Abstract

Hypoxia and immunity are highly intertwined at clinical, cellular, and molecular levels. The prevention of tissue hypoxia and modulation of systemic inflammation are cornerstones of daily practice in the intensive care unit. Potentially, immunologic effects of hypoxia may contribute to outcome and represent possible therapeutic targets. Hypoxia and activation of downstream signaling pathways result in enhanced innate immune responses, aimed to augment pathogen clearance. On the other hand, hypoxia also exerts antiinflammatory and tissue-protective effects in lymphocytes and other tissues. Although human data on the net immunologic effects of hypoxia and pharmacologic modulation of downstream pathways are limited, preclinical data support the concept of tailoring the immune response through modulation of the oxygen status or pharmacologic modulation of hypoxia-signaling pathways in critically ill patients.

Abstract

Hypoxia affects molecular and cellular inflammatory processes and may thereby affect outcome in critical illness. Modulating oxygenation and pharmacologic interventions in hypoxia-singling pathways could support immunologic functions in these patients.

OPTIMIZATION of oxygenation to prevent tissue hypoxia is one of the cornerstones of critical care. Concurrently, in the majority of patients admitted to the intensive care unit (ICU), inflammatory processes take place, which may affect outcome. As hypoxia and immunity are highly interdependent at molecular, cellular, and clinical levels, immunologic effects of hypoxia may represent therapeutic targets in critically ill patients. At the cellular level, hypoxia activates distinct hypoxia-signaling pathways, including a group of transcription factors known as hypoxia-inducible factors and adenosine signaling. In vitro and animal studies have shown that these pathways are involved in modulation of inflammatory responses, and animal studies have demonstrated that these pathways are relevant to inflammatory conditions that are frequently encountered in critically ill patients, such as sepsis1,2  and lung injury.3,4  In addition, inflammatory conditions are frequently characterized by tissue hypoxia due to enhanced metabolic demand as well as decreased metabolic substrates resulting from edema, microthrombi, and atelectasis, in turn causing “inflammatory hypoxia.”5,6  As such, aiming for specific tissue oxygenation levels could be favorable in a range of inflammatory conditions in critically ill patients. Alternatively, these effects may also be achieved with pharmacologic interventions targeting hypoxia-signaling pathways.

In the current review, we provide an overview of the immunologic consequences of hypoxia. We focus on in vitro, animal, and human studies concerning inflammatory conditions relevant to critically ill patients, including a discussion of oxygen-dependent signaling pathways and intermediate signaling systems (e.g., the hypoxia-inducible factor [HIF] system and adenosine metabolism).2,7  Furthermore, we discuss the clinical potential of intervening in these mechanisms, including evidence on potential drawbacks of hyperoxia, feasibility of therapeutic permissive hypoxia, and pharmacologic therapies that act on oxygen-dependent pathways. The role of hypoxia and HIFs outside the scope of inflammatory conditions in critically ill patients is reviewed elsewhere.2,7–9 

Immunologic Effects of Hypoxia

Evidence for immunologic effects of hypoxia has mainly been established in in vitro studies using myeloid cells (table 1).10–12  Long-term hypoxia has been shown to represent an inflammatory stimulus in itself, as prolonged hypoxia results in production of cytokines in a human macrophage cell line.14  In addition, hypoxia increases the production of proinflammatory cytokines upon stimulation with the toxins lipopolysaccharide or phytohemagglutinin in primary human mononuclear cells.13,15  In contrast, other studies have demonstrated that hypoxia skews the proinflammatory character (M1-like) of macrophages toward an antiinflammatory M2-like phenotype.18,19  In addition to these contradictory findings, these in vitro studies are difficult to interpret, as the control condition is usually room air, which has a higher Pao2 compared to physiologic tissue Pao2. Nevertheless, these in vitro studies demonstrate that oxygenation exerts immunologic effects, although the direction of this response may depend on the cell type and activation state.

Table 1.

In Vitro and (Pre)Clinical Studies on the Effects of Hypoxia on Immunity

In Vitro and (Pre)Clinical Studies on the Effects of Hypoxia on Immunity
In Vitro and (Pre)Clinical Studies on the Effects of Hypoxia on Immunity

Healthy volunteers subjected to hypoxia in vivo display enhanced ex vivo neutrophil chemotaxis, phagocytosis, and reactive oxygen species production24  and increased activity of the key inflammatory transcription factor nuclear factor of kappa-light-chain-enhancer of activated B cells (NF-κB) in monocytes.25  Furthermore, exposure of healthy subjects to high-altitude hypoxia (arterial oxygen saturation [Sao2], 75 to 90%) for 4 days results in increased plasma levels of the proinflammatory interleukin-6,21,22  while shorter periods of hypoxia do not induce such systemic responses17,23  (table 1). Taken together, in vivo, prolonged hypoxia increases inflammatory responses of myeloid cells ex vivo and elicits a systemic immune response.

Concerning the underlying mechanisms, hypoxia in vitro induces an expansive cascade of cellular processes, regulated by oxygen-sensitive pathways consisting of prolyl hydroxylases (PHDs), the transcription factors HIFs and NF-κB, adenosine signaling pathways, and other oxygen-sensitive processes. These cellular mechanisms provide adaptation toward conditions of limited oxygen availability, and each pathway contributes in different ways to the immunologic effects of hypoxia. This may explain why hypoxia causes both pro- and antiinflammatory, as well as tissue-protective effects, as further detailed below.

Regulation of HIF-1α

HIFs represent a group of transcription factors that mediate a plethora of cellular adaptations in response to hypoxia.26  HIFs are heterodimers consisting of HIF-β and one of the three oxygen-dependent transcriptionally active α subunits: HIF-1α, HIF-2α, and HIF-3α, of which HIF-1α is the most widely studied isoform. The cellular mechanisms responsible for the regulation of HIF-1α protein stabilization and signaling under normoxic, hypoxic, and inflammatory conditions are detailed in figure 1. Under normoxic conditions, the oxygen-dependent PHD-1, PHD2, and PHD3 and the asparaginyl-hydroxylase factor–inhibiting HIF (FIH) hydroxylate HIF-1α, after which hydroxylated HIF-1α binds to the Von Hippel–Lindau complex. Binding of HIFs to Von Hippel–Lindau ultimately results in ubiquitination and degradation in the proteasome. Under hypoxic conditions, the oxygen-dependent hydroxylases are inactive, which prevents degradation of HIF-1α. As such, hypoxia regulates HIF-1α in a posttranslational manner. A second, oxygen-independent, posttranslational mechanism of HIF-1α regulation involves heat shock protein (HSP) 90. HSPs are key players in the response to cellular stress, functioning as chaperone proteins that facilitate conformation, localization, and function of a diversity of proteins. HSP90 blocks the oxygen-independent degradation of HIF-1α and thereby results in stabilization of HIF-1α.27–29  Furthermore, HSP90 binding to HIF-1α facilitates coupling with HIFβ and subsequent transactivation.29 

Fig. 1.

Hypoxia-inducible factor (HIF)-1α regulation and signaling under normoxic, hypoxic, and inflammatory conditions. HIF-1α subunits are constantly produced but rapidly degraded under normoxic conditions. Several pathways of HIF-1α regulation have been described. First, under normoxic conditions, HIF-1α subunits are rapidly hydroxylated by oxygen-dependent prolyl hydroxylase domain enzymes (PHDs), which are subsequently captured by the ubiquitin ligase Von Hippel–Lindau (VHL) protein and degraded by the proteasome. Second, the oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF (FIH) hydroxylates a conserved asparaginyl residue, preventing the recruitment of coactivators P300 and cAMP-response element–binding protein (CBP), in turn inhibiting dimerization with HIFβ. During oxygen deficiency, PHD and FIH activities decrease, resulting in accumulation of HIF-1α subunits in the cytosol. The receptor for activated C kinase 1 (RACK1) and heat shock protein 90 (HSP90) regulate HIF-1α in an oxygen-independent manner: RACK facilitates oxygen-independent proteasomal degradation of HIF-1α, while HSP90 competes with RACK, thereby stabilizing HIF-1α, and facilitates its transactivation. Upon accumulation, HIF-1α is coactivated by P300/CBP and dimerizes with HIFβ to form stable HIF-1αβ dimers. These dimers translocate to the nucleus and bind to hypoxia response elements (HREs) in promoter enhancer regions of genes, resulting in transcriptional activity. HIF-1α stabilization results in transcription of many (greater than 100) hypoxia responsive genes. As FIH remains active at lower oxygen concentrations than PHDs, FIH suppresses the activity of HIF-1α proteins that escape destruction during moderate hypoxia. Not only hypoxia but also exposure to bacteria and bacterial products such as lipopolysaccharide (LPS) results in HIF-1α accumulation. NF-κB = nuclear factor of kappa-light-chain-enhancer of activated B cells; TLR = toll-like receptor.

Fig. 1.

