scholarly journals Collateral damage: necroptosis in the development of lung injury

2020 ◽  
Vol 318 (2) ◽  
pp. L215-L225 ◽  
Author(s):  
Hilary Faust ◽  
Nilam S. Mangalmurti
Keyword(s):  
Cell Death ◽  
Lung Injury ◽  
Bacterial Pneumonia ◽  
Collateral Damage ◽  
Laboratory Findings ◽  
Diverse Range ◽  
Regulated Cell Death ◽  
Extracellular Release ◽  
Cell Death Program

Cell death is increasingly recognized as a driving factor in the development of acute lung injury. Necroptosis, an immunogenic regulated cell death program important in innate immunity, has been implicated in the development of lung injury in a diverse range of conditions. Characterized by lytic cell death and consequent extracellular release of endogenous inflammatory mediators, necroptosis can be both beneficial and deleterious to the host, depending on the context. Here, we review recent investigations linking necroptosis and the development of experimental lung injury. We assess the consequences of necroptosis during bacterial pneumonia, viral infection, sepsis, and sterile injury, highlighting increasing evidence from in vitro studies, animal models, and clinical studies that implicates necroptosis in the pathogenesis of ARDS. Lastly, we highlight current challenges in translating laboratory findings to the bedside.

scholarly journals TLR4-dependent GM-CSF protects against lung injury in Gram-negative bacterial pneumonia

2012 ◽  
Vol 302 (5) ◽  
pp. L447-L454 ◽  
Author(s):  
Louis R. Standiford ◽  
Theodore J. Standiford ◽  
Michael J. Newstead ◽  
Xianying Zeng ◽  
Megan N. Ballinger ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bacterial Pneumonia ◽  
Lavage Fluid ◽  
Alveolar Epithelial Cells ◽  
Intratracheal Administration ◽  
Bacterial Colony ◽  
Gram Negative ◽  
Gm Csf

Toll-like receptors (TLRs) are required for protective host defense against bacterial pathogens. However, the role of TLRs in regulating lung injury during Gram-negative bacterial pneumonia has not been thoroughly investigated. In this study, experiments were performed to evaluate the role of TLR4 in pulmonary responses against Klebsiella pneumoniae (Kp). Compared with wild-type (WT) (Balb/c) mice, mice with defective TLR4 signaling (TLR4lps-d mice) had substantially higher lung bacterial colony-forming units after intratracheal challenge with Kp, which was associated with considerably greater lung permeability and lung cell death. Reduced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA and protein was noted in lungs and bronchoalveolar lavage fluid of TLR4 mutant mice postintratracheal Kp compared with WT mice, and primary alveolar epithelial cells (AEC) harvested from TLR4lps-d mice produced significantly less GM-CSF in vitro in response to heat-killed Kp compared with WT AEC. TLR4lps-d AEC underwent significantly more apoptosis in response to heat-killed Kp in vitro, and treatment with GM-CSF protected these cells from apoptosis in response to Kp. Finally, intratracheal administration of GM-CSF in TLR4lps-d mice significantly decreased albumin leak, lung cell apoptosis, and bacteremia in Kp-infected mice. Based on these observations, we conclude that TLR4 plays a protective role on lung epithelium during Gram-negative bacterial pneumonia, an effect that is partially mediated by GM-CSF.

scholarly journals Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

2020 ◽  
Vol 8 (1) ◽  
pp. e000337 ◽  
Author(s):  
Lorenzo Galluzzi ◽  
Ilio Vitale ◽  
Sarah Warren ◽  
Sandy Adjemian ◽  
Patrizia Agostinis ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Adaptive Immune Response ◽  
Operational Definition ◽  
Immunogenic Cell Death ◽  
Adaptive Immune ◽  
Regulated Cell Death ◽  
Definition Of

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.

scholarly journals Bcl-2 overexpression in type II epithelial cells does not prevent hyperoxia-induced acute lung injury in mice

2010 ◽  
Vol 299 (3) ◽  
pp. L312-L322 ◽  
Author(s):  
Isabelle Métrailler-Ruchonnet ◽  
Alessandra Pagano ◽  
Stéphanie Carnesecchi ◽  
Karim Khatib ◽  
Pedro Herrera ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Ex Vivo ◽  
Lung Damage ◽  
Type Ii Cells ◽  
Type Ii ◽  
Lung Weight

