Effects of different simulated submarine escape depths by free ascent in animal models.

Objective: If a damaged submarine cannot be rescued in time, it is necessary to carry out a submarine escape by free ascent. Decompression illness is the greatest threat to the safety of submariners. The maximum depth at which a safe escape can be carried out is unknown. This study intends to explore the maximum safe escape depth by observing the effects of simulated submarine escape at different depths on animal models. Methods: We evaluated pulmonary function indexes, blood gas values, blood cell counts, the myocardial enzyme spectrum, coagulation parameters, and proinflammatory cytokine levels in rats, electrocardiographic activity in rabbits after simulated 150-m, 200-m, 220-m, and 250-m submarine escape by free ascent. Results: An escape depth of 150 m did not cause significant changes in the indicators. An escape depth of >200 m led to pulmonary ventilation and gas diffusion dysfunction, hypoxemia, myocardial ischemia, and activation of the fibrinolytic and inflammatory systems. The magnitudes of the changes in the indicators were proportional to escape depth. Conclusion: An escape depth of 150 m in animal models is safe, whereas escape at > 200 m can be harmful.

Lung function changes in divers after a single deep helium-oxygen dive.

INTRODUCTION: This study measured pulmonary function in divers after a single helium-oxygen (heliox) dive to 80, 100, or 120 metres of sea water (msw). METHODS: A total of 26 divers participated, of whom 15, five, and six performed a 80, 100, or 120 msw dive, respectively. While immersed, the divers breathed heliox and air, then oxygen during surface decompression in a hyperbaric chamber. Pulmonary function was measured twice before diving, 30 min after diving, and 24 h after diving. RESULTS: At 30 min after the 80 msw dive the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio and the maximum expiratory flow at 25% of vital capacity (MEF25) values decreased (89.2% to 87.1% and 2.57 L·s⁻¹ to 2.35 L·s⁻¹, P = 0.04, P = 0.048 respectively) but FEV1/FVC returned to the baseline values by 24 h post-dive. Other pulmonary indicators exhibited downward trends at 30 min after the dive, but statistical significance was lacking. Interestingly, though several parameters decreased after the 100 msw dive, statistical significance was not reached. After the 120 msw dive, the FEV1/FVC and MEF75 decreased (90.4% to 85.6% and 8.05 L·s⁻¹ to 7.46 L·s⁻¹, P = 0.01, P = 0.007). The relatively small numbers of subjects who dived to 100 and 120 msw depths may explain the inconsistent results. The subjects diving to 100 and 120 msw were more trained / skilled, but this would not explain the inconsistencies in results between these depths. CONCLUSIONS: We conclude that single deep heliox dives cause a temporary decrease in FEV1/FEV and MEF25 or MEF75, but these changes can recover at 24 h after the dive.

[Effect of nuclear radiation on rat model of decompression sickness induced by large depth rapid floating escape].

Objective: To investigate the effects of different doses of nuclei exposure at different time on morbidity, mortality, and damage indicators in a rat model of decompression sickness caused by rapid flotation escape at a large depth. Methods: Eighty male SD rats were randomly divided into blank control group, escape control group and six intervention groups (escape at 4 hours after 4 Gy radiation, escape at 4 hours after 6 Gy radiation, escape at 4 hours after 12 Gy radiation, escape at 8 hours after 4 Gy radiation, escape at 8 hours after 6 Gy radiation, escape at 8 hours after 12 Gy radiation). Rats in intervention groups were exposed to different doses of γ-ray (4,6,12 Gy, respectively), and then were carried out a large depth and rapid buoyancy escape experiment (maximum pressure depth of 150 m). The changes of lung W/D, spleen index and plasma IL-1ß levels were analyzed. Results: Compared with the blank control group, decompression sickness incidence and mortality of rats in escape groups after nuclear exposure were increased significantly. In 4 Gy and 6 Gy irradiation groups, higher morbidity and mortality were observed in rats which escaped at 4 h post nuclear exposure when compared with rats in 8 h groups. Consistent with the changes in morbidity and mortality, the wet / dry ratio of lung tissue, the pathological damage of lung tissue, and the decrease of spleen index showed the same trends: the changes were obvious at 4 h after lower doses nuclear radiation (4 Gy and 6 Gy), not at 8 h. However, these indicators all changed markedly at 4 and 8 h after higher doses nuclear radiation (12 Gy). Plasma IL-1ß levels were significantly increased in each post-radiation exposure group when compared with the blank control group and the exposed control group. Conclusion: Nuclear radiation-induced lung injury, the damaged immune function and elevated plasma inflammatory factor concentrations increase the risk of decompression sickness after rapid ascent.

