Lung injury caused by high tidal volume mechanical ventilation and hyperoxia is dependent on oxidant-mediated c-Jun NH2-terminal kinase activation

Both prolonged exposure to hyperoxia and large tidal volume mechanical ventilation can each independently cause lung injury. However, the combined impact of these insults is poorly understood. We recently reported that preexposure to hyperoxia for 12 h, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone (Makena et al. Am J Physiol Lung Cell Mol Physiol 299: L711-L719, 2010). The upstream mechanisms of this lung injury and apoptosis have not been clearly elucidated. We hypothesized that lung injury in this model was dependent on oxidative signaling via the c-Jun NH(2)-terminal kinases (JNK). We, therefore, evaluated lung injury and apoptosis in the presence of N-acetyl-cysteine (NAC) in both mouse and cell culture models, and we provide evidence that NAC significantly inhibited lung injury and apoptosis by reducing the production of ROS, activation of JNK, and apoptosis. To confirm JNK involvement in apoptosis, cells treated with a specific JNK inhibitor, SP600125, and subjected to preexposure to hyperoxia, followed by mechanical stretch, exhibited significantly reduced evidence of apoptosis. In conclusion, lung injury and apoptosis caused by preexposure to hyperoxia, followed by high tidal volume mechanical ventilation, induces ROS-mediated activation of JNK and mitochondrial-mediated apoptosis. NAC protects lung injury and apoptosis by inhibiting ROS-mediated activation of JNK and downstream proapoptotic signaling.     

Inhibition of breathing after surfactant depletion is achieved at a higher arterial PCO2 during ventilation with liquid than with gas

Background

Inhibition of phrenic nerve activity (PNA) can be achieved when alveolar ventilation is adequate and when stretching of lung tissue stimulates mechanoreceptors to inhibit inspiratory activity. During mechanical ventilation under different lung conditions, inhibition of PNA can provide a physiological setting at which ventilatory parameters can be compared and related to arterial blood gases and pH.

Objective

To study lung mechanics and gas exchange at inhibition of PNA during controlled gas ventilation (GV) and during partial liquid ventilation (PLV) before and after lung lavage.

Methods

Nine anaesthetised, mechanically ventilated young cats (age 3.8 ± 0.5 months, weight 2.3 ± 0.1 kg) (mean ± SD) were studied with stepwise increases in peak inspiratory pressure (PIP) until total inhibition of PNA was attained before lavage (with GV) and after lavage (GV and PLV). Tidal volume (V_t), PIP, oesophageal pressure and arterial blood gases were measured at inhibition of PNA. One way repeated measures analysis of variance and Student Newman Keuls-tests were used for statistical analysis.

Results

During GV, inhibition of PNA occurred at lower PIP, transpulmonary pressure (Ptp) and Vt before than after lung lavage. After lavage, inhibition of inspiratory activity was achieved at the same PIP, Ptp and Vt during GV and PLV, but occurred at a higher PaCO₂ during PLV. After lavage compliance at inhibition was almost the same during GV and PLV and resistance was lower during GV than during PLV.

Conclusion

Inhibition of inspiratory activity occurs at a higher PaCO₂ during PLV than during GV in cats with surfactant-depleted lungs. This could indicate that PLV induces better recruitment of mechanoreceptors than GV.     

Initial responses to ventilation of premature lambs exposed to intra-amniotic endotoxin 4 days before delivery

Preterm delivery is frequently preceded by chorioamnionitis, resulting in exposure of the fetal lung to inflammation. We hypothesized that ventilation of the antenatally inflamed lung would result in amplification of the lung injury. Therefore, we induced fetal lung inflammation with intra-amniotic endotoxin (10 mg of Escherichia coli 055:B5) 4 days before premature delivery at 130 days of gestation. Lung function and lung inflammation after surfactant treatment and 4 h of mechanical ventilation were evaluated. Inflammatory cell numbers in amniotic fluid were increased >10-fold by antenatal endotoxin exposure. Antenatal endotoxin exposure had minimal effects on blood pressure, heart rate, lung compliance, and blood gas values. The endotoxin-exposed lungs required higher ventilation pressures. Ventilation did not increase the number of inflammatory cells or the protein in bronchoalveolar lavage fluid of the endotoxin-exposed animals above that measured in endotoxin-exposed fetuses that were not ventilated. IL-1beta, IL-6, and IL-8 mRNA in cells from bronchoalveolar lavage fluid were increased by antenatal endotoxin exposure but not changed by ventilation. IL-1beta and IL-8 protein was increased in lung tissue by 4 h of ventilation. Very little inflammation was induced by ventilation in this premature lamb model of surfactant treatment and gentle ventilation. After lung inflammation was induced by intra-amniotic endotoxin injection, ventilation did not increase lung injury.     