Hypoxia-inducible factor (HIF)-1α regulation and signaling under normoxic, hypoxic, and inflammatory conditions. HIF-1α subunits are constantly produced but rapidly degraded under normoxic conditions. Several pathways of HIF-1α regulation have been described. First, under normoxic conditions, HIF-1α subunits are rapidly hydroxylated by oxygen-dependent prolyl hydroxylase domain enzymes (PHDs), which are subsequently captured by the ubiquitin ligase Von Hippel–Lindau (VHL) protein and degraded by the proteasome. Second, the oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF (FIH) hydroxylates a conserved asparaginyl residue, preventing the recruitment of coactivators P300 and cAMP-response element–binding protein (CBP), in turn inhibiting dimerization with HIFβ. During oxygen deficiency, PHD and FIH activities decrease, resulting in accumulation of HIF-1α subunits in the cytosol. The receptor for activated C kinase 1 (RACK1) and heat shock protein 90 (HSP90) regulate HIF-1α in an oxygen-independent manner: RACK facilitates oxygen-independent proteasomal degradation of HIF-1α, while HSP90 competes with RACK, thereby stabilizing HIF-1α, and facilitates its transactivation. Upon accumulation, HIF-1α is coactivated by P300/CBP and dimerizes with HIFβ to form stable HIF-1αβ dimers. These dimers translocate to the nucleus and bind to hypoxia response elements (HREs) in promoter enhancer regions of genes, resulting in transcriptional activity. HIF-1α stabilization results in transcription of many (greater than 100) hypoxia responsive genes. As FIH remains active at lower oxygen concentrations than PHDs, FIH suppresses the activity of HIF-1α proteins that escape destruction during moderate hypoxia. Not only hypoxia but also exposure to bacteria and bacterial products such as lipopolysaccharide (LPS) results in HIF-1α accumulation. NF-κB = nuclear factor of kappa-light-chain-enhancer of activated B cells; TLR = toll-like receptor.

Finally, the transcription and translation of HIF-1α are increased by inflammatory stimuli. Therefore, hypoxia, cellular stress, and inflammation (synergistically) enhance HIF-1α stabilization.2,7 

HIF-1α stabilization facilitates transcription of more than 100 hypoxia-responsive genes,30  many of which result in hypoxia adaptation, e.g., erythropoietin and vascular endothelial growth factor.31  Although the autoregulatory system of HIF-1α has not been fully elucidated, there appears to be a negative feedback system.32 In vitro, hypoxia induces HIF-1α expression in a dose-dependent fashion, but prolonged hypoxia results in down-regulation of HIF-1α, mediated by a micro-RNA, which targets HIF (aHIF), of which levels increase over time under hypoxic conditions.33  In contrast to in vitro data, where hypoxia has only been shown to prevent HIF-1α degradation, hypoxia in vivo stimulates transcription of HIF-1α, followed by a decrease to baseline levels, possibly resulting from the aHIF-mediated negative feedback.34  Human studies revealed a large interindividual variability in leukocyte HIF-1α expression35  and downstream target gene expression36  in response to hypoxia, implicating phenotypical differences in HIF regulation.

Involvement of HIF-1α and Adenosine Signaling in the Immunologic Effects of Hypoxia

The Molecular Interplay among Hypoxia, HIFs, and NF-κB

The regulation of HIF-1α and NF-κB, the latter considered the master regulator of inflammatory responses, is highly intertwined.37,38  In the inactivated state, NF-κB is bound to the inhibitory protein IκBα in the cytosol. Not only inflammatory stimuli but also other signals, activate the enzyme IκB kinase (IKK), resulting in phosphorylation of IκBα. Subsequently, NF-κB translocates into the nucleus, and an inflammatory response characterized by production of inflammatory cytokines is generated.39  Another downstream effect of NF-κB activity is enhanced HIF-1α transcription.40–42  Conversely, HIF-1α activity enhances NF-κB activity by increasing abundance of IKK and the NF-κB subunit p65.41,43  Moreover, hypoxia prevents PHD-dependent IKK degradation.44 In vitro studies confirmed this effect, as combined inhibition of PHD-1 and FIH enhanced basal NF-κB activity in a HIF-1α-independent fashion.45  Paradoxically, PHD-1 and FIH inhibition suppress NF-κB activity under inflammatory conditions.45  These data illustrate that there is extensive interplay between hypoxia, oxygen-dependent hydroxylases, HIF-1α, and NF-κB. Furthermore, as alluded to before, effects are dependent on the cellular activation state.

Cellular and In Vivo Immunologic Effects of HIF-1α

At the cellular level, HIF-1α stabilization in immune cells results in a differentiated response, highly depending on the cell type. In neutrophils, the induction of β2-integrin involved in epithelial neutrophil binding,16  regulation of pathogen-binding neutrophil extracellular traps, and antibacterial activity46  are all HIF-1α dependent.46  HIF-1α stabilization inhibits apoptosis of macrophages and neutrophils43,47  and is involved in the differentiation of monocytes to macrophages as well as in macrophage maturation.48  HIF-1α also results in increased expression of toll-like receptor 449  as well as in enhanced macrophage phagocytosis50  and bacterial killing.51 

A wide diversity of animal studies using cell-specific transgenic knockout mice and pharmacologic HIF-1α modulation also demonstrate the cell type–specific effects of HIF-1α. Myeloid HIF-1α knockout mice have a higher morbidity in streptococcal skin infections than their wild-type littermates, which indicates that HIF-1α in myeloid cells is essential to mount an inflammatory response required to clear local infection.51  In severe systemic inflammation induced by lipopolysaccharide (to mimic Gram-negative infection)52  or lipoteichoic acid and peptidoglycan (to mimic Gram-positive infection),53  myeloid HIF-1α–deficient mice display an attenuated inflammatory response, associated with less tissue damage and improved survival.52  In accordance, HIF-1α gain of function results in an overwhelming inflammatory response in sterile and bacterial peritonitis, with aggravated organ damage and impaired survival.1  As such, in myeloid cells, HIF-1α is essential for the generation of an effective inflammatory response to clear infections, while simultaneously, HIF-1α overexpression leads to the clinical picture of the early, proinflammatory phase of sepsis in mice.

In contrast to the proinflammatory effects observed in myeloid cells, HIF-1α activity induces antiinflammatory and tissue-protective effects in lymphocytes. For instance, HIF-1α induction results in increased numbers of regulatory T cells, with subsequent tissue protection due to attenuation of inflammation.54  Furthermore, in a murine bacterial peritonitis model, T-cell–specific HIF-1α deficiency results in increased levels of proinflammatory cytokines.55  Suggestive of antiinflammatory effects of HIF-1α in B cells, PHD inhibition with dimethyloxalylglycine before lipopolysaccharide administration in mice resulted in enhanced interleukin-10 production by B1 cells, which skewed macrophages toward an antiinflammatory M2-like phenotype.56  Moreover, other studies demonstrate that the transcriptional program that drives antiinflammatory regulatory T-cell differentiation is under the control of HIF via the induction of the HIF-target gene FoxP3.54 

Apart from effects in dedicated immune cells, HIF-1α stabilization also exerts immunologic effects in other cells, e.g., intestinal and alveolar epithelium and myocytes. Pharmacologic stabilization of HIF-1α through PHD inhibition in murine chemical-induced colitis results in reduced levels of TNFα, interleukin-6, and interleukin-1β, while levels of antiinflammatory interleukin-10 increase57  and clinical outcome improves.58,59  Similarly, pharmacologic PHD inhibition in ventilator-induced lung injury results in HIF-1α–dependent reduced lung injury and prolonged survival, whereas HIF-1α inhibition aggravates lung injury and shortened survival.4  The tissue-protective effects of HIF-1α are also involved in protection against ischemic injury. For instance, myocardial protection by remote ischemic preconditioning is dependent on increased interleukin-10 production mediated through HIF-1α,60,61  and myocardial HIF-1α expression mediates a metabolic switch to glycolysis, which is crucial for adaptation to ischemia.62  An overview of the immunologic effects of PHD inhibition in in vitro and animal studies is provided in table 2.45,63–74 

Table 2.

In Vitro and Preclinical Studies on the Effects of PHD Inhibitors on Immunity

In Vitro and Preclinical Studies on the Effects of PHD Inhibitors on Immunity
In Vitro and Preclinical Studies on the Effects of PHD Inhibitors on Immunity

Altogether, HIF-1α activity in myeloid cells is involved in the orchestration of immune responses aimed at pathogen clearance, whereas HIF-1α activity in lymphocytes, epithelium, and myocytes induces antiinflammatory and tissue protective effects (an overview is provided in fig. 2). Although these opposing effects may seem contradictory, studies in the field of oncology have shown that myeloid HIF-1α activity suppresses T-cell responses.75  Therefore, it is conceivable that, in the context of inflammation and infection, local interplay between different immune cells is required to optimize infection control and simultaneously prevent tissue damage.76 

Fig. 2.

The interaction between hypoxia and inflammation. Hypoxia enhances the immune response and is an inflammatory stimulus by itself. Hypoxia leads to cellular stabilization of hypoxia-inducible factor 1α (HIF-1α), resulting in a synergistic effect with the key inflammatory transcription factor nuclear factor of kappa-light-chain-enhancer of activated B cells (NF-κB). In addition, inflammation enhances transcription and translation of HIF-1α, leading to a synergistic effect in case of hypoxia and inflammation. In myeloid cells, such as neutrophils and monocytes, HIF-1α activity exerts proinflammatory effects, aimed at clearance of pathogens. Conversely, in many other cells, such as T cells, pulmonary and interstitial epithelium, and myocytes, HIF-1α activity has antiinflammatory effects. Furthermore, hypoxia exerts antiinflammatory effects through the adenosine pathway, as it increases the availability of adenosine progenitors adenosine triphosphate (ATP) and adenosine diphosphate (ADP), upregulates the converting enzymes CD39 and CD73 to enhance adenosine production, and increases the expression of the antiinflammatory adenosine 2A and 2B receptors (A2A and A2B). The up-regulation of CD73 and adenosine receptors is HIF-1α dependent. IL-10 = interleukin-10; TLR4 = toll-like receptor 4.

