Mesenchymal stem cells from different sources show distinct therapeutic effects in hyperoxia-induced bronchopulmonary dysplasia in rats.

Mesenchymal stem cells (MSCs) have been shown as an effective medicinal means to treat bronchopulmonary dysplasia (BPD). The widely used MSCs were from Wharton's jelly of umbilical cord (UC-MSCs) and bone marrow (BM-MSCs). Amniotic fluid MSCs (AF-MSCs) may be produced before an individual is born to treat foetal diseases by autoplastic transplantation. We evaluated intratracheal (IT) MSCs as an approach to treat an hyperoxia-induced BPD animal model and compared the therapeutic effects between AF-, UC- and BM-MSCs. A BPD animal model was generated by exposing newborn rats to 95% O2 . The continued stress lasted 21 days, and the treatment of IT MSCs was conducted for 4 days. The therapeutic effects were analysed, including lung histology, level of inflammatory cytokines, cell death ratio and state of angiogenesis, by sacrificing the experimental animal at day 21. The lasting hyperoxia stress induced BPD similar to the biological phenotype. The treatment of IT MSCs was safe without deaths and normal organ histopathology. Specifically, the treatment was effective by inhibiting the alveolar dilatation, reducing inflammatory cytokines, inducing angiogenesis and lowering the cell death ratio. AF-MSCs had better therapeutic effects compared with UC-MSCs in relieving the pulmonary alveoli histological changes and promoting neovascularization, and UC-MSCs had the best immunosuppressive effect in plasma and lung lysis compared with AF-MSCs and BM-MSCs. This study demonstrated the therapeutic effects of AF-, UC- and BM-MSCs in BPD model. Superior treatment effect was provided by antenatal MSCs compared to BM-MSC in a statistical comparison.

Efficacy and safety of normobaric hyperoxia combined with intravenous thrombolysis on acute ischemic stroke patients.

Intravenous thrombolysis elevates the prognostic level of acute ischemic stroke (AIS) patients. Normobaric hyperoxia (NBO) delays the progression of the infarct core and promotes neurological recovery. However, it is uncertain whether NBO can further raise the prognostic level of AIS patients based on intravenous thrombolysis. To explore the efficacy and safety of NBO combined with intravenous thrombolysis on AIS patients. This observational study included anterior circulation stroke patients who received intravenous thrombolysis within 4.5 h after stroke onset. These patients were divided into two groups based on whether or not they received NBO therapy. The baseline data and the prognosis of the two groups were compared. The primary outcome was the proportion of functional independence (modified Rankin Scale 0-2) at 90 days post discharge. A total of 227 patients were included in this study. 125 patients received NBO therapy combined with intravenous thrombolysis, while 102 patients received intravenous thrombolysis only. Overall, the rate of recanalization was 83.3%. Consequently, 101 patients (80.8%) who received NBO combined with intravenous thrombolysis and 63 patients (61.8%) in the control group achieved functional independence (P = 0.002). Multivariable logistic regression analysis showed that NBO combined with intravenous thrombolysis over intravenous thrombolysis alone was associated with 90-day functional independence (OR: 2.318; 95% CI: 1.226-4.381; P = 0.01). This study verified the efficacy and safety of NBO combined with intravenous thrombolysis in AIS patients. Prospective study is needed to further substantiate these findings.

The Impact of Hyperoxia on Outcome of Patients Treated with Noninvasive Respiratory Support.