Distribution of pulmonary ventilation using Xe-enhanced computed tomography in prone and supine dogs.

Xe-enhanced computed tomography (CT; Xe-CT) is a method for the noninvasive measurement of regional pulmonary ventilation in intact subjects, determined from the washin and washout rates of the radiodense, nonradioactive gas Xe, as measured in serial CT scans. We used the Xe-CT ventilation method, along with other quantitative CT measurements, to investigate the distribution of regional lung ventilation and air content in healthy, anesthetized, mechanically ventilated dogs in the prone and supine postures. Vertical gradients in regional ventilation and air content were measured in five mongrel dogs in both prone and supine postures at four axial lung locations. In the supine position, ventilation increased with dependent location, with a mean slope of 7.3%/cm lung height, whereas no ventilation gradients were found at any location in the prone position. These results agree quantitatively with other published studies. In addition, six different animals were studied (3 supine, 3 prone) to examine the longitudinal distribution of ventilation and air content. The prone lungs were more uniformly inflated compared with the supine, which were less well expanded at the base than apex. Ventilation index, a measure of regional ventilation relative to whole lung ventilation, increased steeply from apex to base in the supine animals, whereas it was again more uniform in the prone condition. We conclude that the Xe-CT method provides a reasonable, quantitative measurement of regional ventilation and promises to be a valuable tool for the noninvasive determination of regional lung function.     

Control of ventilation in elite synchronized swimmers

Synchronized swimmers perform strenuous underwater exercise during prolonged breath holds. To investigate the role of the control of ventilation and lung volumes in these athletes, we studied the 10 members of the National Synchronized Swim Team including an olympic gold medalist and 10 age-matched controls. We evaluated static pulmonary function, hypoxic and hypercapnic ventilatory drives, and normoxic and hyperoxic breath holding. Synchronized swimmers had an increased total lung capacity and vital capacity compared with controls (P less than 0.005). The hypoxic ventilatory response (expressed as the hyperbolic shape parameter A) was lower in the synchronized swimmers than controls with a mean value of 29.2 +/- 2.6 (SE) and 65.6 +/- 7.1, respectively (P less than 0.001). The hypercapnic ventilatory response [expressed as S, minute ventilation (1/min)/alveolar CO2 partial pressure (Torr)] was no different between synchronized swimmers and controls. Breath-hold duration during normoxia was greater in the synchronized swimmers, with a mean value of 108.6 +/- 4.8 (SE) vs. 68.03 +/- 8.1 s in the controls (P less than 0.001). No difference was seen in hyperoxic breath-hold times between groups. During breath holding synchronized swimmers demonstrated marked apneic bradycardia expressed as either absolute or heart rate change from basal heart rate as opposed to the controls, in whom heart rate increased during breath holds. Therefore the results show that elite synchronized swimmers have increased lung volumes, blunted hypoxic ventilatory responses, and a marked apneic bradycardia that may provide physiological characteristics that offer a competitive advantage for championship performance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gas exchange and intrapulmonary distribution of ventilation during continuous-flow ventilation

