Postoperative Hyperoxia (60%) Worsens Hepatic Injury in Mice

Zangl, Quirin; Martignoni, André; Jackson, Sharon H.; Ohta, Akio; Klaunberg, Brenda A.; Kaufmann, Inès; Lukashev, Dimitry; Ward, Jerrold M.; Sitkovsky, Michail V.; Thiel, Manfred; Choukèr, Alexander

doi:10.1097/aln.0000000000000447

Cited by 19 publications

(17 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With drug toxicity being a concern with studies pushing past two targets, approaches like this that can simultaneously dampen multiple immune checkpoints may be better tolerated and provide greater benefit (263). Although a drawback of hyperoxia therapy is that it may/does cause tissue damage (263,264), it is interesting to consider whether this response also benefits in helping to recover antitumor immunity. Hyperoxia is in clinical trials for many conditions/diseases (ClinicalTrials.gov; hyperoxia, 87 studies).…”

Section: Discussionmentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

View full text Add to dashboard Cite

CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

show abstract

Section: Discussionmentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Furthermore, hyperoxia is also involved in the development of hepatic pathology, including liver in ammation. Moreover, hyperoxia causes a signi cant aggravation of hepatic tissue damage [35].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Analysis Reveals Alteration of Lung Macrophages Following Mesenchymal Stem Cell Therapy in Neonatal Mice With Hyperoxia-Induced Injury

Al-Rubaie

DeMatteo

Sozo

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Lung immaturity is one of the most serious consequences of growth restriction and premature birth. Preterm babies often require mechanical ventilation to survive, but exposure to high levels of oxygen can permanently damage the lungs and interrupts normal development. As lung macrophages play an important role in hyperoxic lung injury and repair, our objective was to use next generation sequencing (NGS) to identify changes in the macrophage transcriptome following neonatal hyperoxia, with and without treatment with human mesenchymal stem cells (hMSCs). We provide the first report of RNA-sequencing of lung macrophages following neonatal hyperoxia and hMSCs therapy. Methods Neonatal mice exposed to normoxia (21%O2) or hyperoxia (90% O2) from birth to postnatal day 4 were randomized to receive either hMSCs or vehicle via intratracheal delivery on postnatal day 4. Mouse lungs from normoxia and hyperoxia groups with and without hMSCs therapy were examined at day 14. RNA-sequencing was performed on flow-cytometric CD45+CD11b+CD11c+ sorted lung macrophages. Purified total RNA was used to construct barcoded multiplex-compatible sequencing libraries using: 1) Illumina Stranded mRNA Sample Preparation chemistry (for transcriptomics) and 2) Bio Scientific NEXTFlex Small RNA chemistry (for small RNA). Results Sorted CD45+CD11b+CD11c+ lung macrophages from hyperoxia-exposed neonatal mice showed differentially expressed macrophage genes and miRNA compared to mice exposed to normoxia or hyperoxia+hMSCs. The administration of hMSCs was found to differentially upregulate 421 genes and downregulate 651 genes in CD45+CD11b+CD11c+ lung macrophages from neonatal mice exposed to hyperoxia, compared to normoxia. Integrity pathway analysis (IPA) analysis of macrophage-specific gene pathways revealed the effectiveness of hMSCs in altering macrophage function towards an anti-inflammatory ‘M2’ phenotype. Small-RNA sequencing provided further evidence on the effects of hMSCs, where 1,098 small RNAs transcriptomes were expressed as either significantly up- or down-regulated in response to hMSCs therapy following hyperoxia-induced lung damage. Conclusions Pathway analysis of the predicted mRNA targets of differentially expressed genes provides insight into miRNAs that preferentially target several important pathways. These miRNAs will be functionally relevant for lung macrophages, and will provide a greater understanding of the interaction between macrophage genotype and the associated phenotypes in the setting of inflammation or tissue repair.

show abstract

“…107 In myocardial infarction, the recent AVOID trial (Air Verses Oxygen In ST-segment elevation myocarDial infarction) showed that unnecessary supplementary oxygen exacerbated myocardial injury. 108,109 In vivo data show that hyperoxia after CA increased reactive oxygen species production 25 and lipid oxidation, 110 and exacerbation of neuronal death. 24,111 When appropriate, limiting FiO 2 to 50% after CA can reduce oxidative stress, and has shown improvements in myocardial function and survival.…”

Section: Some Caveats and Confounds For Human Translation: The Impactmentioning

confidence: 99%

Moving to human trials for argon neuroprotection in neurological injury: a narrative review

Gardner

Menon

2018

British Journal of Anaesthesia

View full text Add to dashboard Cite

Despite the global burden of brain injury, neuroprotective agents remain elusive. There are no clinically effective therapies which reduce mortality or improve long-term cognitive outcome. Ventilation could be an easily modifiable variable in resuscitation; gases are relatively simple to administer. Xenon is the prototypic agent of a new generation of experimental treatments which show promise. However, use is hindered by its prohibitive cost and anaesthetic properties. Argon is an attractive option, being cheaper, easy to transport, non-sedating, and mechanistically distinct from xenon. In vitro and in vivo models provide evidence of argon reducing brain injury, with improvements in neurocognitive, histological, and biomarker metrics, as well as improved survival. Current data suggest that the effect of argon is mediated via the toll-like receptors 2 and 4, the extracellular signal-regulated kinase 1/2, and phosphatidylinositol 3 kinase (PI-3K)-AKT pathways. Ventilation with argon appears to be safe in pigs and preliminary human trials. Given recent evidence that arterial hyperoxia may be harmful, the supplementation of high-concentration argon may not necessitate changes to clinical practice. Given the logistic benefits, and the evidence for argon neuroprotection summarized in this manuscript, we believe that the time has come to consider developing Phase II clinical trials to assess its benefit in acute neurological injury.

show abstract

Postoperative Hyperoxia (60%) Worsens Hepatic Injury in Mice

Abstract: Liver injury after ischemia was significantly aggravated by hyperoxia as a consequence of immune cell-mediated oxidative burst. Further studies are needed to elucidate whether routine delivery of high inspirational oxygen concentrations postoperatively should be limited.

Cited by 19 publications

References 52 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Transcriptional Analysis Reveals Alteration of Lung Macrophages Following Mesenchymal Stem Cell Therapy in Neonatal Mice With Hyperoxia-Induced Injury

Moving to human trials for argon neuroprotection in neurological injury: a narrative review

Contact Info

Product

Resources

About