ABSTRACT
Background: This study sought to investigate therapeutic effects of hydrogen-rich saline (HRS) combined with hyperbaric oxygen (HBO2) in an experimental rat model of acute lung injury (ALI). Method: Forty male Sprague-Dawley rats were randomly divided into sham, LPS, LPS + HBO2, LPS + HRS, and LPS + HBO2 + HRS groups. After an intratracheal injection of LPS-induced ALI, the rats were given a single-agent HBO2 or HRS or HBO2 + HRS treatment. The treatments were continued for three days in this experimental rat model of ALI. At the end of experiment, the lung pathological, inflammatory factors, and cell apoptosis in the pulmonary tissue were detected by Tunel method and cell apoptosis rate was calculated accordingly. Results: In the groups treated with HBO2 + HRS, pulmonary pathological data, wet-dry weight ratio, and inflammatory factors of pulmonary tissues and alveolar lavage fluid were significantly superior to those of the sham group (pâº0.05). Cell apoptosis detection revealed that no single agent treatment of HRS or HBO2, or combination treatment, could alleviate all cell apoptosis. HRS combined with HBO2 treatment was superior to single treatment (pâº0.05). Conclusion: HRS or HBO2 single treatment could decrease inflammatory cytokines release in lung tissue, reduce the accumulation of oxidative products and alleviate apoptosis of pulmonary cells, then lead to positive therapeutic effects on ALI induced by LPS. Furthermore, HBO2 combined with HRS treatment presented a synergy effect on cell apoptosis decrease and a decline in inflammatory cytokine release and related inflammatory product generation, compared with a single treatment.
Subject(s)
Acute Lung Injury , Hyperbaric Oxygenation , Rats , Male , Animals , Rats, Sprague-Dawley , Lipopolysaccharides/adverse effects , Acute Lung Injury/chemically induced , Acute Lung Injury/prevention & control , Lung/pathology , Oxygen/adverse effects , Cytokines , Hydrogen/therapeutic use , Hydrogen/pharmacologyABSTRACT
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⻹ to 2.35 L·s⻹, 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⻹ to 7.46 L·s⻹, 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.
Subject(s)
Diving , Helium , Humans , Lung , OxygenABSTRACT
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.
Subject(s)
Decompression Sickness , Gamma Rays/adverse effects , Lung Injury , Lung/radiation effects , Animals , Male , Rats , Rats, Sprague-DawleyABSTRACT
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.
ABSTRACT
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.
Subject(s)
Acid-Base Imbalance/blood , Acidosis, Respiratory/metabolism , Alkalosis, Respiratory/metabolism , Hyperbaric Oxygenation/adverse effects , Oxygen/toxicity , Acid-Base Imbalance/etiology , Animals , Atmospheric Pressure , Bicarbonates/blood , Blood Chemical Analysis , Blood Gas Analysis , Carbon Dioxide/blood , Hyperbaric Oxygenation/methods , Lung/pathology , Male , Models, Animal , Organ Size , Partial Pressure , Random Allocation , Rats , Rats, Sprague-Dawley , Time Factors , Vital CapacityABSTRACT
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.
Subject(s)
Edaravone/therapeutic use , Hyperoxia/drug therapy , Oxygen/toxicity , Protective Agents/therapeutic use , Animals , Apoptosis , Inflammation , Lung , Male , Mice , Mice, Inbred C57BL , Random AllocationABSTRACT
The effect of variations in the expression of cytochrome P450 reductase (CPR or POR) is determined in mice with decreased POR expression to identify potential vulnerabilities in people with low POR expression. There is an age-dependent appearance of increasing vacuolization in the proximal tubules of the renal cortex in 4- to 9-month-old male (but not female) Cpr-low (CL) mice. These mice have low POR expression in all cells of the body and upregulation of lysosome-associated membrane protein 1 expression in the renal cortex. Vacuolization is also seen in extrahepatic CL and extrarenal CL male mice, but not in mice with tissue-specific Por deletion in liver, intestinal epithelium, or kidney. The occurrence of vacuolization is accompanied by increases in serum blood-urea-nitrogen levels. Male CL mice are hypersensitive to cisplatin- and gentamicin-induced renal toxicity at 3 months of age, before proximal tubular (PT) vacuoles are detectable. At doses that do not cause renal toxicity in wild-type mice, both drugs cause substantial increases in serum blood-urea-nitrogen levels and PT vacuolization in male but not female CL mice. The hypersensitivity to drug-induced renal toxicity is accompanied by increases in circulating drug levels. These novel findings demonstrate deficiency of renal function in mice with globally reduced POR expression and suggest that low POR expression may be a risk factor for drug-induced nephrotoxicity in humans.