In 12 anesthetized paralyzed dogs, pulmonary gas exchange and intrapulmonary inspired gas distribution were compared between continuous-flow ventilation (CFV) and conventional mechanical ventilation (CMV). Nine dogs were studied while they were lying supine, and three dogs were studied while they were lying prone. A single-lumen catheter for tracheal insufflation and a double-lumen catheter for bilateral endobronchial insufflation [inspired O2 fraction = 0.4; inspired minute ventilation = 1.7 +/- 0.3 (SD) 1.kg-1.min-1] were evaluated. Intrapulmonary gas distribution was assessed from regional 133Xe clearances. In dogs lying supine, CO2 elimination was more efficient with endobronchial insufflation than with tracheal insufflation, but the alveolar-arterial O2 partial pressure difference was larger during CFV than during CMV, regardless of the type of insufflation. By contrast, endobronchial insufflation maintained both arterial PCO2 and alveolar-arterial O2 partial pressure difference at significantly lower levels in dogs lying prone than in dogs lying supine. In dogs lying supine, the dependent lung was preferentially ventilated during CMV but not during CFV. In dogs lying prone, gas distribution was uniform with both modes of ventilation. The alveolar-arterial O2 partial pressure difference during CFV in dogs lying supine was negatively correlated with the reduced ventilation of the dependent lung, which suggests that increased ventilation-perfusion mismatching was responsible for the increase in alveolar-arterial O2 partial pressure difference. The more efficient oxygenation during CFV in dogs lying prone suggests a more efficient matching of ventilation to perfusion, presumably because the distribution of blood flow is also nearly uniform.     

High oxygen concentrations predispose mouse lungs to the deleterious effects of high stretch ventilation.

Mechanical ventilation is a necessary intervention for patients with acute lung injury. However, mechanical ventilation can propagate acute lung injury and increase systemic inflammation. The exposure to >21% oxygen is often associated with mechanical ventilation yet has not been examined within the context of lung stretch. We hypothesized that mice exposed to >90% oxygen will be more susceptible to the deleterious effects of high stretch mechanical ventilation. C57B1/6 mice were randomized into 48-h exposure of 21 or >90% oxygen; mice were then killed, and isolated lungs were randomized into a nonstretch or an ex vivo, high-stretch mechanical ventilation group. Lungs were assessed for compliance and lavaged for surfactant analysis, and cytokine measurements or lungs were homogenized for surfactant-associated protein analysis. Mice exposed to >90% oxygen + stretch had significantly lower compliance, altered pulmonary surfactant, and increased inflammatory cytokines compared with all other groups. Our conclusion is that 48 h of >90% oxygen and high-stretch mechanical ventilation deleteriously affect lung function to a greater degree than stretch alone.     

Pulmonary inflammation induced by high-stretch ventilation is mediated by tumor necrosis factor signaling in mice

Although high-stretch mechanical ventilation has been demonstrated to induce lung inflammation, the roles of soluble mediators, in particular TNF, remain controversial. We have previously shown in mice that high-stretch ventilation, in the absence of preceding lung injury, induces expression of bioactive TNF in lung lavage fluid early in the course of injury, but the biological significance of this, if any, has yet to be determined. We therefore investigated the pulmonary inflammatory response to a transient period of high-stretch ventilation in anesthetized mice lacking TNF receptors and mice treated with anti-TNF antibodies. A standardized stretch-induced lung injury (assessed by lung mechanics, blood gases, and lavage protein content), followed by noninjurious low-stretch ventilation for 3 h, produced significant alveolar neutrophil infiltration in wild-type mice. However, neutrophil recruitment was substantially attenuated in TNF receptor double knockout mice and in wild-type mice treated with intratracheal anti-TNF antibody. This attenuation was not associated with decreased concentrations of neutrophil attractant CXC chemokines (macrophage inflammatory protein-2 and keratinocyte-derived chemokine) in lavage fluid. In contrast to intratracheal antibody, intravenous anti-TNF antibody did not reduce neutrophil infiltration, suggesting that the role of TNF signaling is localized within the alveolar space and does not require decompartmentalization of TNF into the circulation. These findings provide the first direct evidence that pulmonary inflammation induced by high-stretch ventilation without underlying lung injury possesses a significant TNF-dependent component. The results suggest a potential for regional anti-TNF treatment in attenuating stretch-induced pulmonary inflammation.     