Human Physiological Responses to a Single Deep Helium-Oxygen Diving.

Objective: The objective of this study was to explore whether a single deep helium-oxygen (heliox) dive affects physiological function. Methods: A total of 40 male divers performed an open-water heliox dive to 80 m of seawater (msw). The total diving time was 280 min, and the breathing helium-oxygen time was 20 min. Before and after the dive, blood and saliva samples were collected, and blood cell counts, cardiac damage, oxidative stress, vascular endothelial activation, and hormonal biomarkers were assayed. Results: An 80 msw heliox dive induced a significant increase in the percentage of granulocytes (GR %), whereas the percentage of lymphocytes (LYM %), percentage of intermediate cells (MID %), red blood cell number (RBC), hematocrit (hCT), and platelets (PLT) decreased. During the dive, concentrations of creatine kinase (CK), a myocardial-specific isoenzyme of creatine kinase (CK-MB) in serum and amylase alpha 1 (AMY1), and testosterone levels in saliva increased, in contrast, IgA levels in saliva decreased. Diving caused a significant increase in serum glutathione (GSH) levels and reduced vascular cell adhesion molecule-1 (VCAM-1) levels but had no effect on malondialdehyde (MDA) and endothelin-1 (ET-1) levels. Conclusion: A single 80 msw heliox dive activates the endothelium, causes skeletal-muscle damage, and induces oxidative stress and physiological stress responses, as reflected in changes in biomarker concentrations.

Changes in acid-base status in oxygen toxicity at 230 kPa oxygen as a function of exposure time.

Breathing less than 50 kPa of oxygen over time can lead to pulmonary oxygen toxicity (POT). Vital capacity (VC) as the sole parameter for POT has its limitations. In this study we try to find out the changes of acid-base status in a POT rat model. Fifty male rats were randomly divided into five groups, exposed to 230 kPa oxygen for three, six, nine and 12 hours, respectively. Rats exposed to air were used as controls. After exposure the mortality and behavior of rats were observed. Arterial blood samples were collected for acid-base status detection and wet-dry (W/D) ratios of lung tissues were tested. Results showed that the acid-base status in rats exposed to 230 kPa oxygen presented a dynamic change. The primary status was in the compensatory period when primary respiratory acidosis was mixed with compensated metabolic alkalosis. Then the status changed to decompensated alkalosis and developed to decompensated acidosis in the end. pH, PCO2, HCO3-, TCO2, and BE values had two phases: an increase and a later decrease with increasing oxygen exposure time, while PaO2 and lung W/D ratio showed continuously increasing trends with the extension of oxygen exposure time. Lung W/D ratio was significantly associated with PaO2 (r = 0.6385, p = 0.002), while other parameters did not show a significant correlation. It is concluded that acid-base status in POT rats presents a dynamic change: in the compensatory period first, then turns to decompensated alkalosis and ends up with decompensated acidosis status. Blood gas analysis is a useful method to monitor the development of POT.

Simulation stress model of the undersea environment activates the central nervous, neuroendocrine and immune systems and anxiety in rats.