Objective: Oxygen therapy is one of the most common treatment modalities for hypoxemic patients, but target goals for normoxemia are not clearly defined. Therefore, iatrogenic hyperoxia is a very common situation. The results from the recent clinical researches about hyperoxia indicate that hyperoxia can be related to worse outcomes than expected in some critically ill patients. According to our literature knowledge, there are not any reports researching the effect of hyperoxia on clinical course of patients who are not treated with invasive mechanical ventilation. In this study, we aimed to determine the effect of hyperoxia on mortality, and length of stay and also possible side effects of hyperoxia on the patients who are treated with oxygen by noninvasive devices. Materials and Methods: One hundred and eighty-seven patients who met inclusion criteria, treated in Dokuz Eylul University Medical Intensive Care Unit between January 1, 2016, and October 31, 2018, were examined retrospectively. These patients' demographic data, oxygen saturation (SpO2) values for the first 24 hours, APACHE II (Acute Physiology and Chronic Health Evaluation II) scores, whether they needed intubation, if they did how many days they got ventilated, length of stay in intensive care unit and hospital, maximum PaO2 values of the first day, oxygen treatment method of the first 24 hours, and the rates of mortality were recorded. Results: Hyperoxemia was determined in 62 of 187 patients who were not treated with invasive mechanic ventilation in the first 24 hours of admission. Upon further investigation of the relation between comorbid situations and hyperoxia, hyperoxia frequency in patients with COPD was detected to be statistically low (16% vs. 35%, p < 0.008). Hospital mortality was significantly high (51.6% vs. 35.2%, p < 0.04) in patients with hyperoxia. When the types of oxygen support therapies were investigated, hyperoxia frequency was found higher in patients treated with supplemental oxygen (nasal cannula, oronasal mask, high flow oxygen therapy) than patients treated with NIMV (44.2% vs. 25.5%, p < 0.008). After exclusion of 56 patients who were intubated and treated with invasive mechanical ventilation after the first 24 hours, hyperoxemia was determined in 46 of 131 patients. Mortality in patients with hyperoxemia who were not treated with invasive mechanical ventilation during hospital stay was statistically higher when compared to normoxemic patients (41.3% vs 15.3%, p < 0.001). Conclusion: We report that hyperoxemia increases the hospital mortality in patients treated with noninvasive respiratory support. At the same time, we determined that hyperoxemia frequency was lower in COPD patients and the ones treated with NIMV. Conservative oxygen therapy strategy can be suggested to decrease the hyperoxia prevalence and mortality rates.

Oxygen metabolism and oxygenation of the newborn.

The premature infant is to some extent protected from hypoxia, however defense against hyperoxia is poorly developed. The optimal assessment of oxygenation is to measure oxygen delivery and extraction. At the bedside PaO2 and SpO2 are approximations of oxygenation at the tissue level. After birth asphyxia it is crucial to know whether or not to give oxygen supplementation, when, how much, and for how long. Oxygen saturation targets in the delivery room have been studied, but the optimal targets might still be unknown because factors like gender and delayed cord clamping influence saturation levels. However, SpO2 > 80% at 5 min of age is associated with favorable long term outcome in preterm babies. Immature infants most often need oxygen supplementation beyond the delivery room. Predefined saturation levels, and narrow alarm limits together with the total oxygen exposure may impact on development of oxygen related diseases like ROP and BPD. Hyperoxia is a strong trigger for genetic and epigenetic changes, contributing to the development of these conditions and perhaps lifelong changes.

Association of Early Oxygenation Levels with Mortality in Acute Ischemic Stroke - A Retrospective Cohort Study.

