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Objective To explore the effects of different degrees of intermittent hypoxia (IH) on the activation and the secretion of extracellular matrix in MLg lung fibroblast cell line. Methods MLg lung fibroblast cells in logarithmic growth phase were exposed for 5%O2 for 100 seconds and 21%O2 for 120 seconds in 1 h, 4 h and 8 h groups (IH1, IH4 and IH8) and normoxia group (21%O2 for 8 h, N group). The cells in each group were collected at the end of experiment. Real-time PCR was used to measure the mRNA expression levels ofα-SMA and typeⅠcollagen (COL1) A1, and Western blot assay was used to detect the protein expression levels ofα-SMA and COL1. Results The mRNA and protein expression levels ofα-SMA and COL1 were significantly increased in IH1, IH4 and IH8 groups than those in N group (all P < 0.05). Furthermore, expression levels of α-SMA and COL1 showed a time-dependent increase with IH exposure time. Conclusion The intermittent hypoxia can promote the cell activation and the extracellular matrix secretion of mouse lung fibroblast cells, which may be related with the oxidative stress.
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Objective To explore the effect of obstructive sleep apnea syndrome (OSAS), OSAS-like intermittent hypoxia (IH)on the expression levels of P-YAP and YAP in A549 lung cancer cell lines. Methods A549 cells were treated with IH exposure ( exposed to 5%O2 for 300 seconds and 21%O2 for 300 seconds) for 1, 3 and 6 h (IH1, IH3, IH6) or normoxia exposure (N group). Quantificational real-time PCR was used to measure the mRNA expression levels of YAP. Western blot assay was used to detect the protein expression levels of YAP and P-YAP. Results The mRNA expression levels of YAP were significantly increased with the increase of IH exposure time points in IH1 (2.50±0.18), IH3 (4.07±0.25) and IH6 (9.18 ± 0.58) groups than those in N group (1.00 ± 0.01) (all P<0.05). The protein expression levels of YAP were significantly increased with the increase of IH exposure time points in IH1, IH3 and IH6 groups than those in N group. The protein expression levels of P-YAP were significantly decreased with the increase of IH exposure time points in IH 1, IH3 and IH6 groups than those in N group. Conclusion YAP cell signaling plays an important role in the process of OSAS-like IH induced tumor development.
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Objective To explore the effects of cobalt chloride (CoCl2)-induced hypoxia on migration of melanoma cells, and to detect the transcription, expression and secretion of Follistatin-like 1(FSTL1) in this process. Methods B16F10 melanoma cell line was treated with CoCl2 in order to mimic hypoxia. Experimental cells were divided into three groups: 0μmol/L, 50μmol/L and 100μmol/L CoCl2 treatment groups. MTT assay was used to assure cell viability, and to determine the treatment concentration of CoCl2. Transwell assay was used to determine the migration ability of B16F10 melanoma cell line. Real-time PCR was used to measure the mRNA expression of Fstl1. Western blot assay was used to detect the intracel?lular and extracellular protein expression of FSTL1. Results The cell viability of B16F10 melanoma cell line was signifi?cantly reduced by CoCl2 treatment, with a time and concentration-dependent manner. The migration ability of B16F10 cell line was significantly increased in CoCl2 treated group compared with that of control group (P<0.05). The mRNA level of Fstl1 was obviously higher in CoCl2 treated group than that of control group (P<0.05). The intracellular expression of FSTL1 protein was consistent with the expression trend of Fstl1 mRNA. Simultaneously, the extracellular protein level of FSTL1 was significantly decreased compared with that of control group. There was no expression of FSTL1 in 100μmol/L CoCl2 treat?ment group. Conclusion The migration ability of melanoma cell line is enhanced by CoCl2 treatment, which may be associ?ated with expression and secretion of FSTL1, however, the relevant mechanism still needs further investigation.
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Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for atherosclerosis. Accumulated evidence has revealed that OSAS can induce systemic inflammation, oxidative stress, and endothelial dysfunction, which will contribute to the pathogenesis of atherosclerosis. T lymphocytes can be activated by inflammation and oxidative stress, resulting in the elevated cytotoxicity towards vascular endothelial cells. Thus, T lymphocytes play a key role in OSAS-related atherosclerosis development or progression via immuno-inflammatory alterations. This review described the current development of the role of T lymphocytes in OSAS-related atherosclerosis.