The present study was designed to assess the stress responses to a simulation model of the undersea environment that is similar to some undersea working conditions such as submarine rescue, underwater salvage and underwater construction. Restraint, hyperbaric air and immersion were chosen to produce the simulation stress model in rats for four hours. Rats were randomized into five groups: control group, restraint (R) group, hyperbaric air (H) group, restraint plus hyperbaric air (RH) group, and restraint plus hyperbaric air plus immersion (RHI) group. The results showed that the responses to the simulation stress model of the undersea environment induced by R, H, RH and RHI involved the upregulated norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) of the central nervous system (CNS), upregulated adrenocorticotropic hormone (ACTH), corticosterone (CORT) and blood glucose of the neuroendocrine system, upregulated interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) of the immune system, and increased anxiety in rats. Compared with hyperbaric air, restraint tended to activate stronger stress responses. Conclusively, this work established a simulation stress model of the undersea environment induced by restraint, hyperbaric air and immersion. It further provided experimental data of such a model that showed significant activation of the CNS, neuroendocrine and immune systems and anxiety in rats. In this experiment we provided an experimental basis for undersea work such as working aboard a submarine.

[Edaravone has a protective role in a mouse model of pulmonary oxygen toxicity].

OBJECTIVE: To find if edaravone can play a protective role in a mouse model of pulmonary oxygen toxicity and explore the intervention mechanism. METHODS: Thirty male C57BL/6 mice were randomly divided into 3 groups(Air +Vehicle, Hyperbaric oxygen(HBO) +Vehicle and HBO + Edaravone). Mice were either given edaravone (5 mg/(kg·d)) in sterilized water or a sterilized water vehicle for 3 days before oxygen exposure. Mice in HBO groups were exposed to 0.23 MPa hyperoxia (≥95% O2) for 6 h. Lung tissues were collected and the wet/dry ratio of lung were analyzed. For histologic analysis, lung sections were stained with hematoxylin and eosin (HE). Proinflammatory cytokine levels and antioxidant enzyme activities in lungs were determined by using ELISA kits. The expression levels of pro-apoptosis protein were determined with Western blot analysis. RESULTS: Edaravone treatment could significantly reduce lung permeability, decrease tissue pro-apoptosis protein (cleaved-caspase3) and inflammation (IL-1ß). However, edaravone treatment had no effect on antioxidant enzyme activities. CONCLUSION: These results showed that edaravone treatment had a protective role in pulmonary oxygen toxicity through curbing inflammation and apoptosis.

PDTC ameliorates decompression induced-lung injury caused by unsafe fast buoyancy ascent escape via inhibition of NF-κB pathway.

Nuclear factor kappa B (NF-κB) is the critical transcriptional factor in the pathogenesis of acute lung injury (ALI). NF-κB regulates the expression changes of inflammatory factors such as tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß) and interleukin 6 (IL-6). In a previous study we showed that decompression sickness (DCS) caused by simulated unsafe fast buoyancy ascent escape (FBAE) could result in ALI, which was characterized by expression changes of inflammatory factors in rat lung tissue. The purpose of the present work was to study the roles of NF-κB and TNF-α in the process of DCS-induced rat lung injury caused by simulated unsafe FBAE. The research methods aimed to detect the rat lung tissue messenger ribonucleic acid (mRNA) and protein level variations of NF-κB, inhibitory ×B (I×B), TNF-α, IL-1ß, IL-6, IL-10 and IL-13 by using pretreatment of the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) and TNF-α antibody (Ab). Our experimental results demonstrated that PDTC could improve the survival rate of the rats with DCS caused by unsafe FBAE more effectively than TNF-α Ab. However, the inhibition of TNF-α Ab on the nuclear translocated protein expression of NF-κB was more effective than PDTC. Both PDTC and TNF-α Ab can abrogate the increment of the rat lung tissue mRNA levels of TNF-α, IL-1ß, IL-6 and protein levels of NF-κB, TNF-α, IL-1ß effectively and increase the rat lung tissue content of I×B significantly. In conclusion, TNF-α-mediated NF-κB signaling may be one of the critical signaling pathways in the pathogenesis of DCS-induced rat lung injury caused by simulated unsafe FBAE. PDTC may ameliorate this type of injury partly through inhibiting the NF-κB pathway.