BACKGROUND: Ischemic stroke is an emergency with elevated risk for morbidity and mortality. Hypoxia is harmful in acute ischemic stroke. Recent evidence raises concerns regarding hyperoxia as well in acute illness, and for supplemental oxygen therapy when SpO2greater than 92%. Current AHA/ASA guidelines recommend maintaining SpO2greater than 94%. In this study, we aimed to assess the relationship between the oxygenation levels within the first 6-hour of ischemic stroke admission and mortality. METHODS: With the approval of the Human Studies Committee (IRB #: 13.0396), we performed a retrospective cohort study of ischemic stroke patients consecutively admitted to our hospital in the years 2013-14 and 2017-18 (n = 1479). Relationship between the first 6 hours oxygenation status and in-house mortality was assessed. SpO2/FiO2 ratio was used as the oxygenation outcome parameter. Patients who were intubated at admission were excluded. Additionally, demographics, baseline confounding factors, neurological status, and laboratory values on admission were examined for their association with mortality in a multivariate logistic regression analysis. RESULTS: Mean age of patients was 64 ± 15 years. Time interval from last seen normal to hospital admission was 7 ± 5 hours (mean ± standard deviation). NIHSS on arrival was 41-9 (median-IQR). Fourteen percent of patients received IV alteplase and 6% were treated with mechanical thrombectomy. Baseline SpO2 was 97 ± 2%, and 47% of the patients required supplemental oxygen treatment per AHA/ASA guidelines. In hospital mortality rate of this cohort was 5.7%. Lower mean SpO2 /FiO2 levels were strongly correlated with increasing mortality rates (R2 = .973). Age (1.048 [1.028-1.068]), NIHSS (1.120 [1.088-1.154]), WBC (1.116 [1.061-1.175]) and Mean SpO2/FiO2 (.995 [.992-.999]) independently risk associated with mortality. CONCLUSIONS: Baseline oxygenation varies within the acute ischemic stroke patient population. In this retrospective cohort study, we are reporting a strong association between lower SpO2/FiO2 levels in the first few hours of admission and mortality. In the light of these results, we plan to prospectively assess the role of oxygenation further in the context of recanalization status of stroke.

Impact of hyperoxia on patients hospitalized in an intensive care unit for acute heart failure.

BACKGROUND: Oxygen therapy remains a cornerstone of treatment for acute heart failure in patients with pulmonary congestion. While avoiding hypoxaemia has long been a goal of critical care practitioners, less attention has been paid to the potential hazard related to excessive hyperoxia. AIM: To evaluate the impact of early hyperoxia exposure among critically ill patients hospitalized in an intensive care unit for acute heart failure. METHODS: In this preliminary study conducted in a Parisian intensive care unit, we assessed patients with acute heart failure admitted with pulmonary congestion and treated with oxygen therapy from 1 January 2015 to 31 December 2016. The hyperoxia group was defined by having at least one partial pressure of oxygen measurement>100mmHg on the first day following admission to the intensive care unit. The primary endpoint was 30-day all-cause mortality. Secondary endpoints were 30-day unplanned hospital admissions, occurrence of infections and intensive care unit and hospital lengths of stay. RESULTS: Seventy-five patients were included. Forty-three patients (57.3%) presented hyperoxia, whereas 32 patients (42.7%) did not (control group). The baseline clinical characteristics did not differ between the two groups. The primary endpoint was not statistically different between the two groups (14.0% in the hyperoxia group vs 18.8% in the control group; P=0.85). The secondary endpoints were also not significantly different between the two groups. In the multivariable analysis, hyperoxia was not associated with increased 30-day mortality (odds ratio 0.77, 95% confidence interval 0.24-2.41). CONCLUSION: In patients referred to an intensive care unit for acute heart failure, we did not find any difference in outcomes according to the presence of hyperoxia.

Effects of the duration of postresuscitation hyperoxic ventilation on neurological outcome and survival in an asphyxial cardiac arrest rat model.