Fig. 2.

The interaction between hypoxia and inflammation. Hypoxia enhances the immune response and is an inflammatory stimulus by itself. Hypoxia leads to cellular stabilization of hypoxia-inducible factor 1α (HIF-1α), resulting in a synergistic effect with the key inflammatory transcription factor nuclear factor of kappa-light-chain-enhancer of activated B cells (NF-κB). In addition, inflammation enhances transcription and translation of HIF-1α, leading to a synergistic effect in case of hypoxia and inflammation. In myeloid cells, such as neutrophils and monocytes, HIF-1α activity exerts proinflammatory effects, aimed at clearance of pathogens. Conversely, in many other cells, such as T cells, pulmonary and interstitial epithelium, and myocytes, HIF-1α activity has antiinflammatory effects. Furthermore, hypoxia exerts antiinflammatory effects through the adenosine pathway, as it increases the availability of adenosine progenitors adenosine triphosphate (ATP) and adenosine diphosphate (ADP), upregulates the converting enzymes CD39 and CD73 to enhance adenosine production, and increases the expression of the antiinflammatory adenosine 2A and 2B receptors (A2A and A2B). The up-regulation of CD73 and adenosine receptors is HIF-1α dependent. IL-10 = interleukin-10; TLR4 = toll-like receptor 4.

HIF-1α in Sepsis

The role of HIF-1α in sepsis is of particular interest, as inflammation and tissue hypoxia often coexist, the latter due to a mismatch of oxygen demand and availability. The immunologic host response during early sepsis is characterized by (over)production of proinflammatory cytokines, which is aimed at pathogen clearance, but also results in the clinical syndrome of septic shock. However, an antiinflammatory reaction is mounted simultaneously, presumably to curtail the proinflammatory response and thereby prevent collateral tissue damage. When too pronounced and/or sustained, this antiinflammatory response results in a profoundly suppressed state of the immune system. It is increasingly recognized that this phenomenon, known as “sepsis-induced immunoparalysis,” renders patients more vulnerable to secondary infections and is a major contributor to late mortality in septic patients.77 

Based on the data described earlier, HIF-1α activity may enhance proinflammatory effects and innate immune functions, which could be beneficial in sepsis-induced immunoparalysis. This concept is supported by the observation that endotoxin tolerance, which bears similarities to sepsis-induced immunoparalysis, was partially reversed by chronic mild hypoxia in mice.20  However, this single animal study does not fully reflect the complex dynamics of HIF-1α during human sepsis. Furthermore, it needs to be emphasized that the abovementioned studies on (the interplay between) inflammation and hypoxia have been conducted in vitro and in animals. The translation from animal studies to the human situation is an important topic of debate.78,79  Fortunately, two recent observational studies in sepsis patients have increased our understanding of the dynamics of HIF-1α during sepsis. In one of these, samples were obtained within 2 to 4 h after admission, and HIF-1α mRNA expression in monocytes was increased.80  Furthermore, HIF-1α induced the negative toll-like receptor regulator interleukin-1 receptor-associated kinase M, resulting in immunosuppression.80  In contrast, the other study found reduced leukocytic HIF-1α protein and mRNA expression, but samples were obtained at later time points (i.e., within 24 h after admission).81  Although one has to be cautious when interpreting data from preclinical work in the context of clinical patient studies, it could be envisioned that the early proinflammatory response drives increased HIF-1α expression, resulting in the induction of negative regulators such as interleukin-1 receptor-associated kinase M to counteract excessive inflammation, ultimately resulting in reduced HIF-1α levels later in the course of sepsis.

Tissue-protective and Antiinflammatory Effects through the Adenosine Pathway

Hypoxia can also exert antiinflammatory and tissue-protective effects through the adenosine pathway, of which some elements have been reported to be HIF-1α dependent.82,83 

Cellular distress (e.g., hypoxia84 ) results in increased availability of the adenosine progenitors adenosine triphosphate and adenosine diphosphate.85  Hypoxia leads to up-regulation of CD39 (ectoapyrase),86,87  which converts adenosine triphosphate and adenosine diphosphate into adenosine monophosphate, and to HIF-1α–dependent up-regulation of CD73 (5′-ectonucleotidase), which converts adenosine monophosphate into adenosine.82  The tissue-protective effects of these enzymes have been demonstrated in studies using knockout mice. For example, mice lacking either CD39 or CD73 display increased morbidity and mortality after inflammatory or ischemic injury.88–90  Correspondingly, genetic overexpression of HIF-1α results in increased epithelial expression of CD73 and improves outcome in murine chemically induced colitis.91  Finally, hypoxia increases the expression of the adenosine 2A (A2A) and 2B (A2B) receptors, the latter in a HIF-1α–dependent manner.83  Stimulation of these receptors results in systemic antiinflammatory effects in murine models of ischemia–reperfusion,89  hypoxia,92  and inflammation.93  Furthermore, permissive hypoxia (fraction of inspired oxygen [Fio2], 10%) attenuated lung damage and improved survival in a murine model of acute lung injury in an A2A receptor-dependent manner,94  and induction of the A2B-receptor in type 1 alveolar cells during ventilator-induced lung injury was shown to be dependent on HIF-1α3. Similarly, hypoxic preconditioning protected mice from liver ischemia and reperfusion injury in an A2B receptor-dependent manner.95 

The limited human data available substantiate that hypoxia results in enhanced adenosine availability. For instance, exposure to short-term hypoxia (20 min; Sao2, 80%) in healthy volunteers increases plasma adenosine levels.96  Furthermore, several experimental human studies have demonstrated antiinflammatory effects of adenosine signaling, as intravenous adenosine administration97  as well as oral treatment with the adenosine uptake inhibitor dipyridamole98  attenuated the proinflammatory interleukin-6 response during experimental human endotoxemia, and dipyridamole treatment also augmented antiinflammatory interleukin-10 production.98  However, increased adenosine availability in these latter studies was not induced by hypoxia. Finally, a proof-of-concept clinical study revealed that interferon-β-1a enhances CD73 expression in human lung tissue and that administration of this cytokine to acute respiratory distress syndrome (ARDS) patients is associated with reduced interleukin-6 and interleukin-8 levels as well as improved Pao2/Fio2 ratios and survival.99 

In addition to HIF-1α, NF-κB, and adenosine metabolism and signaling pathways, other oxygen-sensitive transcription factors have been identified although the exact oxygen-dependent mechanisms and downstream effects are not fully elucidated (reviewed in Ref. 100 ).

A schematic overview of the complex interplay between hypoxia and inflammation is depicted in figure 2.

Hypoxia in Critically Ill Patients

Hypoxic respiratory failure is a common condition in ICU patients, with an incidence of 22 to 33%,101,102  depending on the definition (usually the need for mechanical ventilation and/or a Pao2/Fio2 ratio of less than 300 mmHg101–103 ), and is associated with a mortality of 31 to 52%.101–103  A subcategory of hypoxic respiratory failure is ARDS, comprising 3 to 70% of patients with respiratory failure.101–103  ARDS severity can be classified according to the Berlin definitions as mild (200 to 300 mmHg), moderate (100 to 200 mmHg), or severe (less than 100 mmHg), with mortality ranging from 32 to 65%.103–109  It is important to differentiate between the diagnosis of hypoxic respiratory failure (i.e., an indication for intubation and mechanical ventilation due to hypoxia) and actual hypoxia (i.e., low Pao2), as patients with hypoxic respiratory failure can have normal Pao2 levels. The occurrence of hypoxia (i.e., Pao2 less than 80 mmHg) at ICU admission is frequent (40%),110  and in a retrospective cohort study in Dutch ICU patients, hypoxia at ICU admission or during ICU stay was shown to be associated with increased mortality, even after correction for disease severity and other confounders.110  The association between hypoxia at ICU admission and increased mortality was confirmed in a similar analysis in Australian and New Zealand ICU patients.111  However, these studies are observational in nature, and although efforts have been made to eliminate bias, confounding factors may still play a role. Therefore, these studies cannot be used to guide oxygen therapy. Currently, oxygenation targets for critically ill patients are lacking. Since the landmark study on tidal volumes in ARDS, a target of 55 to 80 mmHg or Sao2 88 to 95% is used in ARDS studies,112  even though there is no solid evidence supporting these targets.113 

Results of clinical trials on the effects of oxygenation in ICU patients are necessary to determine optimal oxygenation targets in diverse subsets of patients. Currently, the O2-ICU study randomizes ICU patients with systemic inflammation to either a target Pao2 of 120 or 75 mmHg (Clinicaltrials.gov Identifier NCT02321072). The Hyper2S study (Clinicaltrials.gov Identifier NCT01722422), in which patients with septic shock were randomized in a 2 × 2 fashion to normoxia (Sao2, 88 to 95%) versus Fio2 100% for 24 h and resuscitation with isotonic saline versus hypertonic saline, was preliminary terminated because of a borderline significant increase in mortality in the hyperoxic/hypertonic group.114  Additionally, the Air Versus Oxygen in ST-Segment Elevation Myocardial Infarction trial has shown that normoxic patients with ST-elevation myocardial infarction treated with supplemental oxygen exhibit increased creatine kinase levels and myocardial infarct sizes compared with normoxic patients who did not receive additional oxygen.115  The putative harmful effects of hyperoxia have instigated further exploration of the safety and feasibility of conservative oxygenation targets. Two before-after studies in mechanically ventilated ICU patients applied Sao2 targets of 90 to 92%116  and 92 to 95%,117  respectively, which was not associated with adverse outcomes. The safety and feasibility of a conservative oxygenation strategy was recently affirmed by a randomized controlled pilot study comparing a liberal oxygenation strategy (SpO2, greater than 96%) with a conservative strategy (SpO2, 88 to 92%).118 These results may pave the way for the exploration of a personalized oxygen target to influence inflammation in critically ill patients.