Group V phospholipase A2 in bone marrow-derived myeloid cells and bronchial epithelial cells promotes bacterial clearance after Escherichia coli pneumonia

Group V-secreted phospholipase A(2) (GV sPLA(2)) hydrolyzes bacterial phospholipids and initiates eicosanoid biosynthesis. Here, we elucidate the role of GV sPLA(2) in the pathophysiology of Escherichia coli pneumonia. Inflammatory cells and bronchial epithelial cells both express GV sPLA(2) after pulmonary E. coli infection. GV(-/-) mice accumulate fewer polymorphonuclear leukocytes in alveoli, have higher levels of E. coli in bronchoalveolar lavage fluid and lung, and develop respiratory acidosis, more severe hypothermia, and higher IL-6, IL-10, and TNF-α levels than GV(+/+) mice after pulmonary E. coli infection. Eicosanoid levels in bronchoalveolar lavage are similar in GV(+/+) and GV(-/-) mice after lung E. coli infection. In contrast, GV(+/+) mice have higher levels of prostaglandin D(2) (PGD(2)), PGF(2α), and 15-keto-PGE(2) in lung and express higher levels of ICAM-1 and PECAM-1 on pulmonary endothelial cells than GV(-/-) mice after lung infection with E. coli. Selective deletion of GV sPLA(2) in non-myeloid cells impairs leukocyte accumulation after pulmonary E. coli infection, and lack of GV sPLA(2) in either bone marrow-derived myeloid cells or non-myeloid cells attenuates E. coli clearance from the alveolar space and the lung parenchyma. These observations show that GV sPLA(2) in bone marrow-derived myeloid cells as well as non-myeloid cells, which are likely bronchial epithelial cells, participate in the regulation of the innate immune response to pulmonary infection with E. coli.     

Effect of ventilation on pulmonary blood volume of the fetal lamb.

Blood volume changes in the fetal lung following the onset of ventilation were studied by isotopic measurement of red blood cell and plasma volume in rapidly frozen lungs of ten near term fetal lambs. Total pulmonary blood volumes of fetal lambs ventilated with 3% O2 and 7% CO2 in nitrogen (so that blood gas levels were little changed from fetal values), or with air, were compared with measurements in unventilated lambs. Regional correlations of blood volume and blood flow (measured with isotope-labeled microemboli) within the lungs were also examined. Total pulmonary blood volume averaged 5.6 ml/kg body weight in unventilated fetal lambs and was approximately 43% greated in fetal lambs after 5-20 min of air ventilation, but not significantly different in lambs ventilated with 3% O2 and 7% CO2 in nitrogen. Thus it is ventilation with air, rather than the introduction of gas into the alveoli, which enlarges the fetal pulmonary vascular bed. Regional pulmonary blood volume and blood flow were correlated, though poorly, in air-ventilated lungs, but not in lungs ventilated with 3% O2 and 7% CO2 in nitrogen; this suggests that a common factor may operate to increase both blood flow and blood volume in the fetal lung following the introduction of air.     

Hemodynamic effects of synchronous high-frequency jet ventilation in mitral regurgitation

We tested the hypothesis that increases in intrathoracic pressure (ITP), by decreasing the pressure gradient for anterograde left ventricular (LV) ejection, should augment cardiac output in acute mitral regurgitation (MR). In a pentobarbital-anesthetized closed-chest canine model, LV stroke volume (SLLV) was measured by integration from an aortic flow probe signal. MR was induced by a regurgitant ring. ITP was elevated over apnea by means of intermittent positive-pressure ventilation (IPPV), asynchronous (asynch) high-frequency jet ventilation (HFJV), and cardiac cycle-specific (synch) HFJV. IPPV resulted in the greatest increase in ITP. MR caused a fall in SVLV and a rise in LV filling pressure that were not altered by IPPV. Compared with IPPV or apnea, both asynch and synch HFJV increased SVLV and reduced LV filling pressures (P less than 0.05). Systolic synch HFJV induced a greater increase in SVLV (32%) than diastolic synch HFJV (26%) despite similar ventilatory settings. Our data suggest that when LV contractility is normal but MR impairs forward flow, cardiac cycle-specific increases in ITP will augment forward flow.     

Lung function and ventilation inhomogeneity in rat lungs after allergen challenge.

