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Hyperbaric Environment: Oxygen and Cellular Damage versus Protection

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ABSTRACT

The elevation of tissue pO2 induced by hyperbaric oxygen (HBO) is a physiological stimulus that elicits a variety of cellular responses. These effects are largely mediated by, or in response to, an increase in the production of reactive oxygen and nitrogen species (RONS). The major consequences of elevated RONS include increased oxidative stress and enhanced antioxidant capacity, and modulation of redox‐sensitive cell signaling pathways. Interestingly, these phenomena underlie both the therapeutic and potentially toxic effects of HBO. Emerging evidence indicates that supporting mitochondrial health is a potential method of enhancing the therapeutic efficacy of, and preventing oxygen toxicity during, HBO. This review will focus on the cellular consequences of HBO, and explore how these processes mediate a delicate balance of cellular protection versus damage. © 2017 American Physiological Society. Compr Physiol 7:213‐234, 2017.

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Figure 1. Figure 1. Mitochondrial RONS production—OxS versus signaling. The mitochondrion is implicated in the generation of ROS and RNS. In most cells, the mitochondrial respiratory chain is recognized as the major site of RONS production in the form of superoxide, hydrogen peroxide and the hydroxyl radical. These RONS are considered important for normal cell signaling. However, excessive amounts of RONS are deleterious for the cell, contributing to a variety of pathological processes. RONS production can result in the setup of a vicious cycle of oxidative damage causing a progressive alteration of mtDNA and mitochondrial functions that lead to energy deprivation, redox imbalance, and cell dysfunction. (, by permission.)
Figure 2. Figure 2. Endogenous sources of ROS signal. Intracellular ROS is primarily produced by NADPH oxidase enzymes (NOXs), the mitochondria, the endoplasmic reticulum, and the peroxisome. Cytosolic superoxide is rapidly converted into hydrogen peroxide (H2O2) by superoxide dismutase 1 (SOD1). H2O2 can either act as a signaling molecule by oxidizing critical thiols within proteins to regulate biological processes, including metabolic adaptation, differentiation, and proliferation or be detoxified to water (H2O) by the scavenging enzymes peroxiredoxin (PRX), GPx, and CAT. In addition, H2O2 can react with metal cations (Fe+2 or Cu+) to generate the hydroxyl radical (OH·), which causes oxidative damage to lipids, proteins, and DNA. (, by permission).
Figure 3. Figure 3. Hypoxia activates HIF‐1. HIF1α subunit is hydroxylated by prolyl hydroxylase at distinct proline residues thereby targeting the protein for von Hippel‐Lindau protein (pVHL)‐mediated proteasomal degradation. Hypoxia concomitantly diminishes PHD2 activity and induces the production of mitochondrial ROS at complex III resulting in an inhibition of hydroxylation of HIF1α subunit. Once HIF1α subunit is stabilized, it binds with HIF‐β and p300 coactivators to HREs in the promoters and enhancers of target genes that modulate metabolism. (, by permission).
Figure 4. Figure 4. Summary of hyperoxia signaling pathways in cells. Summary of hyperoxia signaling pathways in cells. activator protein‐1 (AP‐1); growth arrest and DNA damage (GADD); HO‐1; intracellular adhesion molecule (ICAM); insulin‐like growth factor (IGF); interleukin (IL); keratinocyte growth factor (KdcsGF); MAPK; nuclear factor κB (NFκB); poly (ADP‐ribosyl) polymerase (PARP); protein kinase C (PKC); reactive oxygen species (ROS); superoxide oxide dismutase (SOD); tumor necrosis factor α(TNF‐α); vascular endothelial cell growth factor (VEGF). (, by permission.)
Figure 5. Figure 5. Overview on therapeutic mechanisms of HBO2 related to elevations of tissue oxygen tensions. The figure outlines initial effects (denoted by boxes) that occur due to increased production of ROS and RNS and their consequences. Other abbreviations: growth factor (GH), VEGF, HIF, stem/progenitor cells (SPCs), HO‐1, heat‐shock proteins (HSP). (, by permission.)
Figure 6. Figure 6. HIF target genes. The HIF transcription factor regulates the expression of a number of genes involved in many cellular functions, including inflammation, proliferation, survival, metabolism and mitochondrial function, extracellular matrix function, motility, and angiogenesis. carbonic anhydrase IX (CAIX); C‐X‐C chemokine receptor 4 (CXCR4); insulin‐like growth factor II (IGF‐2); metastasis (MET); PDGF B; pyruvate dehydrogenase kinase 1 (PDK1); stromal cell‐derived factor 1alpha (SDF1alpha); vascular endothelial growth factor A (VEGFA). (, by permission.)
Figure 7. Figure 7. Ketone ester delays hyperoxia‐induced seizures. Example of EEG raw data acquisition after the administration of water (n = 38) (A), butanediol BD (n = 6) (B), and ketone ester BD‐AcAc2 (n = 16) (C). Test substances were administered 30 min before 5 ATA O2. (D) Percent change in latency to seizure (LS) (means SE) relative to control. Oral administration of BD‐AcAc2 caused a significant increase in LS at 5 ATA O2 compared with water or BD (P 0.001). (E) Individual responses in LS of rats in control, BD, and DB‐AcAc2 groups. ***Significance (P 0.001) of BD‐AcAc2 group from control (water) treated and BD‐treated animals as determined by t test. (, by permission.)
Figure 8. Figure 8. Suppression of tumor growth with HBO and KD therapy. (A) Representative animals from each treatment group demonstrating tumor bioluminescence at day 21 after tumor cell inoculation. Treated animals showed less bioluminescence than controls with KD+HBOT mice exhibiting a profound decrease in tumor bioluminescence compared to all groups. (B) Total body bioluminescence was measured weekly as a measure of tumor size; error bars represent ±SEM. KD+HBOT mice exhibited significantly less tumor bioluminescence than control animals at week 3 (P = 0.0062; two‐tailed student's t test) and an overall trend of notably slower tumor growth than controls and other treated animals throughout the study. (C, D) Day 21 ex vivo organ bioluminescence of SD and KD+HBOT animals (N = 8) demonstrated a trend of reduced metastatic tumor burden in animals receiving the combined therapy. Spleen bioluminescence was significantly decreased in KD+HBOT mice (*P = 0.0266; two‐tailed student's t test). Results were considered significant when P < 0.05. (, by permission.)