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Objective To observe the curative effect of continuous airway positive pressure ventilation (CPAP) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and cough syncope. Methods Forty-three hospitalized patients with OSAHS and cough syncope were collected in the Department of Respiration of Tianjin General Hospital, and analyzed the related information. They were given CPAP treatment, and were divided into good compliance group (n=26) and poor compliance group (n=17) according to CPAP compliance after a half-year treatment. The apnea hypoventilation index (AHI) and c-reactive protein (CRP) were compared before and after treatment between two groups. Results The positive correlation was found between the frequency of the cough syncope and indicators of OSAHS, such as AHI, body mass index (BMI), CRP, sleepiness score (ESS) and circumference of abdomen and neck (r=0.612, 0.431, 0.224, 0.654, 0.435 and 0.344,P<0.05). All these patients were cured after the treatment of both CPAP and medication for 1 or 2 weeks. During a half-year follow-up, the cough syncope didn’t occur in those patients of good compliance group, otherwise cough syncope still happened but with less frequency in patitents of poor compliance group. Before the treatment , there was no significant difference in AHI (45.00±15.69 vs. 48.70±16.47) and CRP (3.46± 1.15 vs. 3.38±0.72) between the two groups. After treatment, AHI (26.97±14.06 vs. 48.18±15.96) and CRP (1.56±0.76 vs. 3.18± 0.78) were significantly lower in the good compliance group than those of the poor compliance group (P<0.01). Conclusion Timely and sustained treatment of OSAHS may help reduce the incidence of cough syncope and significantly improve AHI, CRP and cough symptoms.
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Objective To investigate the effect of emphysema and intermittent hypoxia (IH) on the hepatic oxidative stress and inflammatory injury in rats. Methods Sixty male Wistar rats were randomly assigned to 4 groups, control group (A), emphysema group (B), IH group (C) and emphysema+IH group (D). Group A was normally fed. Group B was exposed to smoke, 30 min per time, twice everyday. Group C was exposed to 5%O2 30 s/Air 90 s for 8 h/d. Group D was exposed to smoke twice, about 30 min each time, and exposed 5%O2 30 s/Air 90 s for 8 h/d. After continues exposure for 8 weeks, five rats in each group were randomly selected for arterial blood gas analysis. The tissue blocks of liver was obtained for pathologi-cal scoring and measurements of liver oxidative stress in the rest 10 rats of each group. HE staining was used to calculate the mean lining interval (MLI) and mean alveolar number (MAN). The hepatic inflammatory factor interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), superoxide dismutase (SOD) activity, catalase (CAT) activity and malondialdehyde (MDA) con-centration were measured in four groups. Results Characteristics of emphysema were found in group B and group D. The values of MLI were significantly higher in Group B and group D than those of group A and group C (P<0.05). The values of MAN were significantly lower in group B and group D than those of group A and group C (P<0.05). The levels of SOD and CAT were significantly lower in group B, group C and group D than those of group A (P<0.05). And the levels of SOD and CAT were significantly lower in group D than those of group B and group C (P<0.05). The values of liver MDA were signifi-cantly higher in group B, group C and group D than those of group A, and the values were significantly higher in group D than those of group B and group C (P<0.05). The liver histological scores and the levels of IL-6 and TNF-αwere signifi-cantly higher in group B, group C and group D than those of group A, and the values were significantly higher in group D than those of group B and group C (P<0.05). Conclusion Emphysema and IH have synergistic action in causing hepatic oxidative stress and inflammation.