Subject(s)
Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/pathology , NADPH-Ferrihemoprotein Reductase/metabolism , Renal Insufficiency/chemically induced , Animals , Blood Urea Nitrogen , Cisplatin/pharmacokinetics , Creatinine/blood , Gentamicins/pharmacokinetics , Kidney Tubules, Proximal/drug effects , Lysosomes/ultrastructure , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Vacuoles/pathology , Vacuoles/ultrastructureABSTRACT
Cognitive behavior therapy (CBT) is effective for the treatment of Internet gaming disorder (IGD). However, the mechanisms by which CBT improves IGD-related clinical symptoms remain unknown. This study aimed to discover the therapeutic mechanism of CBT in IGD subjects using resting-state functional magnetic resonance imaging (rsfMRI). Twenty-six IGD subjects and 30 matched healthy controls (HCs) received rsfMRI scan and clinical assessments; 20 IGD subjects completed CBT and then were scanned again. The amplitude of low-frequency (ALFF) values and the functional connectivity (FC) between the IGD group and the HC group were compared at baseline, as well as the ALFF values and FC before and after the CBT in the IGD group. Prior to treatment, the IGD group exhibited significantly increased ALFF values in the bilateral putamen, the right medial orbitofrontal cortex (OFC), the bilateral supplementary motor area (SMA), the left postcentral gyrus, and the left anterior cingulate (ACC) compared with the HC group. The HC group showed significantly increased FC values between the left medial OFC and the putamen compared with the IGD group, the FC values of IGD group were negatively associated with the BIS-11 scores before treatment. After the CBT, the weekly gaming time was significantly shorter, and the CIAS and BIS-II scores were significantly lower. The ALFF values in the IGD subjects significantly decreased in the left superior OFC and the left putamen, and the FC between them significantly increased after the CBT. The degree of the FC changes (ΔFC/Pre-FC) was positively correlated with the scale of the CIAS scores changes (ΔCIAS/Pre-CIAS) in the IGD subjects. CBT could regulate the abnormal low-frequency fluctuations in prefrontal-striatal regions in IGD subjects and could improve IGD-related symptoms. Resting-state alternations in prefrontal-striatal regions may reveal the therapeutic mechanism of CBT in IGD subjects.
ABSTRACT
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.
Subject(s)
Acute Lung Injury/metabolism , Antioxidants/pharmacology , Decompression Sickness/complications , Interleukins/metabolism , NF-kappa B/metabolism , Pyrrolidines/pharmacology , Thiocarbamates/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Acute Lung Injury/etiology , Acute Lung Injury/pathology , Animals , Interleukin-10/metabolism , Interleukin-13/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Lung/metabolism , Lung/pathology , Male , NF-kappa B/antagonists & inhibitors , RNA, Messenger/metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Survival Rate , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
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.
Subject(s)
Acute Lung Injury/prevention & control , Anticholesteremic Agents/pharmacology , Gene Expression Regulation/drug effects , Hyperbaric Oxygenation/adverse effects , Nitric Oxide Synthase Type III/metabolism , Simvastatin/pharmacology , Acute Lung Injury/enzymology , Acute Lung Injury/etiology , Animals , Male , Mice , Mice, Inbred C57BL , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/genetics , Transcriptional ActivationABSTRACT
Phenobarbital (PB) promotes liver tumorigenesis in rodents, in part through activation of the constitutive androstane receptor (CAR) and the consequent changes in hepatic gene expression and increases in hepatocyte proliferation. A typical effect of CAR activation by PB is a marked induction of Cyp2b10 expression in the liver; the latter has been suspected to be vital for PB-induced hepatocellular proliferation. This hypothesis was tested here by using a Cyp2a(4/5)bgs-null (null) mouse model in which all Cyp2b genes are deleted. Adult male and female wild-type (WT) and null mice were treated intraperitoneally with PB at 50 mg/kg once daily for 5 successive days and tested on day 6. The liver-to-body weight ratio, an indicator of liver hypertrophy, was increased by 47% in male WT mice, but by only 22% in male Cyp2a(4/5)bgs-null mice, by the PB treatment. The fractions of bromodeoxyuridine-positive hepatocyte nuclei, assessed as a measure of the rate of hepatocyte proliferation, were also significantly lower in PB-treated male null mice compared with PB-treated male WT mice. However, whereas few proliferating hepatocytes were detected in saline-treated mice, many proliferating hepatocytes were still detected in PB-treated male null mice. In contrast, female WT mice were much less sensitive than male WT mice to PB-induced hepatocyte proliferation, and PB-treated female WT and PB-treated female null mice did not show significant difference in rates of hepatocyte proliferation. These results indicate that CYP2B induction plays a significant, but partial, role in PB-induced hepatocyte proliferation in male mice.