Figure 1. Mitochondrial RONS production—OxS versus signaling. The mitochondrion is implicated in the generation of ROS and RNS. In most cells, the mitochondrial respiratory chain is recognized as the major site of RONS production in the form of superoxide, hydrogen peroxide and the hydroxyl radical. These RONS are considered important for normal cell signaling. However, excessive amounts of RONS are deleterious for the cell, contributing to a variety of pathological processes. RONS production can result in the setup of a vicious cycle of oxidative damage causing a progressive alteration of mtDNA and mitochondrial functions that lead to energy deprivation, redox imbalance, and cell dysfunction. (, by permission.)


Figure 2. Endogenous sources of ROS signal. Intracellular ROS is primarily produced by NADPH oxidase enzymes (NOXs), the mitochondria, the endoplasmic reticulum, and the peroxisome. Cytosolic superoxide is rapidly converted into hydrogen peroxide (H2O2) by superoxide dismutase 1 (SOD1). H2O2 can either act as a signaling molecule by oxidizing critical thiols within proteins to regulate biological processes, including metabolic adaptation, differentiation, and proliferation or be detoxified to water (H2O) by the scavenging enzymes peroxiredoxin (PRX), GPx, and CAT. In addition, H2O2 can react with metal cations (Fe+2 or Cu+) to generate the hydroxyl radical (OH·), which causes oxidative damage to lipids, proteins, and DNA. (, by permission).