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Objective To establish the rat overlap syndrome (OS) model of intermittent hypoxia (IH) and emphyse-ma, explore the systematic and endothelial inflammation status, and observe the changes of endothelial progenitor cell (EPC) level in peripheral blood. Methods Sixty male Wistar rats were randomly divided into four groups:normal oxygen control group (A), IH group (B), emphysema group (C) and OS group (D). The rat model of emphysema was established by smoke ex-posure for 16 weeks. From the 13-week, pre-programmed intermittent hypoxia/re-oxygenation (IH/ROX) exposure was giv-en in the meantime of smoke exposure. After exposure, ELISA method was used to detect values of tumor necrosis factor al-pha (TNF-α) and interleukin (IL)-6 in plasma and in the endothelium of right common carotid artery. Real-time-PCR assay was used to analyze RhoA mRNA level in the endothelium of right common carotid artery. The percentage of intima-media thickness (IMT) in the all wall of right carotid artery (C-IMT%) was measured. Flow cytometry was used to detect EPC levels. Results The values of TNF-α, IL-6, RhoA mRNA and C-IMT%were significantly higher in D group than those of A, B and C groups (P<0.05). The EPC levels were significantly lower in D group than those of A, B and C groups (P<0.05). Con-clusion OS rats had more serious vascular endothelial injury than that of emphysema or IH rats. Meanwhile, the repair ca-pacity of EPC for endothelium was worse, which increased the risk of cardiovascular diseases.
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Rapid on site evaluation (ROSE) technology of interventional pulmonology includes“cytological ROSE”(C-ROSE) and“microbiological ROSE”(M-ROSE). Recently, this“ROSE”has gradually become one of core technologies in modern interventional pulmonology. In this commentary, perspectives on origin and development, classification and clini-cal value, operational approach, clinical application, and how to carry out effective work related to ROSE were summarized and remarked.
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To study the effect of different levels intermittent hypoxia on inflammatory cytokines and adipokines in a rat model. 160 male Wistar rats were divided into five groups, three groups with intermittent hypoxia (5% O2:IH-1 group;7. 5% O2: IH-2 group;10% O2: IH-3 group), continuous hypoxia group (10% O2, CH group);and the intermittent normal oxygen control group(IN). Before the exposure and at the second, fourth, sixth, and eighth week after the exposure, eight rats in each group were selected randomly with blood samples collected. Blood glucose was measured by glucose oxidase-peroxidase ( GOD-POD ) reagents, double sandwich enzyme-linked immunosorbent assay ( ELISA) was used to detect serum concentration of insulin, tumor necrosis factor alpha( TNF)-α, interleukin ( IL)-6, leptin, and adiponectin and adipocyte nuclear factor kappa B ( NF-κB) levels. In IH-1, IH-2, and IH-3 group, blood glucose, insulin, TNF-α, IL-6, leptin, and nuclear NF-κB in rats showed consecutive increment after exposure to intermittent hypoxia, and those findings in IH-1 group were higher than those in IH-2 and IH-3 group (P0. 05). These results demonstrate that intermittent hypoxia could activate NF-κB and result in extensive changes of proinflammatory cytokines and adipokines in the serum of rats. The release of pro-inflammatory cytokines and adipokines keeps pace with the degree of intermittent hypoxia.
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Obstructive sleep apnea (OSA) is characterized by repeated intermittent hypoxia (IH), hypercapnia, sleep fragmentation and intrathoracic pressure change. IH is related to the clinical pathophysiological processes of hypertension, atherosclerosis, coronary heart disease, arrhythmia, stroke, heart failure and sudden death. IH from OSA can lead to metabol-ic dysregulation, endothelial dysfunction, systemic inflammation, oxidative stress and the change of nerve body fluids, which has been shown to increase the risk of cardiovascular diseases. This study mainly describes the pathogenesis of IH leading to the various cardiovascular diseases.