We studied the early response to ovalbumin challenge in sensitized Brown-Norway rats through its effect on N(2), He, and SF(6) phase III slopes of the single-breath washout and on indexes of lung function. Sensitized rats showed varying degrees of response in terms of pulmonary pressure (PL), with increases ranging between 125 and 225% of baseline. The sensitized rats presented decreased quasistatic compliance, forced vital capacity, and end-expiratory flow, with all three lung function indexes showing a significant negative correlation with corresponding PL values. They also showed significant positive correlations of PL with the N(2), He, and SF(6) phase III slopes, reflecting diffusion-convection-dependent inhomogeneities generated by conformation changes throughout the entire rat lung. In addition, the rats showing the most marked PL increases (>150% baseline PL) also revealed a reversal of the SF(6)-He slope difference because of a more marked SF(6) than He slope increase. This latter finding suggests that the degree of structural heterogeneity during early response is even more marked in the most peripheral rat lung generations.     

Inhibition of mitochondrial autophagy protects donor lungs for lung transplantation against ischaemia‐reperfusion injury in rats via the mTOR pathway

Impaired mitochondrial function is a key factor attributing to lung ischaemia‐reperfusion (IR) injury, which contributes to major post‐transplant complications. Thus, the current study was performed to investigate the role of mitochondrial autophagy in lung I/R injury and the involvement of the mTOR pathway. We established rat models of orthotopic left lung transplantation to investigate the role of mitochondrial autophagy in I/R injury following lung transplantation. Next, we treated the donor lungs with 3‐MA and Rapamycin to evaluate mitochondrial autophagy, lung function and cell apoptosis with different time intervals of cold ischaemia preservation and reperfusion. In addition, mitochondrial autophagy, and cell proliferation and apoptosis of pulmonary microvascular endothelial cells (PMVECs) exposed to hypoxia‐reoxygenation (H/R) were monitored after 3‐MA administration or Rapamycin treatment. The cell apoptosis could be inhibited by mitochondrial autophagy at the beginning of lung ischaemia, but was rendered out of control when mitochondrial autophagy reached normal levels. After I/R of donor lung, the mitochondrial autophagy was increased until 6 hours after reperfusion and then gradually decreased. The elevation of mitochondrial autophagy was accompanied by promoted apoptosis, aggravated lung injury and deteriorated lung function. Moreover, the suppression of mitochondrial autophagy by 3‐MA inhibited cell apoptosis of donor lung to alleviate I/R‐induced lung injury as well as inhibited H/R‐induced PMVEC apoptosis, and enhanced its proliferation. Finally, mTOR pathway participated in I/R‐ and H/R‐mediated mitochondrial autophagy in regulation of cell apoptosis. Inhibition of I/R‐induced mitochondrial autophagy alleviated lung injury via the mTOR pathway, suggesting a potential therapeutic strategy for lung I/R injury.     

Aggravation of myocardial dysfunction by injurious mechanical ventilation in LPS-induced pneumonia in rats

Background

Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI) and may thereby contribute to fatal multiple organ failure. We tested the hypothesis that injurious MV of lipopolysaccharide (LPS) pre-injured lungs induces myocardial inflammation and further dysfunction ex vivo, through calcium (Ca²⁺)-dependent mechanism.

Materials and methods

N = 35 male anesthetized and paralyzed male Wistar rats were randomized to intratracheal instillation of 2 mg/kg LPS or nothing and subsequent MV with lung-protective settings (low tidal volume (V_t) of 6 mL/kg and 5 cmH₂O positive end-expiratory pressure (PEEP)) or injurious ventilation (high V_t of 19 mL/kg and 1 cmH₂O PEEP) for 4 hours. Myocardial function ex vivo was evaluated in a Langendorff setup and Ca²⁺ exposure. Key mediators were determined in lung and heart at the mRNA level.

Results

Instillation of LPS and high V_t MV impaired gas exchange and, particularly when combined, increased pulmonary wet/dry ratio; heat shock protein (HSP)70 mRNA expression also increased by the interaction between LPS and high V_t MV. For the heart, C-X-C motif ligand (CXCL)1 and Toll-like receptor (TLR)2 mRNA expression increased, and ventricular (LV) systolic pressure, LV developed pressure, LV +dP/dt_max and contractile responses to increasing Ca²⁺ exposure ex vivo decreased by LPS. High V_t ventilation aggravated the effects of LPS on myocardial inflammation and dysfunction but not on Ca²⁺ responses.

