Wu ◽

Dan Chen ◽

...

Keyword(s):

Cell Death ◽

Acute Lung Injury ◽

Lung Injury ◽

Knockout Mice ◽

Lipid Peroxide ◽

Dimethyl Fumarate ◽

Redox Balance ◽

Glutathione Depletion ◽

Stress Injury ◽

Nrf2 Knockout

Abstract Background Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis. Methods we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms. Results Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning. Conclusions These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.

Download Full-text

PAMAM Nanoparticles Promote Acute Lung Injury by Inducing Autophagic Cell Death through the Akt-TSC2-mTOR Signaling Pathway

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjp002 ◽

2009 ◽

Vol 1 (1) ◽

pp. 37-45 ◽

Cited By ~ 185

Author(s):

C. Li ◽

H. Liu ◽

Y. Sun ◽

H. Wang ◽

F. Guo ◽

...

Keyword(s):

Cell Death ◽

Acute Lung Injury ◽

Lung Injury ◽

Signaling Pathway ◽

Mtor Signaling ◽

Autophagic Cell Death ◽

Mtor Signaling Pathway

Download Full-text

Acute lung injury and cell death: how many ways can cells die?

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00262.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. L632-L641 ◽

Cited By ~ 134

Author(s):

Peter S. Tang ◽

Marco Mura ◽

Rashmi Seth ◽

Mingyao Liu

Keyword(s):

Cell Death ◽

Acute Lung Injury ◽

Lung Injury ◽

Fas Ligand ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Parenchymal Cell ◽

Underlying Mechanism ◽

Alternative Pathways ◽

Cell Death Pathways

Apoptosis has been considered as an underlying mechanism in acute lung injury/acute respiratory distress syndrome and multiorgan dysfunction syndrome. Recently, several alternative pathways for cell death (such as caspase-independent cell death, oncosis, and autophagy) have been discovered. Evidence of these pathways in the pathogenesis of acute lung injury has also come into light. In this article, we briefly introduce cell death pathways and then focus on studies related to lung injury. The different types of cell death that occur and the underlying mechanisms utilized depend on both experimental and clinical conditions. Lipopolysaccharide-induced acute lung injury is associated with apoptosis via Fas/Fas ligand mechanisms. Hyperoxia and ischemia-reperfusion injury generate reactive oxidative species, which induce complex cell death patterns composed of apoptosis, oncosis, and necrosis. Prolonged overexpression of inflammatory mediators results in increased production and activation of proteases, especially cathepsins. Activation and resistance to death of neutrophils also plays an important role in promoting parenchymal cell death. Knowledge of the coexisting multiple cell death pathways and awareness of the pharmacological inhibitors targeting different proteases critical to cell death may lead to the development of novel therapies for acute lung injury.

Download Full-text

Mechanisms of acute lung injury: Programmed Cell Death Receptor (PD)‐1 ligation as a regulator of Angiopoietin‐2 expression

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.57.7 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Joanne Lomas‐Neira ◽

Sean Monaghan ◽

Xin Huang ◽

Yaping Chen ◽

Alfred Ayala

Keyword(s):

Cell Death ◽

Acute Lung Injury ◽

Programmed Cell Death ◽

Lung Injury ◽

Death Receptor ◽

Angiopoietin 2 ◽

Cell Death Receptor

Download Full-text

Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis

10.21203/rs.3.rs-34579/v3 ◽

2020 ◽

Author(s):

Yu-bao Qiu ◽

Bin-bin Wan ◽

Gang Liu ◽

Ya-xian Wu ◽

Dan Chen ◽

...

Keyword(s):

Cell Death ◽

Acute Lung Injury ◽

Lung Injury ◽

Knockout Mice ◽

Lipid Peroxide ◽

Dimethyl Fumarate ◽

Redox Balance ◽

Glutathione Depletion ◽

Stress Injury ◽

Nrf2 Knockout

Abstract Background: Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis.Methods: we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms.Results: Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning.Conclusions: These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.

Download Full-text