Cardiac arrest leads to sudden cessation of oxygen supply and cerebral hypoxia occurs when there is not sufficient oxygen supplied to the brain. Current Guidelines for adult cardiopulmonary resuscitation (CPR) and emergency cardiovascular care recommend the use of 100% oxygen during resuscitative efforts to maximize the probability of achieving the return of spontaneous circulation (ROSC). However, the optimal strategy for oxygen management after ROSC is still debatable. The aim of the present study was to evaluate the effects of the duration of post-resuscitation hyperoxic ventilation on neurological outcomes in asphyxial cardiac arrest rats treated with targeted temperature management (TTM). Asphyxia was induced by blocking the endotracheal tube in 80 adult male Sprague-Dawley rats. CPR begun after 7 min of untreated cardiac arrest. Animals were randomized to either the normoxic control under normothermia (NNC) group or to one of the 4 experimental groups (n = 16 each) immediately after ROSC: ventilated with 100% oxygen for 0 (O2_0h), 1 (O2_1h), 3 (O2_3h), or 5 (O2_5h) h and ventilated with room air thereafter under TTM. Physiological variables were recorded at baseline and during the 6 h postresuscitation monitoring period. Animals were closely observed for 96 h to assess neurologic recovery and survival. There were no significant differences in baseline measurements between groups, and all animals were successfully resuscitated. There were significant interactions between the duration of 100% oxygen administration and hemodynamics as well as, myocardial and cerebral injuries. Among all the durations of hyperoxic ventilation investigated, significantly lower neurological deficit scores and higher survival rates were observed in the O2_3h group than in the NNC group. In conclusion, postresuscitation hyperoxic ventilation leads to improved PaO2, PaCO2, hemodynamic, myocardial and cerebral recovery in asphyxial cardiac arrest rats treated with TTM. However, the beneficial effects of high concentration-oxygen are duration dependent and ventilation with 100% oxygen during induced hypothermia contributes to improved neurological recovery and survival after 96 h.

Leigh Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation.

Leigh syndrome is a devastating mitochondrial disease for which there are no proven therapies. We previously showed that breathing chronic, continuous hypoxia can prevent and even reverse neurological disease in the Ndufs4 knockout (KO) mouse model of complex I (CI) deficiency and Leigh syndrome. Here, we show that genetic activation of the hypoxia-inducible factor transcriptional program via any of four different strategies is insufficient to rescue disease. Rather, we observe an age-dependent decline in whole-body oxygen consumption. These mice exhibit brain tissue hyperoxia, which is normalized by hypoxic breathing. Alternative experimental strategies to reduce oxygen delivery, including breathing carbon monoxide (600 ppm in air) or severe anemia, can reverse neurological disease. Therefore, unused oxygen is the most likely culprit in the pathology of this disease. While pharmacologic activation of the hypoxia response is unlikely to alleviate disease in vivo, interventions that safely normalize brain tissue hyperoxia may hold therapeutic potential.

The "Just Right" Amount of Oxygen. Improving Oxygen Use in a Rwandan Emergency Department.

Rationale: Despite oxygen's classification as an essential medication by the World Health Organization, it is inconsistently available in many resource-constrained settings. Hypoxemia is associated with increased mortality, and mounting evidence suggests that hyperoxia may also be associated with adverse outcomes.Objectives: To determine if overuse of oxygen for some patients in a Rwandan tertiary care hospital emergency department might coexist with oxygen shortages and underuse of oxygen for other patients, and whether an educational intervention coupled with provision of pulse oximeters could improve the distribution of limited oxygen resources.Methods: We screened all patients in the adult emergency department (ED) of the University Teaching Hospital of Kigali for hypoxemia and receipt of oxygen therapy for 5 weeks. After completing baseline data collection, we provided pulse oximeters and conducted a didactic training with pre- and posttests on oxygen titration, with a chosen target oxygen saturation (SpO2) of 90% to 95%. Four and 12 weeks after the intervention, we evaluated all patients in the ED again for SpO2 and receipt of oxygen therapy for 4 weeks each period. We also recorded ED oxygen use and availability of reserve oxygen for the hospital during the three study periods.Results: During all data collection periods, 214 of 1,765 (12.1%) unique patients screened were hypoxemic. The proportion of patient-days with appropriately titrated oxygen therapy (SpO2, 90-95%) increased from 18.7% at baseline to 38.5% and 42.0% at 4 and 12 weeks postintervention (P < 0.001). On a multiple-choice examination testing knowledge of appropriate oxygen titration, clinicians' scores improved from average 60% (interquartile range [IQR], 40-80%) correct to 80% (IQR, 60-80%) correct immediately after the educational intervention (P < 0.001). Oxygen use in the ED decreased from a median of 32.0 (IQR, 28.0-35.0) tanks per day to 25.5 (IQR, 24.0-29.0) and 16.0 (IQR, 12.5-21.0) tanks per day at Weeks 4 and 12, respectively (P < 0.001), and the median daily number of tanks in reserve for the hospital appeared to increase, although this did not reach statistical significance (30.0 [IQR, 9.0-46.0], 86.5 [IQR, 74.0-92.0], and 75.5 [IQR, 8.5-88.5], respectively; P = 0.07).Conclusions: Among patients in a Rwandan adult ED, 12.1% of patients were hypoxemic and 81.3% of patient-days were either under- or overtreated with oxygen during baseline data collection on the basis of our defined target of SpO2 90% to 95%. Follow-up results at 4 and 12 weeks postintervention demonstrated sustained improvement in oxygen titration and likely increased availability of oxygen resources.