The Translation of Preclinical Data on Hypoxia and Inflammation toward Treatment in Critically Ill Patients

As illustrated by animal studies and the limited clinical data available, hypoxia and downstream signaling pathways may represent important and amendable factors in the pathophysiology of inflammatory conditions in critically ill patients, such as sepsis and lung injury. However, many hurdles still have to be taken before we can translate these insights into clinical practice. The host responses in inflammatory conditions in critically ill patients are complex, with considerable interindividual differences and changes over time. Nevertheless, it is conceivable that modulating the immune response toward a targeted, personalized, favorable immunologic phenotype, e.g., immunostimulatory therapy in sepsis-induced immunoparalysis or antiinflammatory therapy in acute lung injury, may be of clinical benefit.119  As many specific therapeutic target interventions have failed to show benefit in clinical trials,120  it would be naive to assume that targeting hypoxia-dependent pathways is “the magic bullet.” Nonetheless, optimization of all amendable parameters to tailor the inflammatory host response toward a more preferable profile should still be considered. As oxygen management is a daily practice in the ICU, the immunologic effects of oxygenation should therefore also be taken into account as a means of optimizing host responses.

Although grossly based on in vitro and animal data, oxygenation-dependent immunomodulatory strategies could be envisioned as either pursuing a nullification of hypoxia-induced immunologic effects by preventing hypoxia or enhancing immunologic effects of hypoxia by preventing hyperoxia or even permitting or inducing hypoxia. For example, animal data suggest that averting hyperoxia and even permitting hypoxia is beneficial in acute lung injury,94  apart from prevention of direct oxygen toxicity. Naturally, intentional or permissive hypoxia as a therapeutic strategy is only expedient when safety margins are taken into account, especially as Pao2 targets would be at the steep part of the oxygen–hemoglobin dissociation curve. As previously proposed, a suitable oxygenation monitoring and control system should use real-time data on pulse oximetry, tissue oxygenation, and arterial oxygen tension to achieve a predefined oxygenation121  and should naturally be extensively tested for safety, feasibility, and efficacy.

However, caution is warranted, as there is an association between long-term neurocognitive impairment and the amount of time that ARDS patients were hypoxic (i.e., Sao2, less than 90%).122  Therefore, short-term benefits of hypoxia, i.e., putative therapeutic effects in inflammation, and long-term effects, i.e., neurocognitive impairment, need to be carefully weighed.

Alongside hypoxia, or if permissive hypoxia does not prove to be feasible, HIF-1α–mediated effects could also be pursued through pharmacologic inhibition of PHDs. The PHD inhibitor FG-4497 increased HIF-1α stabilization in mice, with subsequent resistance of stem cells to irradiation,123  improved kidney transplantation survival,124  and attenuated TNFα expression and weight loss during colitis.58  A comparable PHD inhibitor (FG-2216) resulted in increased plasma erythropoietin levels in hemodialysis patients125 ; however, due to a case of fatal hepatic necrosis and other patients developing abnormal liver enzyme tests, the U.S. Food and Drug Administration suspended this clinical trial, and further development was discontinued.126  Nonetheless, clinical trials with new drugs targeting PHDs for treatment of anemia in patients with chronic renal disease and dialysis are currently being performed.26  Whether pharmacologic HIF stimulation affects the immune response in humans has not been established yet. Additionally, the frequently used PHD inhibitor dimethyloxalylglycine and the aforementioned FG compounds are pan-hydroxylase inhibitors and are not specific for HIF-1α stabilization, which may lead to undesired effects. For example, dimethyloxalylglycine also stabilizes HIF-2α, which results in increased erythropoietin levels58,59  and could thus cause polycythemia. This can be circumvented by more specific PHD inhibitors, such as the selective PHD-1 inhibitor AKB-4924 and/or local instead of systemic drug delivery.69 

Taken together, although the concept of tailoring the immune response through oxygenation or pharmacologic modulation of hypoxia-signaling pathways is tempting, the question remains if this approach is feasible and will result in clinical benefits for the patient. Therefore, studies assessing the putative therapeutic potential of these effects are highly warranted. Furthermore, immunomodulatory therapy in inflammatory conditions in the ICU still faces many challenges. For example, antiinflammatory strategies in sepsis have been unsuccessful in the past,120  possibly because they render patients increased vulnerability to secondary infections, although it might also be due to the profound heterogeneity of this patient population. Immunostimulatory therapy to prevent and/or reverse immunoparalysis is currently under investigation for sepsis.77  Meanwhile, a search for markers identifying the current “immune status” of ICU patients is ongoing and may result in better identification of patients who could benefit from immunomodulating therapy.127 

Conclusion

There is extensive interplay between hypoxia and the immune system. Hypoxia and inflammation synergistically induce HIF-1α stabilization, resulting in cellular effects directed toward augmented pathogen clearance, of interest, simultaneously antiinflammatory and tissue-protective mechanisms occur, for instance through enhanced adenosine metabolism and signaling. The net effect of these effects is highly dependent on the cell type and activation state. Insights into these hypoxia-driven mechanisms promote the concept of personalizing oxygenation targets to tailor the immune response in inflamed critically ill patients. However, the development of such strategies requires exploration of the putative effects of hypoxia on the immune response in humans in vivo, as these data are currently lacking. Furthermore, additional studies on pharmacologic HIF-1α stabilizers and agents acting on the adenosine pathway are required. In any case, the optimal Pao2 and oxygen delivery in critically ill patients are likely to depend on diagnosis and comorbidities, and clinicians should be aware that their oxygen therapy may affect not only saturation but also the inflammatory host response. As clinical guidelines on optimal oxygenation are currently not present, ongoing clinical trials exploring the feasibility of liberal versus restrictive oxygenation are highly warranted and currently in progress; these could further pave the way toward individualized oxygenation therapy.

Research Support

Supported by grants R01-DK097075, R01-HL092188, R01-HL098294, POI-HL114457, and R01-HL119837 from the National Institutes of Health, Bethesda, Maryland (to Dr. Eltzschig); a Ph.D. grant from the Radboud Centre for Infectious Diseases, Nijmegen, The Netherlands, and a Young Investigator Grant from the Dutch Society of Anesthesiology, Utrecht, The Netherlands (to Dr. Kox).

Competing Interests

The authors declare no competing interests.