Subject(s)
Aryl Hydrocarbon Hydroxylases/physiology , Cytochrome P450 Family 2/physiology , Hepatocytes/drug effects , Hepatocytes/enzymology , Phenobarbital/pharmacology , Steroid Hydroxylases/physiology , Animals , Aryl Hydrocarbon Hydroxylases/deficiency , Aryl Hydrocarbon Hydroxylases/genetics , Cell Proliferation/drug effects , Cell Proliferation/physiology , Enzyme Induction/drug effects , Enzyme Induction/physiology , Female , Hypnotics and Sedatives/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Steroid Hydroxylases/deficiency , Steroid Hydroxylases/geneticsABSTRACT
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.
Subject(s)
Decompression Sickness/metabolism , Interleukins/metabolism , Lung/metabolism , Tumor Necrosis Factor-alpha/metabolism , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Animals , Decompression Sickness/etiology , Decompression Sickness/mortality , Decompression Sickness/pathology , Interleukin-10/genetics , Interleukin-10/metabolism , Interleukin-13/genetics , Interleukin-13/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukins/genetics , Lung/pathology , Male , RNA, Messenger/metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Submarine Medicine , Time Factors , Tumor Necrosis Factor-alpha/geneticsABSTRACT
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.
Subject(s)
Decompression Sickness/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Lung/metabolism , RNA, Messenger/metabolism , Tumor Necrosis Factor-alpha/metabolism , Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Animals , Decompression Sickness/pathology , Interleukin-1beta/genetics , Interleukin-6/genetics , Lung/pathology , Male , Random Allocation , Rats , Rats, Sprague-Dawley , Submarine Medicine , Time Factors , Tumor Necrosis Factor-alpha/geneticsABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Decompression Sickness/drug therapy , Decompression Sickness/immunology , Lung/drug effects , Lung/immunology , Ticlopidine/analogs & derivatives , Animals , Blood Platelets/drug effects , Blood Platelets/immunology , Clopidogrel , Cytokines/metabolism , Decompression Sickness/blood , Decompression Sickness/pathology , Disease Models, Animal , Immunohistochemistry , Leukocytes/drug effects , Leukocytes/physiology , Lung/pathology , Male , Organ Size , Platelet Aggregation Inhibitors/pharmacology , Platelet Membrane Glycoprotein IIb/metabolism , Pressure , Rats, Sprague-Dawley , Ticlopidine/pharmacology , Treatment OutcomeABSTRACT
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.
Subject(s)
Decompression Sickness , Oxygen/physiology , Animals , Bronchoalveolar Lavage Fluid/chemistry , Diving , Lung/pathology , Pressure , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/metabolismABSTRACT
In murine allogeneic transplantation models, ICOS gene-transduced bone marrow-derived mesenchymal stem cells (MSCs(ICOS-EGFP)) were evaluated for their effects on GvHD severity and long-term survival. Lethally irradiated BALB/c or first filial generation of BALB/c and C57BL/6 (CB6F1) mice were transplanted with bone marrow cells and splenocytes from C57BL/6 mice to establish acute GvHD models. Recipient mice were injected with MSCs(ICOS-EGFP), MSCs, MSCs(EGFP), ICOS-Ig fusion protein, MSCs + ICOS-Ig, or PBS (control group). Long-term survival, GvHD rates and severity, CD4(+) T-cell apoptosis and proliferation, and Th1/Th2/Th17 effecter cell polarization were evaluated. In the C57BL/6 â CB6F1 HSCT model, the long-term survival in the MSC(ICOS-EGFP) group was higher than that in the GvHD group (74.29 ± 7.39% vs. 0, p < 0.01), and this survival rate was also higher than that in the MSC, ICOS-Ig, or MSC + ICOS-Ig groups (42.86 ± 8.36%, p = 0.004; 48.57 ± 8.45%, p = 0.03; or 50.43 ± 8.45% p = 0.04, respectively). The survival advantages of MSC(ICOS-EGFP)-treated group were confirmed in the C57BL/6 â BALB/c HSCT model. In both HSCT models, the low mortality in the MSC(ICOS-EGFP) group was associated with lower incidence and severity of acute GvHD. Treatment with MSCs(ICOS-EGFP) induced more CD4(+) T-cell apoptosis compared with that in the GvHD group. The effect on CD4(+) T cells was shown as early as day 2 and maintained until day 14 (p < 0.05 on days 2, 3, 7, and 14). Furthermore, we demonstrated that MSCs(ICOS-EGFP) were able to suppress Th1 and Th17 polarization and promote Th2 polarization on both protein expression and gene transcription levels. Higher serum levels of IL-4, IL-10, and lower levels of IFN-γ, IL-2, IL-12, and IL-17A were detected in the MSC(ICOS-EGFP) group. The MSCs(ICOS-EGFP) could also induce GATA-3, STAT6 expression and inhibit T-bet, STAT4, ROR-γt expression. Our results showed that injection of MSCs(ICOS-EGFP) is a promising strategy for acute GvHD prevention and treatment. It provides synergistic benefits of MSC immune modulation and ICOS-B7h pathway blockage.