Bcl-2 is an anti-apoptotic molecule preventing oxidative stress damage and cell death. We have previously shown that Bcl-2 is able to prevent hyperoxia-induced cell death when overexpressed in a murine fibrosarcoma cell line L929. We hypothesized that its specific overexpression in pulmonary epithelial type II cells could prevent hyperoxia-induced lung injury by protecting the epithelial side of the alveolo-capillary barrier. In the present work, we first showed that in vitro Bcl-2 can rescue murine pulmonary epithelial cells (MLE12) from oxygen-induced cell apoptosis, as shown by analysis of LDH release, annexin V/propidium staining, and caspase-3 activity. We then generated transgenic mice overexpressing specifically Bcl-2 in lung epithelial type II cells under surfactant protein C (SP-C) promoter (Tg-Bcl-2) and exposed them to hyperoxia. Bcl-2 did not hinder hyperoxia-induced mitochondria and DNA oxidative damage of type II cell in vivo. Accordingly, lung damage was identical in both Tg-Bcl-2 and littermate mice strains, as measured by lung weight, bronchoalveolar lavage, and protein content. Nevertheless, we observed a significant lower number of TUNEL-positive cells in type II cells isolated from Tg-Bcl-2 mice exposed to hyperoxia compared with cells isolated from littermate mice. In summary, these results show that although Bcl-2 overexpression is able to prevent hyperoxia-induced cell death at single cell level in vitro and ex vivo, it is not sufficient to prevent cell death of parenchymal cells and to protect the lung from acute damage in mice.

scholarly journals Role of Meconium and Hypoxia in Meconium Aspiration-Induced Lung Injury in Neonatal Rabbits

2010 ◽  
Vol 2010 ◽  
pp. 1-6 ◽  
Author(s):  
Alex Zagariya ◽  
Monica Sierzputovska ◽  
Shan Navale ◽  
Dharmapuri Vidyasagar
Keyword(s):  
Cell Death ◽  
Lung Injury ◽  
Cell Injury ◽  
Apoptotic Cell ◽  
A549 Cells ◽  
Cell Loss ◽  
Lung Lavage ◽  
Cytokine Expression ◽  
Meconium Aspiration

Background. We previously showed that meconium cuases lung cell death by apoptosis and inflammatory cytokine expression. Whether this is due to meconium exposure itself, or meconium related hypoxia remains unclear.Objectives. To elucidate the effects of meconium, saline, milk, hypoxia and hyperoxia induced lung injury.Design/Methods. We studied 5 groups of rabbit pups: (I) normal saline; (II) Milk; (III) 10% solution of meconium; (IV) only to 15 minutes of hypoxia (10% O2), and (V) 5 minutes of hypoxia (95% O2). After exposure lung lavage cells were used for apoptotic cell count and cytokine expression.In vitroresponse of human A 549 epithelial cells to meconium-and milk exposure was also studied.Results. There was no difference in cell death between saline and milk groups. However, meconium caused a significant cell loss compared to saline and milk—Inflammatory cytokines increased significantly in meconium group compared to saline or milk group. Although hypoxic and hyperoxic lungs showed increased inflammatory reaction compared to saline-treated lungs, this injury was not significant compared to meconium group. Studies with A549 cells also showed similar results.Conclusions. We conclude that lung cell injury in meconium aspiration is maily from meconium itself.

Flaxseed Lignans Protect Against Acid Aspiration‐Induced Acute Lung Injury In Vivo and H 2 O 2 ‐Induced Cell Death In Vitro

2007 ◽  
Vol 21 (5) ◽  
Author(s):  
James C Lee ◽  
Evguenia Arguiri ◽  
C. C. Solomides ◽  
Melpo Christofidou Solomidou
Keyword(s):  
Cell Death ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Acid Aspiration ◽  
Flaxseed Lignans

scholarly journals Keratinocyte growth factor reduces alveolar epithelial susceptibility to in vitro mechanical deformation