References

References
1.
Kiss
J
,
Mollenhauer
M
,
Walmsley
SR
,
Kirchberg
J
,
Radhakrishnan
P
,
Niemietz
T
,
Dudda
J
,
Steinert
G
,
Whyte
MK
,
Carmeliet
P
,
Mazzone
M
,
Weitz
J
,
Schneider
M
:
Loss of the oxygen sensor PHD3 enhances the innate immune response to abdominal sepsis.
J Immunol
2012
;
189
:
1955
65
2.
Nizet
V
,
Johnson
RS
:
Interdependence of hypoxic and innate immune responses.
Nat Rev Immunol
2009
;
9
:
609
17
3.
Eckle
T
,
Kewley
EM
,
Brodsky
KS
,
Tak
E
,
Bonney
S
,
Gobel
M
,
Anderson
D
,
Glover
LE
,
Riegel
AK
,
Colgan
SP
,
Eltzschig
HK
:
Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury.
J Immunol
2014
;
192
:
1249
56
4.
Eckle
T
,
Brodsky
K
,
Bonney
M
,
Packard
T
,
Han
J
,
Borchers
CH
,
Mariani
TJ
,
Kominsky
DJ
,
Mittelbronn
M
,
Eltzschig
HK
:
HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.
PLoS Biol
2013
;
11
:
e1001665
5.
Bartels
K
,
Grenz
A
,
Eltzschig
HK
:
Hypoxia and inflammation are two sides of the same coin.
Proc Natl Acad Sci USA
2013
;
110
:
18351
2
6.
Fröhlich
S
,
Boylan
J
,
McLoughlin
P
:
Hypoxia-induced inflammation in the lung: A potential therapeutic target in acute lung injury?
Am J Respir Cell Mol Biol
2013
;
48
:
271
9
7.
Eltzschig
HK
,
Carmeliet
P
:
Hypoxia and inflammation.
N Engl J Med
2011
;
364
:
656
65
8.
Semenza
GL
:
Hypoxia-inducible factors in physiology and medicine.
Cell
2012
;
148
:
399
408
9.
Semenza
GL
:
Oxygen sensing, homeostasis, and disease.
N Engl J Med
2011
;
365
:
537
47
10.
Kuhlicke
J
,
Frick
JS
,
Morote-Garcia
JC
,
Rosenberger
P
,
Eltzschig
HK
:
Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia.
PLoS One
2007
;
2
:
e1364
11.
Querido
JS
,
Sheel
AW
,
Cheema
R
,
Van Eeden
S
,
Mulgrew
AT
,
Ayas
NT
:
Effects of 10 days of modest intermittent hypoxia on circulating measures of inflammation in healthy humans.
Sleep Breath
2012
;
16
:
657
62
12.
Burki
NK
,
Tetenta
SU
:
Inflammatory response to acute hypoxia in humans.
Pulm Pharmacol Ther
2013
, pp
8
11
13.
Ghezzi
P
,
Dinarello
CA
,
Bianchi
M
,
Rosandich
ME
,
Repine
JE
,
White
CW
:
Hypoxia increases production of interleukin-1 and tumor necrosis factor by human mononuclear cells.
Cytokine
1991
;
3
:
189
94
14.
Scannell
G
,
Waxman
K
,
Kaml
GJ
,
Ioli
G
,
Gatanaga
T
,
Yamamoto
R
,
Granger
GA
:
Hypoxia induces a human macrophage cell line to release tumor necrosis factor-alpha and its soluble receptors in vitro.
J Surg Res
1993
;
54
:
281
5
15.
Naldini
A
,
Carraro
F
,
Silvestri
S
,
Bocci
V
:
Hypoxia affects cytokine production and proliferative responses by human peripheral mononuclear cells.
J Cell Physiol
1997
;
173
:
335
42
16.
Kong
T
,
Eltzschig
HK
,
Karhausen
J
,
Colgan
SP
,
Shelley
CS
:
Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of beta2 integrin gene expression.
Proc Natl Acad Sci USA
2004
;
101
:
10440
5
17.
Jantsch
J
,
Chakravortty
D
,
Turza
N
,
Prechtel
AT
,
Buchholz
B
,
Gerlach
RG
,
Volke
M
,
Gläsner
J
,
Warnecke
C
,
Wiesener
MS
,
Eckardt
KU
,
Steinkasserer
A
,
Hensel
M
,
Willam
C
:
Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function.
J Immunol
2008
;
180
:
4697
705
18.
Matuschak
GM
,
Nayak
R
,
Doyle
TM
,
Lechner
AJ
:
Acute hypoxia decreases E. coli LPS-induced cytokine production and NF-kappaB activation in alveolar macrophages.
Respir Physiol Neurobiol
2010
;
172
:
63
71
19.
Rahat
MA
,
Bitterman
H
,
Lahat
N
:
Molecular mechanisms regulating macrophage response to hypoxia.
Front Immunol
2011
;
2
:
45
20.
Baze
MM
,
Hunter
K
,
Hayes
JP
:
Chronic hypoxia stimulates an enhanced response to immune challenge without evidence of an energetic tradeoff.
J Exp Biol
2011
;
214
(
pt 19
):
3255
68
21.
Klausen
T
,
Olsen
NV
,
Poulsen
TD
,
Richalet
JP
,
Pedersen
BK
:
Hypoxemia increases serum interleukin-6 in humans.
Eur J Appl Physiol Occup Physiol
1997
;
76
:
480
2
22.
Hartmann
G
,
Tschöp
M
,
Fischer
R
,
Bidlingmaier
C
,
Riepl
R
,
Tschöp
K
,
Hautmann
H
,
Endres
S
,
Toepfer
M
:
High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein.
Cytokine
2000
;
12
:
246
52
23.
Hitomi
Y
,
Miyamura
M
,
Mori
S
,
Suzuki
K
,
Kizaki
T
,
Itoh
C
,
Murakami
K
,
Haga
S
,
Ohno
H
:
Intermittent hypobaric hypoxia increases the ability of neutrophils to generate superoxide anion in humans.
Clin Exp Pharmacol Physiol
2003
;
30
:
659
64
24.
Wang
JS
,
Liu
HC
:
Systemic hypoxia enhances bactericidal activities of human polymorphonuclear leuocytes.
Clin Sci (Lond)
2009
;
116
:
805
17
25.
Fritzenwanger
M
,
Jung
C
,
Goebel
B
,
Lauten
A
,
Figulla
HR
:
Impact of short-term systemic hypoxia on phagocytosis, cytokine production, and transcription factor activation in peripheral blood cells.
Mediators Inflamm
2011
;
2011
:
429501
26.
Eltzschig
HK
,
Bratton
DL
,
Colgan
SP
:
Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases.
Nat Rev Drug Discov
2014
;
13
:
852
69
27.
Minet
E
,
Mottet
D
,
Michel
G
,
Roland
I
,
Raes
M
,
Remacle
J
,
Michiels
C
:
Hypoxia-induced activation of HIF-1: Role of HIF-1alpha-Hsp90 interaction.
FEBS Lett
1999
;
460
:
251
6
28.
Masoud
GN
,
Li
W
:
HIF-1α pathway: Role, regulation and intervention for cancer therapy.
Acta Pharm Sin B
2015
;
5
:
378
89
29.
Liu
YV
,
Baek
JH
,
Zhang
H
,
Diez
R
,
Cole
RN
,
Semenza
GL
:
RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha.
Mol Cell
2007
;
25
:
207
17
30.
Ke
Q
,
Costa
M
:
Hypoxia-inducible factor-1 (HIF-1).
Mol Pharmacol
2006
;
70
:
1469
80
31.
Hellwig-Bürgel
T
,
Rutkowski
K
,
Metzen
E
,
Fandrey
J
,
Jelkmann
W
:
Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1.
Blood
1999
;
94
:
1561
7
32.
Bruning
U
,
Cerone
L
,
Neufeld
Z
,
Fitzpatrick
SF
,
Cheong
A
,
Scholz
CC
,
Simpson
DA
,
Leonard
MO
,
Tambuwala
MM
,
Cummins
EP
,
Taylor
CT
:
MicroRNA-155 promotes resolution of hypoxia-inducible factor 1alpha activity during prolonged hypoxia.
Mol Cell Biol
2011
;
31
:
4087
96
33.
Poitz
DM
,
Augstein
A
,
Hesse
K
,
Christoph
M
,
Ibrahim
K
,
Braun-Dullaeus
RC
,
Strasser
RH
,
Schmeißer
A
:
Regulation of the HIF-system in human macrophages—Differential regulation of HIF-α subunits under sustained hypoxia.
Mol Immunol
2014
;
57
:
226
35
34.
Pialoux
V
,
Mounier
R
,
Brown
AD
,
Steinback
CD
,
Rawling
JM
,
Poulin
MJ
:
Relationship between oxidative stress and HIF-1 alpha mRNA during sustained hypoxia in humans.
Free Radic Biol Med
2009
;
46
:
321
6
35.
Tissot van Patot
MC
,
Serkova
NJ
,
Haschke
M
,
Kominsky
DJ
,
Roach
RC
,
Christians
U
,
Henthorn
TK
,
Honigman
B
:
Enhanced leukocyte HIF-1alpha and HIF-1 DNA binding in humans after rapid ascent to 4300 m.
Free Radic Biol Med
2009
;
46
:
1551
7
36.
Brooks
JT
,
Elvidge
GP
,
Glenny
L
,
Gleadle
JM
,
Liu
C
,
Ragoussis
J
,
Smith
TG
,
Talbot
NP
,
Winchester
L
,
Maxwell
PH
,
Robbins
PA
:
Variations within oxygen-regulated gene expression in humans.
J Appl Physiol (1985)
2009
;
106
:
212
20
37.
Frede
S
,
Stockmann
C
,
Freitag
P
,
Fandrey
J
:
Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB.