Simvastatin decreases hyperbaric oxygen-induced acute lung injury by upregulating eNOS.

Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase competitive inhibitors, not only lower blood cholesterol but also exert pleiotropic and beneficial effects in various diseases. However, the effects of statins on acute lung injury (ALI) induced by hyperbaric oxygen (HBO) have not been investigated. The present study is the first to investigate the effects of simvastatin in ALI induced by HBO in 8- to 9-wk-old C57BL/6 mice exposed to 0.23 MPa [=2.3 atmosphere absolute (ATA)] hyperoxia (≥95% O2) for 6 h. Mice were either given simvastatin (20 mg·kg·-1·day-1) in saline or a saline vehicle for 3 days before oxygen exposure. Lung tissue, serum, and bronchoalveolar lavage fluid (BALF) were collected for analysis of proapoptotic proteins, low-density lipoprotein cholesterol (LDL-C) levels, and lung inflammation. Simvastatin treatment significantly reduced lung permeability, serum LDL-C levels, tissue apoptosis, and inflammation. However, simvastatin treatment had no effect on antioxidant enzyme activity, nicotinamide adenine dinucleotide phosphate oxidase 4 (NADPH4) expression, and Akt phosphorylation levels. Furthermore, we investigated the role of endothelial nitric oxide synthase (eNOS) in simvastatin protection through inhibiting eNOS activity with NG-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg). Results showed that the beneficial effects of simvastatin on ALI induced by HBO (antiinflammatory, antiapoptotic, lipid lowering, and reduction in lung permeability) were reversed. These results showed that simvastatin curbs HBO-induced lung edema, permeability, inflammation, and apoptosis via upregulating eNOS expression and that simvastatin could be an effective therapy to treat prolonged HBO exposure.

Simulated High Altitude Helium-Oxygen Diving.

BACKGROUND: Experience with commercial heliox diving at high altitude is limited. The purpose of this study was to evaluate the effects of acute high-altitude exposure on fitness to dive and the safety of decompression after heliox diving while using U.S. Navy heliox decompression tables with Cross correction. METHOD: Four professional male divers were consecutively decompressed in a hypo- and hyperbaric chamber to altitudes of 3000 m (9842.5 ft), 4000 m (13,123.4 ft), and 5200 m (17,060.4 ft) during the 8-d study. The dive profiles tested were to 30 m (98.4 ft) for 60 min at all three altitudes and, in addition, a dive to 50 m (164 ft) for 60 min at 5200 m altitude. The decompression followed the U.S. Navy heliox decompression table. The safety of decompression was evaluated by precordial Doppler venous gas emboli (VGE) monitoring during the decompression stages and postdive monitoring of the divers for symptoms of decompression sickness (DCS). Effects of altitude exposure were measured as subjective rating and EEG signs of sleepiness and fatigue, clinical symptoms of high altitude disease, and fitness to dive. RESULTS: A total of 24 person-dives were conducted. There were no VGE detected during the decompression and no postdive symptoms of decompression illness. Both the EEG findings and subjective evaluation indicated increased sleepiness and fatigue at 3000 m, 4000 m, and 5200 m, all compared with the sea level baseline. During the diving phase, both the EEG findings and subjective evaluation scores returned to the baseline and the divers successfully completed diving. DISCUSSION: Diving at high altitude with a short acclimatization period appears safe despite divers exhibiting clinical symptoms and EEG signs of impairment by hypoxia at high altitude. Despite a small number of dives, the results of this study indicate that our application of U.S. Navy standard heliox decompression tables with Cross correction is effective and could be used for underwater constructions up to 5200 m altitude, with due caution.Shi L, Zhang Y, Tetsuo K, Shi Z, Fang Y, Denoble PJ, Li Y. Simulated high altitude helium-oxygen diving. Aerosp Med Hum Perform. 2017; 88(12):1088-1093.

Microbial transformation of the anti-diabetic agent corosolic acid by Cunninghamella echinulata.