Conclusions

Injurious MV by high V_t aggravates the effects of intratracheal instillation of LPS on myocardial dysfunction, possibly through enhancing myocardial inflammation via pulmonary release of HSP70 stimulating cardiac TLR2, not involving Ca²⁺ handling and sensitivity.     

Biomarkers for oxidative stress in acute lung injury induced in rabbits submitted to different strategies of mechanical ventilation

Oxidative damage has been said to play an important role in pulmonary injury, which is associated with the development and progression of acute respiratory distress syndrome (ARDS). We aimed to identify biomarkers to determine the oxidative stress in an animal model of acute lung injury (ALI) using two different strategies of mechanical ventilation. Rabbits were ventilated using either conventional mechanical ventilation (CMV) or high-frequency oscillatory ventilation (HFOV). Lung injury was induced by tracheal saline infusion (30 ml/kg, 38°C). In addition, five healthy rabbits were studied for oxidative stress. Isolated lymphocytes from peripheral blood and lung tissue samples were analyzed by alkaline single cell gel electrophoresis (comet assay) to determine DNA damage. Total antioxidant performance (TAP) assay was applied to measure overall antioxidant performance in plasma and lung tissue. HFOV rabbits had similar results to healthy animals, showing significantly higher antioxidant performance and lower DNA damage compared with CMV in lung tissue and plasma. Total antioxidant performance showed a significant positive correlation (r = 0.58; P = 0.0006) in plasma and lung tissue. In addition, comet assay presented a significant positive correlation (r = 0.66; P = 0.007) between cells recovered from target tissue and peripheral blood. Moreover, antioxidant performance was significantly and negatively correlated with DNA damage (r = -0.50; P = 0.002) in lung tissue. This study indicates that both TAP and comet assay identify increased oxidative stress in CMV rabbits compared with HFOV. Antioxidant performance analyzed by TAP and oxidative DNA damage by comet assay, both in plasma, reflects oxidative stress in the target tissue, which warrants further studies in humans.     

Pulmonary pressure-flow relationships in the fetal lamb during in utero ventilation

Pressure-flow relationships in the ventilated lung have not been previously determined in undelivered fetal sheep. Therefore we studied 11 late-gestation chronically prepared fetal sheep during positive-pressure ventilation with different gas mixtures to determine the roles of mechanical distension and blood gas tensions on pressure-flow relationships in the lung. Ventilation with 3% O2-7% CO2 produced a substantial fall in pulmonary vascular resistance even though arterial blood gases were not changed. Increases in pulmonary arterial PO2 during ventilation were associated with falls in pulmonary vascular resistance beyond that measured during mechanical distension. Decreases in pulmonary arterial PCO2 and associated increases in pH were also associated with falls in pulmonary vascular resistance. Pulmonary blood flow ceased at a pulmonary arterial pressure that exceeded left atrial pressure, indicating that left atrial pressure does not represent the true downstream component of driving pressure through the pulmonary vascular bed. The slope of the driving pressure-flow relationship in the normal mature fetal lamb was therefore different from the ratio of pulmonary arterial pressure to pulmonary arterial flow. We conclude that mechanical ventilation, increased PO2 and decreased PCO2, and/or increased pH has an important influence on the fall in pulmonary vascular resistance elicited by positive pressure in utero ventilation of the fetal lamb and that the downstream driving pressure for pulmonary blood flow exceeds left atrial pressure.     

Effects of continuous positive-pressure ventilation in experimental pulmonary edema.

We compared the effects of continuous positive-pressure ventilation (CPPV), using 10 cmH2O positive end-expiratory pressure (PEEP), with intermittent positive-pressure ventilation (IPPV), on pulmonary extravascular water volume (PEWV) and lung function in dogs with pulmonary edema caused by elevated left atrial pressure and decreased colloid osmotic pressure. The PEWV was measured by gravimetric and double-isotope indicator dilution methods. Animals with high (22-33 mmHg), moderately elevated (12-20 mmHg), and normal (3-11 mmHg) left atrial pressures (Pla) were studied. The PEWV by both methods was significantly increased in the high and moderate Pla groups, the former greater than the latter (P less than 0.05). There was no difference in the PEWV between animals receiving CPPV and those receiving IPPV in both the high and moderately elevated Pla groups. However, in animals with high Pla, the Pao2 was significantly better maintained and the inflation pressure required to deliver a tidal volume of 12 ml/kg was significantly less with the use of CPPV than with IPPV. We conclude that in pulmonary edema associated with high Pla, PEEP does not reduce PEWV but does improve pulmonary function.     