Targeting two different levels of both arterial carbon dioxide and arterial oxygen after cardiac arrest and resuscitation: a randomised pilot trial.

PURPOSE: We assessed the effects of targeting low-normal or high-normal arterial carbon dioxide tension (PaCO2) and normoxia or moderate hyperoxia after out-of-hospital cardiac arrest (OHCA) on markers of cerebral and cardiac injury. METHODS: Using a 23 factorial design, we randomly assigned 123 patients resuscitated from OHCA to low-normal (4.5-4.7 kPa) or high-normal (5.8-6.0 kPa) PaCO2 and to normoxia (arterial oxygen tension [PaO2] 10-15 kPa) or moderate hyperoxia (PaO2 20-25 kPa) and to low-normal or high-normal mean arterial pressure during the first 36 h in the intensive care unit. Here we report the results of the low-normal vs. high-normal PaCO2 and normoxia vs. moderate hyperoxia comparisons. The primary endpoint was the serum concentration of neuron-specific enolase (NSE) 48 h after cardiac arrest. Secondary endpoints included S100B protein and cardiac troponin concentrations, continuous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) results and neurologic outcome at 6 months. RESULTS: In total 120 patients were included in the analyses. There was a clear separation in PaCO2 (p < 0.001) and PaO2 (p < 0.001) between the groups. The median (interquartile range) NSE concentration at 48 h was 18.8 µg/l (13.9-28.3 µg/l) in the low-normal PaCO2 group and 22.5 µg/l (14.2-34.9 µg/l) in the high-normal PaCO2 group, p = 0.400; and 22.3 µg/l (14.8-27.8 µg/l) in the normoxia group and 20.6 µg/l (14.2-34.9 µg/l) in the moderate hyperoxia group, p = 0.594). High-normal PaCO2 and moderate hyperoxia increased NIRS values. There were no differences in other secondary outcomes. CONCLUSIONS: Both high-normal PaCO2 and moderate hyperoxia increased NIRS values, but the NSE concentration was unaffected. REGISTRATION: ClinicalTrials.gov, NCT02698917. Registered on January 26, 2016.

Deletion of p75NTR prevents vaso-obliteration and retinal neovascularization via activation of Trk- A receptor in ischemic retinopathy model.

Ischemic retinopathy is characterized by ischemia followed by retinal neovascularization (RNV) resulting in visual impairment. Given the role of neuron-secreted growth factors in regulating angiogenesis, we examined how genetic deletion of the neurotrophin receptor; p75NTR can overcome retinal ischemia using oxygen-induced retinopathy (OIR) mouse model. Wildtype (WT) or p75NTR-/- mice pups were subjected to hyperoxia (70% O2, p7-p12) then returned to normal air (relative hypoxia, p12-p17). Vascular alterations were assessed at p12 and p17 time-points. Deletion of p75NTR prevented hyperoxia-associated central vascular cell death (p12) and hypoxia-associated RNV and enhanced central vascular repair (p17). Decreased expression of apoptotic markers; preserved Akt survival signal decreased proNGF were also observed at p12. During hypoxia, deletion of p75NTR maintained VEGF and VEGFR2 activation and restored NGF/proNGF and BDNF/proBDNF levels. Deletion of p75NTR coincided with significant increases in expression and activation of NGF survival receptor, TrkA at basal and hyperoxic condition. Pharmacological inhibition of TrkA using compound K-252a (0.5 µg 1 µl-1/eye) resulted in 2-fold increase in pathological RNV and 1.34-fold increase in central vascular cell death in p75NTR-/- pups. In conclusion, deletion of p75NTR protected against retinal ischemia and prevented RNV, in part, through restoring neurotrophic support and activating TrkA receptor.