The pentacyclic triterpenoid corosolic acid was metabolized by Cunninghamella echinulata CGMCC 3.2000 to its C-24 aldehyde group metabolite and five other hydroxylated metabolites: madasiatic acid (2), 2α, 3ß, 7ß-trihydroxyurs-12-en-28-oic acid (3), 2α, 3ß, 15α-trihydroxyurs-12-en-28-oic acid (4), 2α, 3ß, 6ß, 7ß-tetrahydroxyurs-12-en-28-oic acid (5), 2α, 3ß, 7ß, 15α-tetrahydroxyurs-12-en-28-oic acid (6), and 2α, 3ß,7ß-trihydroxy-24-al-urs-12-en-28-oic acid (7); compounds 3, 5, and 7 were new compounds. The α-glucosidase inhibitory effects of the metabolites were also evaluated.

Expression changes of inflammatory factors in the rat lung of decompression sickness induced by fast buoyancy ascent escape.

Fast buoyancy ascent escape is one of the major naval submarine escape maneuvers. Decompression sickness (DCS) is the major bottleneck to increase the depth of fast buoyancy ascent escape. Rapid decompression induces the release of inflammatory mediators and results in tissue inflammation cascades and a protective anti-inflammatory response. In our previous study, we found that DCS caused by simulated fast buoyancy ascent escape could induce acute lung injury (ALI) and the expression changes of the proinflammatory cytokines: tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß and IL-6 in rat lung tissue. In order to study the expression change characteristics of TNF-α, IL-1ß, IL-6, IL-10 and IL-13 in the rat lung of DCS caused by simulated fast buoyancy ascent escape, we detected the rat lung mRNA and protein levels of TNF-α, IL-1ß, IL-6, IL-10 and IL-13 at 0.5 hour after DCS caused by simulated fast buoyancy ascent escape (fast escape group), compared with the normal control group (control group) and diving DCS (decompression group). We observed that DCS caused by simulated fast buoyancy ascent escape could increase the mRNA levels of TNF-α, IL-1ß, IL-6, IL-10, and the protein levels of TNF-α, IL-10 in rat lung tissue. At the same time, we found that the protein level of IL-13 was also downregulated in rat lung tissue. TNF-α, IL-10 and IL-13 may be involved in the process of the rat lung injury of DCS caused by simulated fast buoyancy ascent escape. In conclusion, the expression changes of inflammatory factors in the rat lung of DCS caused by simulated fast buoyancy ascent escape were probably different from that in the rat lung of diving DCS, which indicated that the pathological mechanism of DCS caused by simulated fast buoyancy ascent escape might be different from that of diving DCS.

Expression changes of TNF-α, IL-1ß and IL-6 in the rat lung of decompression sickness induced by fast buoyancy ascent escape.

Fast buoyancy ascent escape is the general submarine escape manner adopted by the majority of naval forces all over the world. However, if hyperbaric exposure time exceeds the time limit, fast buoyancy ascent escape has a high risk to result in decompression sickness (DCS). Tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 have been all implicated in the process of inflammation associated with acute lung injury (ALI). Our work demonstrated that DCS caused by simulated fast buoyancy ascent escape could induce ALß in the rat model. The purpose of the present work was to study the expression changes of TNF-α, IL-1ß and IL-6 in the rat lung affected by DCS caused by simulated fast buoyancy ascent escape. The lung tissue mRNA levels of TNF-α, Il-1ß and Il-6 were significantly increased at 0.5 hour after DCS caused by simulated fast buoyancy ascent escape. The lung contents of TNF-α, IL-1ß and IL-6 were at an expression peak at 0.5 hour, although showing no statistical difference when compared with the normal control group. In conclusion, the rat lung expression variations of TNF-α, IL-1ß and IL-6 are the most obvious at 0.5 hour within 24 hours after the lung injury by DCS caused by simulated fast buoyancy ascent escape.

Clopidogrel reduces the inflammatory response of lung in a rat model of decompression sickness.