Figure 3. Hypoxia activates HIF‐1. HIF1α subunit is hydroxylated by prolyl hydroxylase at distinct proline residues thereby targeting the protein for von Hippel‐Lindau protein (pVHL)‐mediated proteasomal degradation. Hypoxia concomitantly diminishes PHD2 activity and induces the production of mitochondrial ROS at complex III resulting in an inhibition of hydroxylation of HIF1α subunit. Once HIF1α subunit is stabilized, it binds with HIF‐β and p300 coactivators to HREs in the promoters and enhancers of target genes that modulate metabolism. (, by permission).


Figure 4. Summary of hyperoxia signaling pathways in cells. Summary of hyperoxia signaling pathways in cells. activator protein‐1 (AP‐1); growth arrest and DNA damage (GADD); HO‐1; intracellular adhesion molecule (ICAM); insulin‐like growth factor (IGF); interleukin (IL); keratinocyte growth factor (KdcsGF); MAPK; nuclear factor κB (NFκB); poly (ADP‐ribosyl) polymerase (PARP); protein kinase C (PKC); reactive oxygen species (ROS); superoxide oxide dismutase (SOD); tumor necrosis factor α(TNF‐α); vascular endothelial cell growth factor (VEGF). (, by permission.)


Figure 5. Overview on therapeutic mechanisms of HBO2 related to elevations of tissue oxygen tensions. The figure outlines initial effects (denoted by boxes) that occur due to increased production of ROS and RNS and their consequences. Other abbreviations: growth factor (GH), VEGF, HIF, stem/progenitor cells (SPCs), HO‐1, heat‐shock proteins (HSP). (, by permission.)


Figure 6. HIF target genes. The HIF transcription factor regulates the expression of a number of genes involved in many cellular functions, including inflammation, proliferation, survival, metabolism and mitochondrial function, extracellular matrix function, motility, and angiogenesis. carbonic anhydrase IX (CAIX); C‐X‐C chemokine receptor 4 (CXCR4); insulin‐like growth factor II (IGF‐2); metastasis (MET); PDGF B; pyruvate dehydrogenase kinase 1 (PDK1); stromal cell‐derived factor 1alpha (SDF1alpha); vascular endothelial growth factor A (VEGFA). (, by permission.)


Figure 7. Ketone ester delays hyperoxia‐induced seizures. Example of EEG raw data acquisition after the administration of water (n = 38) (A), butanediol BD (n = 6) (B), and ketone ester BD‐AcAc2 (n = 16) (C). Test substances were administered 30 min before 5 ATA O2. (D) Percent change in latency to seizure (LS) (means SE) relative to control. Oral administration of BD‐AcAc2 caused a significant increase in LS at 5 ATA O2 compared with water or BD (P 0.001). (E) Individual responses in LS of rats in control, BD, and DB‐AcAc2 groups. ***Significance (P 0.001) of BD‐AcAc2 group from control (water) treated and BD‐treated animals as determined by t test. (, by permission.)


Figure 8. Suppression of tumor growth with HBO and KD therapy. (A) Representative animals from each treatment group demonstrating tumor bioluminescence at day 21 after tumor cell inoculation. Treated animals showed less bioluminescence than controls with KD+HBOT mice exhibiting a profound decrease in tumor bioluminescence compared to all groups. (B) Total body bioluminescence was measured weekly as a measure of tumor size; error bars represent ±SEM. KD+HBOT mice exhibited significantly less tumor bioluminescence than control animals at week 3 (P = 0.0062; two‐tailed student's t test) and an overall trend of notably slower tumor growth than controls and other treated animals throughout the study. (C, D) Day 21 ex vivo organ bioluminescence of SD and KD+HBOT animals (N = 8) demonstrated a trend of reduced metastatic tumor burden in animals receiving the combined therapy. Spleen bioluminescence was significantly decreased in KD+HBOT mice (*P = 0.0266; two‐tailed student's t test). Results were considered significant when P < 0.05. (, by permission.)
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Angela M. Poff, Dawn Kernagis, Dominic P. D'Agostino. Hyperbaric Environment: Oxygen and Cellular Damage versus Protection. Compr Physiol 2016, 7: 213-234. doi: 10.1002/cphy.c150032