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Objective To study the effect of different degrees of intermittent hypoxia (IH) on inflammatory cytokines and adipokines in 3T3-L1 adipocytes. Methods An intermittent hypoxia/reoxygenation (IH/ROX) from obstructive sleep apnea (OSA) adipocyte model was established. 3T3-L1 adipocytes were divided into five groups, three IH groups (5% O2, 7.5%O2 and 10%O2, referred to as IH-1, IH-2 and IH-3), sustained hypoxia group (10%O2, CH) and the normal oxygen control group (21%O2, IN). ELISA method was used to detect values of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), leptin and adiponectin in cell supernatant. Western blot analysis was used to detect levels of hypoxia-inducible fac-tor-1α(HIF-1α) and glucose transporter-1 (Glut-1). RT-PCR assay was used to analyze HIF-1α, Glut-1, TNF-α, IL-6, leptin and adiponectin mRNA expression levels in adipocytes. Results The expression levels of TNF-α, IL-6 and leptin were significantly higher in IH and CH groups than those of IN group (P<0.05). The expression levels of TNF-α, IL-6 and leptin protein and leptin mRNA were significantly higher in IH-1 group than those of IH-2 and IH-3 groups (P<0.05). The adiponectin and its mRNA levels were significantly lower in IH and CH groups than those of IN group (P<0.05). The adipo-nectin level was significantly lower in IH-1 group than that of IH-2 and IH-3 groups (P<0.05). Conclusion These results demonstrate that IH is related to the extensive changes in the expression and release of inflammation-related adipokines in cultured adipocytes. IH from OSA may underlie the development of the inflammatory response in adipocytes, which is in-volved in insulin resistance in patients with OSA.
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Objective To measure the mRNA expression of immediate-early gene c-fos in endothelial cells by the use of different intermittent hypoxia (IH) protocols. Methods A gas control delivery system was homemade, which pro-duced IH/re-oxygenation(ROX) environmental exposure. The endothelial cells were exposed to IH/ROX cycles, and were di-vided into three groups (A, B and C). There were five sub-groups in each group. Group A included intermittent normoxia group, standard incubator control group, continuous hypoxia group (CH), 1.5%O2 IH group and 10%O2 IH group. There were different frequency IH of 1.5%O2 and 10%O2 sub-groups in group B and group C. Hypoxia time was 15 s. The intermittent hypoxia cycle was 60 and the ROX time was different. The total cycle time was different, including 1.5 h group, 3 h group, 5 h group, 6.5 h group and 9.5 h group. The mRNA expression of immediate-early gene c-fos was measured by real-time PCR. Results There was no significant difference in the level of c-fos mRNA between intermittent normoxia group and CH group. The expression of c-fos mRNA was significantly higher in 1.5%O2 IH group and 10%O2 IH group than that of intermit-tent normoxia group, and there was a higher expression level of c-fos mRNA in 1.5%O2 IH group than that of 10%O2 IH group (P＜0.01). It was found that the mRNA expression of c-fos increased gradually at first, and then gradually decreased. The expression of c-fos mRNA was significantly higher in 5 h group than that of other groups (P＜0.01). Conclusion The mRNA expression of immediate-early gene c-fos is increased after exposing to IH/ROX in endothelial cells, which is closely related with IH extents and frequencies.
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Objective To explore the mechanism of severe intermittent hypoxia on oognitive function by evaluatig the effect of chronic intermittent hypoxia on cognitive function,neurons structure,damage,p38MAPK protein expression and neuronal apoptosis in rats hippocampal CA1.Methods Ninety-six mature and male Wistar rats were randomly divided into two groups:control group (UC) and 5％ chronic intermittent hypoxia group (5％CIH).Rats in IH groups were suffered 8 hours intermittent hypoxia everyday,and the duration of experiment was respectively 2,4,6 and 8 weeks.After exposed for 2,4,6,and 8 weeks,the cognitive function of rats was assessed with the Morris water maze (MWM) ; the changes in the morphology of nerve cells in hippocampus CA1 region were observed; the expression of phosphorylated p38MAPK protein in hippocampus was detected by the methods of immunohistochemistry and western blot; the apoptosis of nerve cells was detected by the method of TUNEL.Results Compared with control group,with prolonged hypoxia,the time of escape latency obviously prolonged and the time of across the target quadrant shortened significantly in rats of 5％ CIH group.The time of escape latency at the 8th week was the longest ((71.71 ± 5.49)s,P＜ 0.05) in 5％ CIH group,and the time of across the target quadrant at the 8th week was the shortest ((26.82 ± 4.30) s,P ＜ 0.05) in 5％ CIH group.There appeared neuronal degeneration and necrosis in hippocampus CA1 in 5％ CIH group.Compared with the control group,the density of the nerve cells survival in the region of hippocampal CA1 reduced dramatically at the 2nd,4th,6th and 8th week and was the lowest at the 8th week(14.16 ± 2.07,P ＜ 0.05).By Immunohistochemical method,the expression of phosphorylated p38 MAPK of 5％ CIH group in hippocampal CA1 was more than UC group at the 2nd,4th,6th and 8th week.By western blot,the expression of phosphorylated p38MAPK of 5％ CIH group was more than UC group at the 2nd,4th,6th and 8th week and was the most at the 6th week (2.45 ± 0.14,P＜ 0.05) ;the index of neuronal apoptosis in hippocampal CA1 was increased significantly at the 2nd,4th,6th and 8th week than UC group and reached to the peak at the 6th week (0.608 ± 0.069,P ＜ 0.05) in the 5 ％ CIH group.Conclusion Chronic intermittent hypoxia could cause the activation of p38MAPK/pathway of neuronal apoptosis and was important mechanism of cognitive dysfunction at the early and middle stage.