Inflammation and platelet activation are critical phenomena in the setting of decompression sickness. Clopidogrel (Clo) inhibits platelet activation and may also reduce inflammation. The goal of this study was to investigate if Clo had a protective role in decompression sickness (DCS) through anti-inflammation way. Male Sprague-Dawley rats (n=111) were assigned to three groups: control+vehicle group, DCS+vehicle, DCS+Clo group. The experimental group received 50 mg/kg of Clo or vehicle for 3 days, then compressed to 1,600 kPa (150 msw) in 28 s, maintained at 150 msw for 242 s and decompressed to surface at 3m/s. In a control experiment, rats were also treated with vehicle for 3 days and maintained at atmospheric pressure for an equivalent period of time. Clinical assessment took place over a period of 30 min after surfacing. At the end, blood samples were collected for blood cells counts and cytokine detection. The pathology and the wet/dry ratio of lung tissues, immunohistochemical detection of lung tissue CD41 expression, the numbers of P-selectin positive platelets and platelet-leukocyte conjugates in blood were tested. We found that Clo significantly reduced the DCS mortality risk (mortality rate: 11/45 with Clo vs. 28/46 in the untreated group, P<0.01). Clo reduced the lung injury, the wet/dry ratio of lung, the accumulation of platelet and leukocyte in lung, the fall in platelet count, the WBC count, the numbers of activated platelets and platelet-leukocyte complexes in peripheral blood. It was concluded that Clo can play a protective role in decompression sickness through reducing post-decompression platelet activation and inflammatory process.

[Effect of different pressure oxygen pre-breathe in diving decompression sickness of rats].

OBJECTIVE: To investigate the effect of different pressure oxygen pre-breathing in preventing decompression sickness of rats. METHODS: Forty male SD rats were randomly divided into 4 groups: decompression sickness (DCS) group and three oxygen pre-breathing groups with 1 ATA, 2 ATA and 3 ATA pressure respectively. The rats of DCS group were placed in the hyperbaric chamber and the chamber was compressed evenly within 3 minutes to depths of 7 absolute atmosphere(ATA) and held at the designated depth for 60 min, then decompressed (3 min) at constant speed to the surface pressure. After that, the rats were taken out for further detection. While the rats of oxygen pretreatment groups pre-breathed different pressure oxygen for 20 min before entering into chamber. The mortality and behavioral of rats were observed with 30 min post decompression. The dry/wet ratio of the lung, protein levels in the bronchoalveolar lavage fluid (BALF), and the inflammatory cytokine tumor necrosis factor (TNF-alpha) expression were also tested. RESULTS: Compared with that of the DCS group, the mortality and morbidity of oxygen pre-breathe groups didn't change obviously. But the total BALF protein level and the inflammatory cytokine TNF-alpha expression of 1 ATA oxygen pre-breathe group were obviously decreased, while the dry/wet ratio of lung as obviously increased instead (P < 0.05). CONCLUSION: Although preoxygenation can' t obviously change the mortality and mobidity of rats, normal pressure oxygen pre-breathing can mitigate the protein infiltration in BALF and the expression of inflammatory cytokine in lung tissue.

[The change of NOS in pulmonary oxygen toxicity induced by different oxygen pressure].

OBJECTIVE: Long time exhaled oxygen will induced oxygen toxicity. Some studies had found that different pathology may exised in normobaric and hyperbaric pulmonary oxygen toxicity, and nitric oxide synthase (NOS) may play a role. In this study, we discussed the change of NOS in normobaric and hyperbaric pulmonary oxygen toxicity. METHODS: Sixty male SD rats were randomly divided into 6 groups (n = 10), exposed to 1 ATA (atmosphere absolute), 1.5 ATA, 2 ATA, 2.5 ATA and 3 ATA, 100% oxygen for 56, 20, 10, 8, 6 hours respectively. Rats were exposed to air as control. After exposure, the protein in bronchoalveolar lavage fluid (BALF), the wet/dry weight of lung and the expression of eNOS, nNOS in lung were defined. RESULTS: As compared to air group, the protein in BALF, the wet/dry of lung were significantly elevated in 1.0 ATA group, while these changes were not so obviously in the other groups, and these changes in hyperbaric oxygen group (approximately 1.0 ATA) were significantly decreased as compared with nonnrmobaric oxygen group (1.0 ATA). The expression of nNOS were not changed in normobaric and hyperbaric pulmonary oxygen toxicity, while the expression of eNOS was significantly decreased in 2 ATA group, and significantly elevated in 2.5 ATA and 3 ATA group. CONCLUSION: The expression of eNOS can change when exposed to different pressures of oxygen.