Effects of vitamin B-6 supplementation on oxidative stress and inflammatory response in neonatal rats receiving hyperoxia therapy.

Hyperoxia is often used in the treatment of neonates. However, protracted use of hyperoxia leads to significant morbidity. The purpose of this study was to evaluate the effects of vitamin B-6 supplementation on oxidative stress and inflammatory responses in neonatal rats undergoing hyperoxia therapy. The study consisted of 2 parts: a survival study and a vitamin B-6 efficacy study for 16 days. Neonatal rats were randomly divided into either the control group, B-6 group (subcutaneously injected with 90 mg/kg/d of pyridoxal 5'-phosphate [PLP]), O2 group (treated with 85% oxygen), or O2 + B-6 group (simultaneously treated with 85% oxygen and 90 mg/kg/d PLP). After the survival study was done, the vitamin B-6 efficacy study was performed with duplicate neonatal rats sacrificed on the 3rd, 6th, 9th, and 16th day. Serum inflammatory cytokines, tissue pathology, and malondialdehyde (MDA) levels were measured. In the survival study, the survival rate of neonatal rats in the control, B-6, O2, and O2 + B-6 group on the 16th day were 100%, 100%, 25%, and 62.50%, respectively. The efficacy study showed lung polymorphonuclear granulocyte (PMN) and macrophage infiltration, increased liver hemopoiesis, and higher MDA levels in liver homogenates at days 3 through 16 in the O2 group. Vitamin B-6 supplementation considerably increased serum inflammatory cytokines in either the 6th or 9th day and decreased liver MDA level before the 6th day. These results indicate that neonatal rats receiving hyperoxia treatment suffered divergent serum inflammatory responses and were in increased liver oxidative stress. Vitamin B-6 supplementation seemed to improve survival rates, change systemic inflammatory response, and decrease liver oxidative stress while neonatal rats were under hyperoxia treatment.

The therapeutic effect of mesenchymal stem cells on pulmonary myeloid cells following neonatal hyperoxic lung injury in mice.