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Objective To investigate the expression of endothelin-1 (ET-1 ), nitrogen monoxidium (NO), vascular endothelial growth factor (VEGF) and brain tissue VEGF induced by chronic intermittent hypoxia (CIH) in aged rats. Methods The CIH model of aged rat was established by using intermittent hypoxia. The levels of ET-1, NO and VEGF in the plasma were detected at 3, 6 and 9 weeks after experiment in each group. The expression of VEGF in brain tissues and the pathological changes of the vessels of the cerebra and the ratio between the thickness of vessel wall and external diameter (WT%) were observed. Results In CIH group, the ET-1 and VEGF levels increased, however NO level decreased. The levels of ET-1 and VEGF were higher at 3 weeks in CIH group than in UC group (t=2.47 and 2.38, both P<0.05), however NO level was lower in CIH group than in UC group (t=2.39, P<0.05). VEGF levels increased significantly at 9 weeks in CIH as compared with UC group [(171.1±13.5) pg/ml vs. (109.8±8.6) pg/ml, t = 3.46, P< 0.01]. The levels of VEGF in CIH group increased remarkably at 9 weeks as compared with 3 weeks [(129.3±12.3) pg/ml, t=2.38, P<0.053. VEGF levels in CIH group showed positive correlation with the time of intermittent hypoxia. The changes of cerebral vessels in UC group were not found, while the aged rats in CIH group showed cerebral neuron cells swelling and blood vessel hyperplasia. The WT% of cerebral small artery was more apparent in CIH group than in UC group at 3 weeks (t=2.34,P<0.05). The expression of VEGF in cerebra was higher in CIH group than in UC group in the three stages (r=2.37, P<0.05). There was an aggravated tendency in the change of the expression of brain tissue VEGF and WT% over time. The change was more apparent at 9 weeks than at 3 weeks (t=2.32 and 2.35, both P<0.05). Conclusions CIH can induce an increase in the expression of ET-1 and VEGF, a decrease in the expression of NO in aged rats. The over expression of VEGF and the disbalance of ET-1 and NO levels can cause brain cellular swelling, arteriola vessel wall thickening,lumens stenosis.
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Objective To develope a novel rabbit carotid body and carotid common artery model in vivo for the simulation of various intermittent hypoxia (IH) intensities, IH durations, IH reoxygenation (ROX) durations and continuous hypoxia (CH) modes.Methods Forty-five adult New Zealand rabbits (2.5～3.0 kg) were anesthetized while spontaneous breathing kept intact.The tissue surrounding the fight earetid common artery and carotid sinus nerve (CSN) were cleared and "single" chemoreceptor bundle of the CSN was revealed.Then suction electrodes were placed and CSN afferent activity was monitored and recorded carefully.The fight common carotid artery was exposed, cannulated to distal part and its proximal part was ligated.Preparations were challenged by changing the PO2 of the gas mixture equilibrating the perfusate.Alternatively perfusion (2 mL/min) of equilibrated porfusate bubbled with normoxia or hypoxia gas mixtures formed IH/ROX cycles in carotid common artery,simulating the pattern of hypoxic episodes seen in obstructive sleep apnea syndrome (OSAS), or with continuously perfusing hypoxia perfusate to form CH modes.All the perfusing procedures were regulated by a customized computer-controlled set and monitored using O2 gas analyzer.After the systematic exposures, carotid body, carotid common artery part distal to cannula,and carotid bifurcation were harvested as samples.Results The frequencies and average amplitudes of CSN chemoreceptor bundles afferent activities with normoxia peffusion were (0.17±0.03) impulse/s and (46.2±4.4) μV, and with hypoxia perfusion were (0.6±0.09) impulse/s and (87.4±6.6) μV, respectively.PO2 was (139±1.5) nun Hg in normoxia perfusate and (35.2±1.3) mm Hg in hypoxia perfusate.Conclusion This new carotid body and carotid common artery model is a valuable tool to study neurological and biochemical changes in various IH and CH modes.