Protective role of peroxisome proliferator-activated receptor ß/δ in acute lung injury induced by prolonged hyperbaric hyperoxia in rats.

Peroxisome proliferator-activated receptor (PPAR)-ß/δ is a transcription factor that belongs to the PPAR family, but the role of PPAR-ß/δ in acute lung injury (ALI) induced by hyperbaric oxygen is unknown. In this study we investigated if PPAR-ß/δ activation protects from hyperoxia-induced ALI in a rat model. ALI was induced by prolonged hyperbaric oxygen (HBO2) (2.3ATA, 100% O2) for 8h. Administration of PPAR-ß/δ agonist GW0742 (0.3mg/kg, i.p.) at 1 and 6h prior to HBO2 exposure significantly reduced the (1) lung injury, (2) proinflammatory cytokines (TNF-α, IL-1ß, IL-6), (3) apoptosis (Bax/Bcl-2, cleaved-caspase-3 and TUNEL), (4) nuclear factor (NF)-κB expression level and DNA binding activity in the nucleus, and (5) extracellular signal-regulated kinase (ERK)1/2 phosphorylation and markedly elevated (6) superoxide dismutase and glutathione peroxidase activities as well as (7) IκB expression. However, administration of the PPAR-ß/δ antagonist GSK0660 abolished these protective effects. These findings indicate that activation of PPAR-ß/δ ameliorates hyperoxia-induced ALI in rats by up-regulating antioxidant enzyme activity as well as suppressing inflammation and apoptosis.

Protective role of peroxisome proliferator-activated receptor-ß/δ against pulmonary oxygen toxicity mediated through changes in NOS expression levels.

Recent studies have demonstrated that peroxisome proliferator-activated receptor-beta/delta (PPAR-ß/δ) has a protective effect during lung injury induced by bleomycin and polymicrobial sepsis, but its function in pulmonary oxygen toxicity is unknown. In this study, we used GW0742, a PPAR-ß/δ agonist, and GSK0660, a PPAR-ß/δ antagonist, to test the role of PPAR-ß/δ in lung injury due to hyperbaric oxygen (HBO2) exposure. Lung injury was induced in rats by HBO2 exposure (2.3 ATA, 100%O2, 8 hours). Sixty male Sprague-Dawley rats were randomly divided into 6 groups: air+vehicle, air+GW0742, air+GSK0660, HBO2+vehicle, HBO2+GW0742, and HBO2+GSK0660. Rats were injected with vehicle or GW0742 (0.3 mg/kg, i.p.) or GSK0660 (1 mg/kg, i.p.) at 1 hour, 6 hours, and 12 hours before either air or oxygen exposure. Administration of GW0742 to rats exposed to HBO2 significantly reduced the observed lung injury, extravascular lung water, total protein levels in bronchoalveolar lavage fluid, and the levels of iNOS and nNOS in the lungs when compared to untreated rats exposed to HBO2. Treatment of rats with GSK0660 exacerbated lung injury and elevated the levels of nNOS and eNOS in the lungs. In addition, nNOS and eNOS knock-out mice were examined. The results indicated that after HBO2 exposure, the lung injury was obviously decreased in the nNOS(-/-)+GSK0660 mice compared to the wild-type +GSK0660 mice; furthermore, administration of GSK0660 significantly elevated the lung injury in the eNOS(-/-) mice. Collectively, these data indicate that PPAR-ß/δ activation can protect against pulmonary oxygen toxicity in the lungs of rats through changes in the expression of NOS.