Biochem J
2006
;
396
:
517
27
38.
Taylor
CT
:
Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation.
J Physiol
2008
;
586
:
4055
9
39.
Taylor
CT
,
Cummins
EP
:
The role of NF-kappaB in hypoxia-induced gene expression.
Ann N Y Acad Sci
2009
;
1177
:
178
84
40.
Bonello
S
,
Zähringer
C
,
BelAiba
RS
,
Djordjevic
T
,
Hess
J
,
Michiels
C
,
Kietzmann
T
,
Görlach
A
:
Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site.
Arterioscler Thromb Vasc Biol
2007
;
27
:
755
61
41.
Rius
J
,
Guma
M
,
Schachtrup
C
,
Akassoglou
K
,
Zinkernagel
AS
,
Nizet
V
,
Johnson
RS
,
Haddad
GG
,
Karin
M
:
NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha.
Nature
2008
;
453
:
807
11
42.
Belaiba
RS
,
Bonello
S
,
Zähringer
C
,
Schmidt
S
,
Hess
J
,
Kietzmann
T
,
Görlach
A
:
Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells.
Mol Biol Cell
2007
;
18
:
4691
7
43.
Walmsley
SR
,
Print
C
,
Farahi
N
,
Peyssonnaux
C
,
Johnson
RS
,
Cramer
T
,
Sobolewski
A
,
Condliffe
AM
,
Cowburn
AS
,
Johnson
N
,
Chilvers
ER
:
Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity.
J Exp Med
2005
;
201
:
105
15
44.
Cummins
EP
,
Berra
E
,
Comerford
KM
,
Ginouves
A
,
Fitzgerald
KT
,
Seeballuck
F
,
Godson
C
,
Nielsen
JE
,
Moynagh
P
,
Pouyssegur
J
,
Taylor
CT
:
Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity.
Proc Natl Acad Sci USA
2006
;
103
:
18154
9
45.
Scholz
CC
,
Cavadas
MA
,
Tambuwala
MM
,
Hams
E
,
Rodríguez
J
,
von Kriegsheim
A
,
Cotter
P
,
Bruning
U
,
Fallon
PG
,
Cheong
A
,
Cummins
EP
,
Taylor
CT
:
Regulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways.
Proc Natl Acad Sci USA
2013
;
110
:
18490
5
46.
McInturff
AM
,
Cody
MJ
,
Elliott
EA
,
Glenn
JW
,
Rowley
JW
,
Rondina
MT
,
Yost
CC
:
Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 α.
Blood
2012
;
120
:
3118
25
47.
McGovern
NN
,
Cowburn
AS
,
Porter
L
,
Walmsley
SR
,
Summers
C
,
Thompson
AA
,
Anwar
S
,
Willcocks
LC
,
Whyte
MK
,
Condliffe
AM
,
Chilvers
ER
:
Hypoxia selectively inhibits respiratory burst activity and killing of Staphylococcus aureus in human neutrophils.
J Immunol
2011
;
186
:
453
63
48.
Oda
T
,
Hirota
K
,
Nishi
K
,
Takabuchi
S
,
Oda
S
,
Yamada
H
,
Arai
T
,
Fukuda
K
,
Kita
T
,
Adachi
T
,
Semenza
GL
,
Nohara
R
:
Activation of hypoxia-inducible factor 1 during macrophage differentiation.
Am J Physiol Cell Physiol
2006
;
291
:
C104
13
49.
Kim
SY
,
Choi
YJ
,
Joung
SM
,
Lee
BH
,
Jung
YS
,
Lee
JY
:
Hypoxic stress up-regulates the expression of toll-like receptor 4 in macrophages via hypoxia-inducible factor.
Immunology
2010
;
129
:
516
24
50.
Anand
RJ
,
Gribar
SC
,
Li
J
,
Kohler
JW
,
Branca
MF
,
Dubowski
T
,
Sodhi
CP
,
Hackam
DJ
:
Hypoxia causes an increase in phagocytosis by macrophages in a HIF-1alpha-dependent manner.
J Leukoc Biol
2007
;
82
:
1257
65
51.
Peyssonnaux
C
,
Datta
V
,
Cramer
T
,
Doedens
A
,
Theodorakis
EA
,
Gallo
RL
,
Hurtado-Ziola
N
,
Nizet
V
,
Johnson
RS
:
HIF-1alpha expression regulates the bactericidal capacity of phagocytes.
J Clin Invest
2005
;
115
:
1806
15
52.
Peyssonnaux
C
,
Cejudo-Martin
P
,
Doedens
A
,
Zinkernagel
AS
,
Johnson
RS
,
Nizet
V
:
Cutting edge: Essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis.
J Immunol
2007
;
178
:
7516
9
53.
Mahabeleshwar
GH
,
Qureshi
MA
,
Takami
Y
,
Sharma
N
,
Lingrel
JB
,
Jain
MK
:
A myeloid hypoxia-inducible factor 1α-Krüppel-like factor 2 pathway regulates gram-positive endotoxin-mediated sepsis.
J Biol Chem
2012
;
287
:
1448
57
54.
Clambey
ET
,
McNamee
EN
,
Westrich
JA
,
Glover
LE
,
Campbell
EL
,
Jedlicka
P
,
de Zoeten
EF
,
Cambier
JC
,
Stenmark
KR
,
Colgan
SP
,
Eltzschig
HK
:
Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa.
Proc Natl Acad Sci USA
2012
;
109
:
E2784
93
55.
Thiel
M
,
Caldwell
CC
,
Kreth
S
,
Kuboki
S
,
Chen
P
,
Smith
P
,
Ohta
A
,
Lentsch
AB
,
Lukashev
D
,
Sitkovsky
MV
:
Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival.
PLoS One
2007
;
2
:
e853
56.
Hams
E
,
Saunders
SP
,
Cummins
EP
,
O’Connor
A
,
Tambuwala
MT
,
Gallagher
WM
,
Byrne
A
,
Campos-Torres
A
,
Moynagh
PM
,
Jobin
C
,
Taylor
CT
,
Fallon
PG
:
The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells.
Shock
2011
;
36
:
295
302
57.
Keely
S
,
Campbell
EL
,
Baird
AW
,
Hansbro
PM
,
Shalwitz
RA
,
Kotsakis
A
,
McNamee
EN
,
Eltzschig
HK
,
Kominsky
DJ
,
Colgan
SP
:
Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis.
Mucosal Immunol
2014
;
7
:
114
23
58.
Robinson
A
,
Keely
S
,
Karhausen
J
,
Gerich
ME
,
Furuta
GT
,
Colgan
SP
:
Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition.
Gastroenterology
2008
;
134
:
145
55
59.
Cummins
EP
,
Seeballuck
F
,
Keely
SJ
,
Mangan
NE
,
Callanan
JJ
,
Fallon
PG
,
Taylor
CT
:
The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis.
Gastroenterology
2008
;
134
:
156
65
60.
Eckle
T
,
Köhler
D
,
Lehmann
R
,
El Kasmi
K
,
Eltzschig
HK
:
Hypoxia-inducible factor-1 is central to cardioprotection: A new paradigm for ischemic preconditioning.
Circulation
2008
;
118
:
166
75
61.
Cai
Z
,
Luo
W
,
Zhan
H
,
Semenza
GL
:
Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart.
Proc Natl Acad Sci USA
2013
;
110
:
17462
7
62.
Eckle
T
,
Hartmann
K
,
Bonney
S
,
Reithel
S
,
Mittelbronn
M
,
Walker
LA
,
Lowes
BD
,
Han
J
,
Borchers
CH
,
Buttrick
PM
,
Kominsky
DJ
,
Colgan
SP
,
Eltzschig
HK
:
Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia.
Nat Med
2012
;
18
:
774
82
63.
Chinta
SJ
,
Rajagopalan
S
,
Ganesan
A
,
Andersen
JK
:
A possible novel anti-inflammatory mechanism for the pharmacological prolyl hydroxylase inhibitor 3,4-dihydroxybenzoate: Implications for use as a therapeutic for Parkinson’s disease.
Parkinsons Dis
2012
;
2012
:
364684
64.
Leire
E
,
Olson
J
,
Isaacs
H
,
Nizet
V
,
Hollands
A
:
Role of hypoxia inducible factor-1 in keratinocyte inflammatory response and neutrophil recruitment.
J Inflamm (Lond)
2013
;
10
:
28
65.
Okumura
CY
,
Hollands
A
,
Tran
DN
,
Olson
J
,
Dahesh
S
,
von Köckritz-Blickwede
M
,
Thienphrapa
W
,
Corle
C
,
Jeung
SN
,
Kotsakis
A
,
Shalwitz
RA
,
Johnson
RS
,
Nizet
V
:
A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection.
J Mol Med (Berl)
2012
;
90
:
1079
89
66.
Cartee
TV
,
White
KJ
,
Newton-West
M
,
Swerlick
RA
:
Hypoxia and hypoxia mimetics inhibit TNF-dependent VCAM1 induction in the 5A32 endothelial cell line via a hypoxia inducible factor dependent mechanism.
J Dermatol Sci
2012
;
65
:
86
94
67.
Takeda
K
,
Ichiki
T
,
Narabayashi
E
,
Inanaga
K
,
Miyazaki
R
,
Hashimoto
T
,
Matsuura
H
,
Ikeda
J
,
Miyata
T
,
Sunagawa
K
:
Inhibition of prolyl hydroxylase domain-containing protein suppressed lipopolysaccharide-induced TNF-alpha expression.
Arterioscler Thromb Vasc Biol
2009
;
29
:
2132
7
68.
Gupta
R
,
Chaudhary
AR
,
Shah
BN
,
Jadhav
AV
,
Zambad
SP
,
Gupta
RC
,
Deshpande
S
,
Chauthaiwale
V
,
Dutt
C
:
Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates murine colitis.
Clin Exp Gastroenterol
2014
;
7
:
13
23
69.
Marks
E
,
Goggins