BACKGROUND: Exposure to high levels of oxygen (hyperoxia) after birth leads to lung injury. Our aims were to investigate the modulation of myeloid cell sub-populations and the reduction of fibrosis in the lungs following administration of human mesenchymal stem cells (hMSC) to neonatal mice exposed to hyperoxia. METHOD: Newborn mice were exposed to 90% O2 (hyperoxia) or 21% O2 (normoxia) from postnatal days 0-4. A sub-group of hyperoxia mice were injected intratracheally with 2.5X105 hMSCs. Using flow cytometry we assessed pulmonary immune cells at postnatal days 0, 4, 7 and 14. The following markers were chosen to identify these cells: CD45+ (leukocytes), Ly6C+Ly6G+ (granulocytes), CD11b+CD11c+ (macrophages); macrophage polarisation was assessed by F4/80 and CD206 expression. hMSCs expressing enhanced green fluorescent protein (eGFP) and firefly luciferase (fluc) were administered via the trachea at day 4. Lung macrophages in all groups were profiled using next generation sequencing (NGS) to assess alterations in macrophage phenotype. Pulmonary collagen deposition and morphometry were assessed at days 14 and 56 respectively. RESULTS: At day 4, hyperoxia increased the number of pulmonary Ly6C+Ly6G+ granulocytes and F4/80lowCD206low macrophages but decreased F4/80highCD206high macrophages. At days 7 and 14, hyperoxia increased numbers of CD45+ leukocytes, CD11b+CD11c+ alveolar macrophages and F4/80lowCD206low macrophages but decreased F4/80highCD206high macrophages. hMSCs administration ameliorated these effects of hyperoxia, notably reducing numbers of CD11b+CD11c+ and F4/80lowCD206low macrophages; in contrast, F4/80highCD206high macrophages were increased. Genes characteristic of anti-inflammatory 'M2' macrophages (Arg1, Stat6, Retnla, Mrc1, Il27ra, Chil3, and Il12b) were up-regulated, and pro-inflammatory 'M1' macrophages (Cd86, Stat1, Socs3, Slamf1, Tnf, Fcgr1, Il12b, Il6, Il1b, and Il27ra) were downregulated in isolated lung macrophages from hyperoxia-exposed mice administered hMSCs, compared to mice without hMSCs. Hydroxyproline assay at day 14 showed that the 2-fold increase in lung collagen following hyperoxia was reduced to control levels in mice administered hMSCs. By day 56 (early adulthood), hMSC administration had attenuated structural changes in hyperoxia-exposed lungs. CONCLUSIONS: Our findings suggest that hMSCs reduce neonatal lung injury caused by hyperoxia by modulation of macrophage phenotype. Not only did our cell-based therapy using hMSC induce structural repair, it limited the progression of pulmonary fibrosis.

Tn (N-acetyl-d-galactosamine-O-serine/threonine) immunization protects against hyperoxia-induced lung injury in adult mice through inhibition of the nuclear factor kappa B activity.

Prolonged hyperoxia exposure leads to inflammation and acute lung injury. Since hyperoxia activates nuclear factor kappa B (NF-κB) and proinflammatory mediators in lung fibroblasts and murine lungs, and proinflammatory cytokines upregulate Tn (N-acetyl-d-galactosamine-O-serine/threonine) expression in human gingival fibroblasts. We hypothesized connections exist between Tn expression and inflammation regulation. Thus, we immunized adult mice with Tn antigen to examine whether Tn vaccine can protect against hyperoxia-induced lung injury by inhibiting NF-κB activity and cytokine expression through the action of anti-Tn antibodies. Five-week-old female C57BL/6NCrlBltw mice were subcutaneously immunized with Tn antigen four times at biweekly intervals, and one additional immunization was performed at 1 week after the fourth immunization. Four days after the last immunization, mice were exposed to room air (RA) or hyperoxia (100% O2) for up to 96 h. Four study groups were examined: carrier protein + RA (n = 6), Tn vaccine + RA (n = 6), carrier protein + O2 (n = 6), and Tn vaccine + O2 (n = 5). We observed that hyperoxia exposure reduced body weight, increased alveolar protein and cytokine (interleukin-6 and tumor necrosis factor-α) levels, increased mean linear intercept (MLI) values and lung injury scores, and increased lung NF-κB activity. By contrast, Tn immunization increased serum anti-Tn antibody titers and reduced the cytokine levels, MLI values, and lung injury scores. Furthermore, the alleviation of lung injury was accompanied by a reduction in NF-κB activity. Therefore, we proposed that Tn immunization attenuates hyperoxia-induced lung injury in adult mice by inhibiting the NF-κB activity.

Fresh Noncultured Endothelial Progenitor Cells Improve Neonatal Lung Hyperoxia-Induced Alveolar Injury.