Subject(s)
Bone Marrow Cells/cytology , Graft vs Host Disease/prevention & control , Inducible T-Cell Co-Stimulator Protein/metabolism , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Acute Disease , Animals , Apoptosis , CD4-Positive T-Lymphocytes/immunology , Cells, Cultured , Cytokines/metabolism , Disease Models, Animal , Female , Graft vs Host Disease/mortality , Graft vs Host Disease/pathology , Inducible T-Cell Co-Stimulator Protein/genetics , Male , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Severity of Illness Index , Survival Rate , Th1 Cells/cytology , Th1 Cells/immunology , Th17 Cells/cytology , Th17 Cells/immunology , Th2 Cells/cytology , Th2 Cells/immunology , Transplantation, Homologous , V-Set Domain-Containing T-Cell Activation Inhibitor 1/deficiency , V-Set Domain-Containing T-Cell Activation Inhibitor 1/metabolismABSTRACT
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.
Subject(s)
Nitric Oxide Synthase Type III/metabolism , Nitric Oxide Synthase Type I/metabolism , Oxygen/poisoning , Pressure , Animals , Disease Models, Animal , Lung/metabolism , Male , Rats , Rats, Sprague-DawleyABSTRACT
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.
Subject(s)
Acute Lung Injury/etiology , Acute Lung Injury/physiopathology , Hyperoxia/complications , PPAR delta/metabolism , PPAR-beta/metabolism , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Animals , Antioxidants/metabolism , Apoptosis/drug effects , Apoptosis/physiology , Cytokines/metabolism , Disease Models, Animal , Lung/drug effects , Lung/pathology , Lung/physiopathology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Male , NF-kappa B/metabolism , Neuroprotective Agents/pharmacology , PPAR delta/agonists , PPAR delta/antagonists & inhibitors , PPAR-beta/agonists , PPAR-beta/antagonists & inhibitors , Pressure , Random Allocation , Rats, Sprague-Dawley , Respiratory System Agents/pharmacology , Sulfones/pharmacology , Thiazoles/pharmacology , Thiophenes/pharmacology , Time FactorsABSTRACT
OBJECTIVE: To observe MMP9 expression in rat lungs under different degrees of hyperbaric oxygen (HBO2) exposure and to observe the relationship of tissue damage and apoptosis rate in the lung tissue. METHODS: 40 Sprague Dawley (SD) rats were randomly divided into five groups: 250 kPa oxygen exposure for two-, four-, six- and eight-hour exposures and a "normal group," each n = 8. After hyperbaric oxygen treatment, the rats were euthanized immediately to collect lung tissue. We used HE staining to detect the pathological changes and immunohistochemistry to detect in situ expression of matrix metalloproteinase 9 (MMP9). Then we tested the expression level of caspase 3 in lung tissue by Western Blot. To understand the antioxidant capacity changes, we detected superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents in lung tissue during HBO2 exposure. Finally, we exposed MMP9 knockout or wild-type mice under hyperbaric oxygen for six hours, and detected the pathological changes with HE staining. RESULT: Lung tissue damage changed gradually under different degrees of hyperbaric oxygen exposure, but eased in the six-hour group. However, MMP9 expression decreased initially and then was upregulated until it reached the peak after six hours of exposure; it then reduced significantly after an eight-hour exposure. Active caspase 3 reached the highest level after eight hours. While SOD activity was upregulated only after six hours of HBO2 exposure, MDA content increased after eight hours of exposure. CONCLUSIONS: MMP9 expression was elevated after exposure to hyperbaric oxygen. This is a compensatory mechanism of the body's antioxidant response by regulating the inflammatory response. This in turn helps to reduce the apoptosis rate and protects lung tissue from oxygen toxicity.
Subject(s)
Apoptosis , Hyperbaric Oxygenation , Lung/enzymology , Matrix Metalloproteinase 9/metabolism , Animals , Caspase 3/metabolism , Gene Knockout Techniques , Lung/metabolism , Lung/pathology , Male , Malondialdehyde/metabolism , Matrix Metalloproteinase 9/genetics , Random Allocation , Rats , Rats, Sprague-Dawley , Superoxide Dismutase/metabolism , Time Factors , Up-RegulationABSTRACT
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.