BJ
,
Cardona
J
,
Cole
S
,
Minahan
K
,
Mateer
S
,
Walker
MM
,
Shalwitz
R
,
Keely
S
:
Oral delivery of prolyl hydroxylase inhibitor: AKB-4924 promotes localized mucosal healing in a mouse model of colitis.
Inflamm Bowel Dis
2015
;
21
:
267
75
70.
Hindryckx
P
,
De Vos
M
,
Jacques
P
,
Ferdinande
L
,
Peeters
H
,
Olievier
K
,
Bogaert
S
,
Brinkman
B
,
Vandenabeele
P
,
Elewaut
D
,
Laukens
D
:
Hydroxylase inhibition abrogates TNF-alpha-induced intestinal epithelial damage by hypoxia-inducible factor-1-dependent repression of FADD.
J Immunol
2010
;
185
:
6306
16
71.
Hams
E
,
Saunders
SP
,
Cummins
EP
,
O’Connor
A
,
Tambuwala
MT
,
Gallagher
WM
,
Byrne
A
,
Campos-Torres
A
,
Moynagh
PM
,
Jobin
C
,
Taylor
CT
,
Fallon
PG
:
The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells.
Shock
2011
;
36
:
295
302
72.
Lin
AE
,
Beasley
FC
,
Olson
J
,
Keller
N
,
Shalwitz
RA
,
Hannan
TJ
,
Hultgren
SJ
,
Nizet
V
:
Role of hypoxia inducible factor-1α (HIF-1α) in innate defense against uropathogenic Escherichia coli infection.
PLoS Pathog
2015
;
11
:
e1004818
73.
Fan
L
,
Li
J
,
Yu
Z
,
Dang
X
,
Wang
K
:
Hypoxia-inducible factor prolyl hydroxylase inhibitor prevents steroid-associated osteonecrosis of the femoral head in rabbits by promoting angiogenesis and inhibiting apoptosis.
PLoS One
2014
;
9
:
e107774
74.
Flannigan
KL
,
Agbor
TA
,
Motta
JP
,
Ferraz
JG
,
Wang
R
,
Buret
AG
,
Wallace
JL
:
Proresolution effects of hydrogen sulfide during colitis are mediated through hypoxia-inducible factor-1α.
FASEB J
2015
;
29
:
1591
602
75.
Doedens
AL
,
Stockmann
C
,
Rubinstein
MP
,
Liao
D
,
Zhang
N
,
DeNardo
DG
,
Coussens
LM
,
Karin
M
,
Goldrath
AW
,
Johnson
RS
:
Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression.
Cancer Res
2010
;
70
:
7465
75
76.
Doedens
AL
,
Phan
AT
,
Stradner
MH
,
Fujimoto
JK
,
Nguyen
JV
,
Yang
E
,
Johnson
RS
,
Goldrath
AW
:
Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen.
Nat Immunol
2013
;
14
:
1173
82
77.
Leentjens
J
,
Kox
M
,
van der Hoeven
JG
,
Netea
MG
,
Pickkers
P
:
Immunotherapy for the adjunctive treatment of sepsis: From immunosuppression to immunostimulation. Time for a paradigm change?
Am J Respir Crit Care Med
2013
;
187
:
1287
93
78.
Seok
J
,
Warren
HS
,
Cuenca
AG
,
Mindrinos
MN
,
Baker
HV
,
Xu
W
,
Richards
DR
,
McDonald-Smith
GP
,
Gao
H
,
Hennessy
L
,
Finnerty
CC
,
López
CM
,
Honari
S
,
Moore
EE
,
Minei
JP
,
Cuschieri
J
,
Bankey
PE
,
Johnson
JL
,
Sperry
J
,
Nathens
AB
,
Billiar
TR
,
West
MA
,
Jeschke
MG
,
Klein
MB
,
Gamelli
RL
,
Gibran
NS
,
Brownstein
BH
,
Miller-Graziano
C
,
Calvano
SE
,
Mason
PH
,
Cobb
JP
,
Rahme
LG
,
Lowry
SF
,
Maier
RV
,
Moldawer
LL
,
Herndon
DN
,
Davis
RW
,
Xiao
W
,
Tompkins
RG
;
Inflammation and Host Response to Injury, Large Scale Collaborative Research Program
:
Genomic responses in mouse models poorly mimic human inflammatory diseases.
Proc Natl Acad Sci USA
2013
;
110
:
3507
12
79.
Takao
K
,
Miyakawa
T
:
Genomic responses in mouse models greatly mimic human inflammatory diseases.
Proc Natl Acad Sci USA
2015
;
112
:
1167
72
80.
Shalova
IN
,
Lim
JY
,
Chittezhath
M
,
Zinkernagel
AS
,
Beasley
F
,
Hernández-Jiménez
E
,
Toledano
V
,
Cubillos-Zapata
C
,
Rapisarda
A
,
Chen
J
,
Duan
K
,
Yang
H
,
Poidinger
M
,
Melillo
G
,
Nizet
V
,
Arnalich
F
,
López-Collazo
E
,
Biswas
SK
:
Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1α.
Immunity
2015
;
42
:
484
98
81.
Schäfer
ST
,
Frede
S
,
Winning
S
,
Bick
A
,
Roshangar
P
,
Fandrey
J
,
Peters
J
,
Adamzik
M
:
Hypoxia-inducible factor and target gene expression are decreased in patients with sepsis: Prospective observational clinical and cellular studies.
Anesthesiology
2013
;
118
:
1426
36
82.
Warner
DS
,
Warner
MA
,
Eltzschig
HK
:
Adenosine : An old drug newly discovered.
Anesthesiology
2009
;
111
:
904
15
83.
Kong
T
,
Westerman
KA
,
Faigle
M
,
Eltzschig
HK
,
Colgan
SP
:
HIF-dependent induction of adenosine A2B receptor in hypoxia.
FASEB J
2006
;
20
:
2242
50
84.
Lim To
WK
,
Kumar
P
,
Marshall
JM
:
Hypoxia is an effective stimulus for vesicular release of ATP from human umbilical vein endothelial cells.
Placenta
2015
;
36
:
759
66
85.
Eltzschig
HK
,
Sitkovsky
MV
,
Robson
SC
:
Purinergic signaling during inflammation.
N Engl J Med
2012
;
367
:
2322
33
86.
Eltzschig
HK
,
Ibla
JC
,
Furuta
GT
,
Leonard
MO
,
Jacobson
KA
,
Enjyoji
K
,
Robson
SC
,
Colgan
SP
:
Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: Role of ectonucleotidases and adenosine A2B receptors.
J Exp Med
2003
;
198
:
783
96
87.
Eltzschig
HK
,
Köhler
D
,
Eckle
T
,
Kong
T
,
Robson
SC
,
Colgan
SP
:
Central role of Sp1-regulated CD39 in hypoxia/ischemia protection.
Blood
2009
;
113
:
224
32
88.
Köhler
D
,
Eckle
T
,
Faigle
M
,
Grenz
A
,
Mittelbronn
M
,
Laucher
S
,
Hart
ML
,
Robson
SC
,
Müller
CE
,
Eltzschig
HK
:
CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury.
Circulation
2007
;
116
:
1784
94
89.
Hart
ML
,
Grenz
A
,
Gorzolla
IC
,
Schittenhelm
J
,
Dalton
JH
,
Eltzschig
HK
:
Hypoxia-inducible factor-1α-dependent protection from intestinal ischemia/reperfusion injury involves ecto-5’-nucleotidase (CD73) and the A2B adenosine receptor.
J Immunol
2011
;
186
:
4367
74
90.
Ehrentraut
H
,
Clambey
ET
,
McNamee
EN
,
Brodsky
KS
,
Ehrentraut
SF
,
Poth
JM
,
Riegel
AK
,
Westrich
JA
,
Colgan
SP
,
Eltzschig
HK
:
CD73+ regulatory T cells contribute to adenosine-mediated resolution of acute lung injury.
FASEB J
2013
;
27
:
2207
19
91.
Karhausen
J
,
Furuta
GT
,
Tomaszewski
JE
,
Johnson
RS
,
Colgan
SP
,
Haase
VH
:
Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis.
J Clin Invest
2004
;
114
:
1098
106
92.
Eckle
T
,
Grenz
A
,
Laucher
S
,
Eltzschig
HK
:
A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice.
J Clin Invest
2008
;
118
:
3301
15
93.
Eckle
T
,
Faigle
M
,
Grenz
A
,
Laucher
S
,
Thompson
LF
,
Eltzschig
HK
:
A2B adenosine receptor dampens hypoxia-induced vascular leak.
Blood
2008
;
111
:
2024
35
94.
Thiel
M
,
Chouker
A
,
Ohta
A
,
Jackson
E
,
Caldwell
C
,
Smith
P
,
Lukashev
D
,
Bittmann
I
,
Sitkovsky
MV
:
Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury.
PLoS Biol
2005
;
3
:
e174
95.
Choukèr
A
,
Ohta
A
,
Martignoni
A
,
Lukashev
D
,
Zacharia
LC
,
Jackson
EK
,
Schnermann
J
,
Ward
JM
,
Kaufmann
I
,
Klaunberg
B
,
Sitkovsky
MV
,
Thiel
M
:
In vivo hypoxic preconditioning protects from warm liver ischemia-reperfusion injury through the adenosine A2B receptor.
Transplantation
2012
;
94
:
894
902
96.
Saito
H
,
Nishimura
M
,
Shinano
H
,
Makita
H
,
Tsujino
I
,
Shibuya
E
,
Sato
F
,
Miyamoto
K
,
Kawakami
Y
:
Plasma concentration of adenosine during normoxia and moderate hypoxia in humans.
Am J Respir Crit Care Med
1999
;
159
:
1014
8
97.
Soop
A
,
Johansson
C
,
Hjemdahl
P
,
Kristiansson
M
,
Gyllenhammar
H
,
Li
N
,
Sollevi
A
:
Adenosine treatment attenuates cytokine interleukin-6 responses to endotoxin challenge in healthy volunteers.
Shock
2003
;
19
:
503
7