2001 ◽  
Vol 281 (5) ◽  
pp. L1068-L1077 ◽  
Author(s):  
Jane Oswari ◽  
Michael A. Matthay ◽  
Susan S. Margulies
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Lung Injury ◽  
Keratinocyte Growth Factor ◽  
Alveolar Type ◽  
Alveolar Epithelial ◽  
Ventilator Induced Lung Injury ◽  
And Control

Keratinocyte growth factor (KGF) is a potent mitogen that prevents lung epithelial injury in vivo. We hypothesized that KGF treatment reduces ventilator-induced lung injury by increasing the alveolar epithelial tolerance to mechanical strain. We evaluated the effects of in vivo KGF treatment to rats on the response of alveolar type II (ATII) cells to in vitro controlled, uniform deformation. KGF (5 mg/kg) or saline (no-treatment control) was instilled intratracheally in rats, and ATII cells were isolated 48 h later. After 24 h in culture, both cell groups were exposed to 1 h of continuous cyclic strain (25% change in surface area); undeformed wells were included as controls. Cytotoxicity was evaluated quantitatively with fluorescent immunocytochemistry. There was >1% cell death in undeformed KGF-treated and control groups. KGF pretreatment significantly reduced deformation-related cell mortality to only 2.2 ± 1.3% (SD) from 49 ± 5.5% in control wells ( P < 0.001). Effects of extracellular matrix, actin cytoskeleton, and phenotype of KGF-treated and control cells were examined. The large reduction in deformation-induced cell death demonstrates that KGF protects ATII cells by increasing their strain tolerance and supports KGF treatment as a potential preventative measure for ventilator-induced lung injury.

scholarly journals Heat stress induces ferroptosis in a photosynthetic prokaryote

2019 ◽  
Author(s):  
Anabella Aguilera ◽  
Federico Berdun ◽  
Carlos Bartoli ◽  
Charlotte Steelheart ◽  
Matías Alegre ◽  
...  
Keyword(s):  
Cell Death ◽  
Heat Stress ◽  
Similar Process ◽  
Cell Death Pathway ◽  
Regulated Cell Death ◽  
Cell Death Program ◽  
Dependent Form ◽  
A Cell ◽  
Eukaryotic Organisms ◽  
Pcc 6803

AbstractFerroptosis is an oxidative iron-dependent form of cell death recently described in eukaryotic organisms like animals, plants and parasites. Here we report that a similar process takes place in the cyanobacterium Synechocystis sp. PCC 6803 in response to heat stress. After a heat shock, Synechocystis cells undergo a cell death pathway that can be suppressed by canonical ferroptosis inhibitors or by external addition of calcium, glutathione or ascorbic acid. Moreover, as described for eukaryotic cells ferroptosis, this pathway is characterized by an early depletion of antioxidants, and by lipid peroxidation. As in general prokaryotes membranes contain poorly oxidizable saturated or monounsaturated lipid molecules, it was thought that they were not susceptible to ferroptosis. Interestingly, cyanobacteria contain thylakoid membranes that are enriched in polyunsaturated-fatty-acid-containing phospholipids, which might explain their sensitivity to ferroptosis. These results indicate that all of the hallmarks described for eukaryotic ferroptosis are conserved in photosynthetic prokaryotes and suggest that ferroptosis might be an ancient cell death program.SummaryAguilera et al, show that ferroptosis, an oxidative and iron-dependent form of regulated cell death, plays an important role in the cyanobacterium Synechocystis sp. PCC 6803 in response to heat stress.

scholarly journals Blunted Fas signaling favors RIPK1-driven neutrophil necroptosis in critically ill COVID-19 patients

2021 ◽  
Author(s):  
Tiziano A Schweizer ◽  
Srikanth Mairpady Shambat ◽  
Clement Vulin ◽  
Sylvia Hoeller ◽  
Claudio Acevedo ◽  
...  
Keyword(s):  
Cell Death ◽  
Disease Severity ◽  
Critically Ill ◽  
Cytokine Profile ◽  
Caspase 8 ◽  
Potential Therapeutic Target ◽  
Regulated Cell Death ◽  
Cell Death Program ◽  
Fas Signaling ◽  
The Impact