Treatment of preterm human infants with high oxygen can result in disrupted lung alveolar and vascular development. Local or systemic administration of endothelial progenitor cells (EPCs) is reported to remedy such disruption in animal models. In this study, the effects of both fresh (enriched for KDR) and cultured bone marrow (BM)-derived cell populations with EPC characteristics were examined following hyperoxia in neonatal mouse lungs. Intraperitoneal injection of fresh EPCs into five-day-old mice treated with 90% oxygen resulted in full recovery of hyperoxia-induced alveolar disruption by 56 days of age. Partial recovery in septal number following hyperoxia was observed following injection of short-term cultured EPCs, yet aberrant tissue growths appeared following injection of long-term cultured cells. Fresh and long-term cultured cells had no impact on blood vessel development. Short-term cultured cells increased blood vessel number in normoxic and hyperoxic mice by 28 days but had no impact on day 56. Injection of fresh EPCs into normoxic mice significantly reduced alveolarization compared with phosphate buffered saline-injected normoxic controls. These results indicate that fresh BM EPCs have a higher and safer corrective profile in a hyperoxia-induced lung injury model compared with cultured BM EPCs but may be detrimental to the normoxic lung. The appearance of aberrant tissue growths and other side effects following injection of cultured EPCs warrants further investigation. Stem Cells Translational Medicine 2017;6:2094-2105.

Oxygen Requirements for Acutely and Critically Ill Patients.

Oxygen administration is often assumed to be required for all patients who are acutely or critically ill. However, in many situations, this assumption is not based on evidence. Injured body tissues and cells throughout the body respond both beneficially and adversely to delivery of supplemental oxygen. Available evidence indicates that oxygen administration is not warranted for patients who are not hypoxemic, and hyperoxia may contribute to increased tissue damage and mortality. Nurses must be aware of implications related to oxygen administration for all types of acutely and critically ill patients. These implications include having knowledge of oxygenation processes and pathophysiology; assessing global, tissue, and organ oxygenation status; avoiding either hypoxia or hyperoxia; and creating partnerships with respiratory therapists. Nurses can contribute to patients' oxygen status well-being by being proficient in determining each patient's specific oxygen needs and appropriate oxygen administration.

Hyperoxia or Therapeutic Hypothermia During Resuscitation from Non-Lethal Hemorrhagic Shock in Swine.

We previously demonstrated beneficial effects of 22 h of hyperoxia following near-lethal porcine hemorrhagic shock, whereas therapeutic hypothermia was detrimental. Therefore, we investigated whether shorter exposure to hyperoxia (12 h) would still improve organ function, and whether 12 h of hypothermia with subsequent rewarming could avoid deleterious effects after less severe hemorrhagic shock.Twenty-seven anesthetized and surgically instrumented pigs underwent 3 h of hemorrhagic shock by removal of 30% of the blood volume and titration of the mean arterial blood pressure (MAP) to 40 mm Hg. Post-shock, pigs were randomly assigned to control, hyperoxia (FIO2 100% for 12 h) or hypothermia group (34°C core temperature for 12 h with subsequent rewarming). Before, at the end of shock, after 12 and 23 h of resuscitation, data sets comprising hemodynamics, blood gases, and parameters of inflammation and organ function were acquired. Postmortem, kidney samples were collected for immunohistochemistry and western blotting.Hyperoxia exerted neither beneficial nor detrimental effects. In contrast, mortality in the hypothermia group was significantly higher compared with controls (67% vs. 11%). Hypothermia impaired circulation (MAP 64 (57;89) mm Hg vs. 104 (98; 114) mm Hg) resulting in metabolic acidosis (lactate 11.0 (6.6;13.6) mmol L vs. 1.0 (0.8;1.5) mmol L) and reduced creatinine clearance (26 (9;61) mL min vs. 77 (52;80) mL min) compared to the control group after 12 h of resuscitation. Impaired kidney function coincided with increased renal 3-nitrotyrosine formation and extravascular albumin accumulation.In conclusion, hyperoxia proved to be safe during resuscitation from hemorrhagic shock. The lacking organ-protective effects of hyperoxia compared to resuscitation from near-lethal hemorrhage suggest a dependence of the effectiveness of hyperoxia from shock severity. In line with our previous report, therapeutic hypothermia (and rewarming) was confirmed to be detrimental most likely due to vascular barrier dysfunction.