98.
Ramakers
BP
,
Riksen
NP
,
Stal
TH
,
Heemskerk
S
,
van den Broek
P
,
Peters
WH
,
van der Hoeven
JG
,
Smits
P
,
Pickkers
P
:
Dipyridamole augments the antiinflammatory response during human endotoxemia.
Crit Care
2011
;
15
:
R289
99.
Bellingan
G
,
Maksimow
M
,
Howell
DC
,
Stotz
M
,
Beale
R
,
Beatty
M
,
Walsh
T
,
Binning
A
,
Davidson
A
,
Kuper
M
,
Shah
S
,
Cooper
J
,
Waris
M
,
Yegutkin
GG
,
Jalkanen
J
,
Salmi
M
,
Piippo
I
,
Jalkanen
M
,
Montgomery
H
,
Jalkanen
S
:
The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: An open-label study.
Lancet Respir Med
2014
;
2
:
98
107
100.
Cummins
EP
,
Taylor
CT
:
Hypoxia-responsive transcription factors.
Pflugers Arch
2005
;
450
:
363
71
101.
Linko
R
,
Okkonen
M
,
Pettilä
V
,
Perttilä
J
,
Parviainen
I
,
Ruokonen
E
,
Tenhunen
J
,
Ala-Kokko
T
,
Varpula
T
;
FINNALI-Study Group
:
Acute respiratory failure in intensive care units. FINNALI: A prospective cohort study.
Intensive Care Med
2009
;
35
:
1352
61
102.
Esteban
A
,
Anzueto
A
,
Frutos
F
,
Alía
I
,
Brochard
L
,
Stewart
TE
,
Benito
S
,
Epstein
SK
,
Apezteguía
C
,
Nightingale
P
,
Arroliga
AC
,
Tobin
MJ
;
Mechanical Ventilation International Study Group
:
Characteristics and outcomes in adult patients receiving mechanical ventilation: A 28-day international study.
JAMA
2002
;
287
:
345
55
103.
Choi
WI
,
Shehu
E
,
Lim
SY
,
Koh
SO
,
Jeon
K
,
Na
S
,
Lim
CM
,
Lee
YJ
,
Kim
SC
,
Kim
IH
,
Kim
JH
,
Kim
JY
,
Lim
J
,
Rhee
CK
,
Park
S
,
Kim
HC
,
Lee
JH
,
Lee
JH
,
Park
J
,
Koh
Y
,
Suh
GY
;
Korean Study Group on Respiratory Failure (KOSREF)
:
Markers of poor outcome in patients with acute hypoxemic respiratory failure.
J Crit Care
2014
;
29
:
797
802
104.
Luhr
OR
,
Antonsen
K
,
Karlsson
M
,
Aardal
S
,
Frostell
CG
,
Bonde
JAN
:
Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland.
Am J Respir Crit Care Med
1999
;
159
:
1849
61
105.
Villar
J
,
Pérez-Méndez
L
,
Kacmarek
RM
:
Current definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome.
Intensive Care Med
1999
;
25
:
930
5
106.
Doyle
RL
,
Szaflarski
N
,
Modin
GW
,
Wiener-kronish
JP
,
Matthay
MA
:
Identification of patients with acute lung injury predictors of mortality.
Am J Respir Crit Care Med
1995
;
152
:
1818
24
107.
Khandelwal
N
,
Hough
CL
,
Bansal
A
,
Veenstra
DL
,
Treggiari
MM
:
Long-term survival in patients with severe acute respiratory distress syndrome and rescue therapies for refractory hypoxemia*.
Crit Care Med
2014
;
42
:
1610
8
108.
Monchi
M
,
Bellenfant
F
,
Cariou
A
,
Joly
LM
,
Thebert
D
,
Laurent
I
,
Dhainaut
JF
,
Brunet
F
:
Early predictive factors of survival in the acute respiratory distress syndrome. A multivariate analysis.
Am J Respir Crit Care Med
1998
;
158
:
1076
81
109.
Zilberberg
MD
,
Epstein
SK
:
Acute lung injury in the medical ICU: Comorbid conditions, age, etiology, and hospital outcome.
Am J Respir Crit Care Med
1998
;
157
(
4 pt 1
):
1159
64
110.
de Jonge
E
,
Peelen
L
,
Keijzers
PJ
,
Joore
H
,
de Lange
D
,
van der Voort
PHJ
,
Bosman
RJ
,
de Waal
RA
,
Wesselink
R
,
de Keizer
NF
:
Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients.
Crit. Care
2008
;
12
:
R156
111.
Eastwood
G
,
Bellomo
R
,
Bailey
M
,
Taori
G
,
Pilcher
D
,
Young
P
,
Beasley
R
:
Arterial oxygen tension and mortality in mechanically ventilated patients.
Intensive Care Med
2012
;
38
:
91
8
112.
Network ARDS
:
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
Roy G Brower Michael Matthay
2000
;
342
:
1301
8
113.
Mikkelsen
ME
,
Anderson
B
,
Christie
JD
,
Hopkins
RO
,
Lanken
PN
:
Can we optimize long-term outcomes in acute respiratory distress syndrome by targeting normoxemia ?
Ann. Am. Thorac. Soc
2014
;
11
:
613
8
114.
Hafner
S
,
Radermacher
P
,
Asfar
P
,
Vincent
J-L
:
Hyperoxia in intensive care and emergency medicine: Dr Jekyll or Mr. Hyde? An update.
Annual Update in Intensive Care and Emergency Medicine 2015
2015
Switzerland
,
Springer International Publishing
167
78
115.
Stub
D
,
Smith
K
,
Bernard
S
,
Nehme
Z
,
Stephenson
M
,
Bray
JE
,
Cameron
P
,
Barger
B
,
Ellims
AH
,
Taylor
AJ
,
Meredith
IT
,
Kaye
DM
;
AVOID Investigators
:
Air versus oxygen in ST-segment-elevation myocardial infarction.
Circulation
2015
;
131
:
2143
50
116.
Suzuki
S
,
Eastwood
GM
,
Glassford
NJ
,
Peck
L
,
Young
H
,
Garcia-Alvarez
M
,
Schneider
AG
,
Bellomo
R
:
Conservative oxygen therapy in mechanically ventilated patients: A pilot before-and-after trial.
Crit Care Med
2014
;
42
:
1414
22
117.
Helmerhorst
HJF
,
Schultz
MJ
,
van der Voort
PHJ
,
Bosman
RJ
,
Juffermans
NP
,
de Wilde
RBP
,
van den Akker-van Marle
ME
,
van Bodegom-Vos
L
,
de Vries
M
,
Eslami
S
,
de Keizer
NF
,
Abu-Hanna
A
,
van Westerloo
DJ
,
de Jonge
E
:
Effectiveness and clinical outcomes of a two-step implementation of conservative oxygenation targets in critically ill patients.
Crit Care Med
2016
;
44
:
554
63
118.
Panwar
R
,
Hardie
M
,
Bellomo
R
,
Barrot
L
,
Eastwood
GM
,
Young
PJ
,
Capellier
G
,
Harrigan
PW
,
Bailey
M
;
CLOSE Study Investigators; ANZICS Clinical Trials Group
:
Conservative versus liberal oxygenation targets for mechanically ventilated patients. A pilot multicenter randomized controlled trial.
Am J Respir Crit Care Med
2016
;
193
:
43
51
119.
Cohen
J
,
Vincent
JL
,
Adhikari
NK
,
Machado
FR
,
Angus
DC
,
Calandra
T
,
Jaton
K
,
Giulieri
S
,
Delaloye
J
,
Opal
S
,
Tracey
K
,
van der Poll
T
,
Pelfrene
E
:
Sepsis: A roadmap for future research.
Lancet Infect Dis
2015
;
15
:
581
614
120.
Angus
DC
,
van der Poll
T
:
Severe sepsis and septic shock.
N Engl J Med
2013
;
369
:
840
51
121.
Martin
DS
,
Grocott
MP
:
Oxygen therapy in critical illness: Precise control of arterial oxygenation and permissive hypoxemia.
Crit Care Med
2013
;
41
:
423
32
122.
Hopkins
RO
,
Weaver
LK
,
Pope
D
,
Orme
JF
,
Bigler
ED
,
Larson-LOHR
V
:
Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.
Am J Respir Crit Care Med
1999
;
160
:
50
6
123.
Forristal
CE
,
Winkler
IG
,
Nowlan
B
,
Barbier
V
,
Walkinshaw
G
,
Levesque
JP
:
Pharmacologic stabilization of HIF-1α increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation.
Blood
2013
;
121
:
759
69
124.
Bernhardt
WM
,
Gottmann
U
,
Doyon
F
,
Buchholz
B
,
Campean
V
,
Schödel
J
,
Reisenbuechler
A
,
Klaus
S
,
Arend
M
,
Flippin
L
,
Willam
C
,
Wiesener
MS
,
Yard
B
,
Warnecke
C
,
Eckardt
KU
:
Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model.
Proc Natl Acad Sci USA
2009
;
106
:
21276
81
125.
Bernhardt
WM
,
Wiesener
MS
,
Scigalla
P
,
Chou
J
,
Schmieder
RE
,
Günzler
V
,
Eckardt
KU
:
Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.
J Am Soc Nephrol
2010
;
21
:
2151
6
126.
Macdougall
IC
:
New anemia therapies: Translating novel strategies from bench to bedside.
Am J Kidney Dis
2012
;
59
:
444
51
127.
Hotchkiss
RS
,
Monneret
G
,
Payen
D
:
Immunosuppression in sepsis: A novel understanding of the disorder and a new therapeutic approach.
Lancet Infect Dis
2013
;
13
:
260
8