Critically ill COVID-19 patients are characterized by a severely dysregulated cytokine profile and elevated neutrophil counts, which are thought to contribute to disease severity. However, to date it remains unclear how neutrophils contribute to pathophysiology during COVID-19. Here, we assessed the impact of the dysregulated cytokine profile on the tightly regulated cell death program of neutrophils. We show that in a subpopulation of neutrophils, canonical apoptosis was skewed towards rapidly occurring necroptosis. This phenotype was characterized by abrogated caspase-8 activity and increased RIPK1 levels, favoring execution of necroptosis via the RIPK1-RIPK3-MLKL axis, as further confirmed in COVID-19 biopsies. Moreover, reduction of sFas-L levels in COVID-19 patients and hence decreased signaling to Fas directly increased RIPK1 levels and correlated with disease severity. Our results suggest an important role for Fas signaling in the regulation of cell death program ambiguity via the ripoptosome in neutrophils during COVID-19 and a potential therapeutic target to curb inflammation and thus influence disease severity and outcome.

scholarly journals STING1 Promotes Ferroptosis Through MFN1/2-Dependent Mitochondrial Fusion

2021 ◽  
Vol 9 ◽  
Author(s):  
Changfeng Li ◽  
Jiao Liu ◽  
Wen Hou ◽  
Rui Kang ◽  
Daolin Tang
Keyword(s):  
Pancreatic Cancer ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Mitochondrial Fusion ◽  
Antioxidant Defenses ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Regulated Cell Death ◽  
Potential Strategy

Ferroptosis is a type of iron-dependent regulated cell death caused by the disruption that occurs when oxidative stress and antioxidant defenses interact, and then driven by lipid peroxidation and subsequent plasma membrane ruptures. The regulation of ferroptosis involves many factors, including the crosstalk between subcellular organelles, such as mitochondria, endoplasmic reticulum (ER), lysosomes, lipid droplets, and peroxisomes. Here, we show that the ER protein STING1 (also known as STING or TMEM173) promotes ferroptosis in human pancreatic cancer cell lines by increasing MFN1/2-dependent mitochondrial fusion, but not mitophagy-mediated mitochondrial removal. The classic ferroptosis inducer erastin, but not sulfasalazine, induces the accumulation of STING1 in the mitochondria, where it binds to MFN1/2 to trigger mitochondrial fusion, leading to subsequent reactive oxygen species production and lipid peroxidation. Consequently, in vitro or xenograft mouse models show that the genetic depletion of STING1 or MFN1/2 (but not the mitophagy regulator PINK1 or PRKN) reduces the sensitivity of pancreatic cancer cells to ferroptosis. These findings not only establish a new mitochondrial fusion-dependent cell death mechanism, but also indicate a potential strategy for enhancing ferroptosis-based therapy.

scholarly journals The Receptor Interacting Protein Kinases in the Liver

2018 ◽  
Vol 38 (01) ◽  
pp. 073-086 ◽  
Author(s):  
Lily Dara
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Kinase Activity ◽  
Cultured Cells ◽  
Interacting Protein ◽  
Regulated Cell Death ◽  
Cell Death Program ◽  
Cell Death Signaling ◽  
Experimental Liver ◽  
Mediate Inflammation

AbstractThe receptor interacting serine/threonine kinase1 and 3 (RIPK1, RIPK3) are regulators of cell death and survival. RIPK1 kinase activity is required for necroptosis and apoptosis, while its scaffolding function is necessary for survival. Although both proteins can mediate apoptosis, RIPK1 and RIPK3 are most well-known for their role in the execution of necroptosis via the mixed lineage domain like pseudokinase. Necroptosis is a caspase-independent regulated cell death program which was first described in cultured cells with unknown physiologic relevance in the liver. Many recent reports have suggested that RIPK1 and/or RIPK3 participate in liver disease pathogenesis and cell death. Notably, both proteins have been shown to mediate inflammation independent of cell death. Whether necroptosis occurs in hepatocytes, and how it is executed in the presence of an intact caspase machinery is controversial. In spite of this controversy, it is evident that RIPK1 and RIPK3 participate in many experimental liver disease models. Therefore, in addition to cell death signaling, their necroptosis-independent role warrants further examination.

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