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ObjectiveTo investigate the therapeutic value of noninvasive mechanical ventilation in patients with conscious disturbance due to severe chronic obstructive pulmonary disease (COPD) with respiratory failure. MethodsForty-two patients with conscious disturbance due to COPD complicated with respiratory failure were selected in the study. GALILEO or PAPHAEL large EMT ventilator produced by Switzerland Hamilton Company was used for noninvasive mechanical ventilation with P-SIMV+PSV+PEEP mode. Meanwhile, the change of vital signs, consciousness, the degree of inspiratory muscle fatigue and blood gas indexes were observed before and after treatment. Glasgow coma scale (GCS) was applied to evaluate the consciousness, and scale for accessory muscle use was adopted to measure the degree of inspiratory muscle fatigue. ResultsAll the patients were treated successfully. Compared with admission, the pH value, the pressure of arterial carbon dioxide (PaCO2) and the arterial oxygen pressure/inhaled oxygen concentration (PaO2/FiO2)were significantly improved 2 hours, 4 hours and 24 hours after treatment. The respiration rate and heart rate were markedly decreased 24 hours after treatment, which indicated that the condition of the patients tended to be stable and the patients could endure the therapy. The average GCS was increased from 5.69-1-0.93 to 10.45±1.23 (t= 31.68, P<0.001), and the state of consciousness was improved significantly. The scale for accessory muscle use was decreased from 3.70±0. 45 to 2. 06±0. 52 (t = 31.21, P < 0. 001), and the respiratory muscle fatigue was relieved. ConclusionsNoninvasive mechanical ventilation has obvious clinical curative effect on severe infection and conscious disturbance due to severe COPD complicated with respiratory failure.
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Objective To investigate the concentration changes of vascular endothelial growth factor(VEGF), nitric oxide(NO) and endothelin (ET) in elderly patients with obstructive sleep apnea syndrome (OSAS) combined with eerebrovascular disease.Methods One hundred and thirty-two subjects were divided into four groups: OSAS with cerebrovaseular disease group (OC group), OSAS without cerebrovascular disease group (O group), cerebrovascular disease without OSAS group (C group) and normal control group (N group).The concentrations of VEGF, NO and ET in the plasma were compared in each subgroup.Results The concentration of VEGF was significantly increased in OC group and O group compared with C group and N group[(195.34±56.7)ng/L, (162.34±48.7)ng/L, (156.4 4±51.8) ng/L, (114.1 ± 54.2) ng/L, F= 21.02, P< 0.05].The concentration of NO was increased gradually in OC group, C group, O group and N group[(62.3±4.9)mmol/L,(64.7±5.1) mmol/L, (66.2± 4.2)retool/L, (77.5 ± 6.8) mmol/L, F= 17.35, P<0.05], and the concentration of ET was decreased gradually in OC group, C group, O group and N group[(59.8±9.6)ng/L, (56.5±4.3)ng/L, (54.7±7.9)ng/L, (37.2±8.5)ng/L, F= 4.27, P<0.05].Conclusions The concentrations of VEGF and ET are increased and the concentration of NO is decreased in patients with OSAS.Patients with OSAS combined with cerebrovascular disease have higher VEGF and ET concentrations and lower NO concentration than in patients with simple OSAS.The results indicate that vascular endothelial dysfunction may play an important role in the development of cerebrovascular disease in patients with OSAS.