Ozone and high ventilation effects on pulmonary function and endurance performance

Ozone (O3) toxicity is potentiated by exercise-induced expired minute ventilation (VE) for a given exposure, which may also impair endurance performance. Ten healthy, well-trained long-distance runners were exposed on six occasions for 1 h to O3 concentrations of 0, 0.20, or 0.35 parts per million (ppm), during exercise simulating either training or competition, with mean VE = 77.5 1 X min -1. Standard pulmonary function tests, subjective symptoms, and periodic observations of exercise ventilatory response and respiratory metabolism were obtained. Statistical analyses revealed no significant exercise mode effect for pulmonary function, but a significant O3 effect for forced vital capacity and expiratory volume at 1 s was observed. Altered exercise ventilatory pattern response was noted, but there was no significant O3 effect on exercise oxygen uptake, heart rate, VE, or alveolar ventilation. Subjective symptoms increased with O3 concentration. Statistically significant pulmonary function impairment observed at 0.20 ppm O3 suggests that endurance athletes may be more susceptible to the effects of a given O3 concentration than normal young adult males as a result of sustained high mean VE incurred during training and competition. Three subjects were unable to complete both the training and competitive simulations at 0.35 ppm O3. Performance decrements appeared to be the result of physiologically induced respiratory discomfort rather than decrements in pulmonary gas exchange and/or oxygen transport and delivery.     

内质网应激在大鼠低氧高二氧化碳性肺动脉高压中的作用

目的：观察低氧高二氧化碳性肺动脉高压大鼠的肺血管重塑并探讨内质网应激（ERS）在肺动脉高压中的作用。方法：将40只SD大鼠随机分为四组：常氧对照组（N）、低氧高二氧化碳组（HH）、ERS通路抑制剂4-苯基丁酸（4-phenylbutyric acid）组（4-PBA）、ERS通路激动剂衣霉素（tunicamycin）组（TM）,n=10。测量各组大鼠的肺动脉平均压（mPAP）、颈动脉平均压以及右心室肥大指数,免疫荧光α-SMA标记法鉴定各组肺中小动脉平滑肌细胞,电镜观察肺组织及肺中小动脉形态学变化,原位末端标记法（TUNEL）检测各组肺动脉平滑肌细胞的凋亡指数,采用RT-PCR和Western blot分别检测各组大鼠葡萄糖调节蛋白78（GRP78）、C/EBP同源蛋白（CHOP）、c-Jun氨基末端激酶（JNK）、天冬氨酸特异性半胱氨酸蛋白酶-12（caspase-12）mRNA及蛋白质表达。结果：①与N组相比,HH组、4-PBA组、TM组mPAP、右心室游离壁重量/左心室加心室间隔重量[RV/（LV+S）]、肺动脉管壁面积/管总面积（WA/TA）比值增加（P<0.0 1）,肺动脉管腔面积/管总面积（LA/TA）比值减小（P<0.01）,细胞凋亡指数降低（P <0.05或P<0.01）。ERS相关蛋白质及mRNA的表达量升高,各差异均有统计学意义。②与HH组相比,4-PB A组mPAP和[RV/（LV+S）]、WA/TA值减小（P<0.01）,LA/TA值和细胞凋亡指数上升（P<0.05或P<0.01）,ERS相关蛋白质和mRNA的表达量均下调（P<0.05或P<0.01）;③与HH组相比,TM组mPAP、[RV/（LV+S）]、WA/TA值升高（P<0.05或P<0.01）;肺动脉中膜层增厚,LA/TA值和细胞凋亡指数降低（P<0.01）。ERS相关蛋白质及mRNA的表达量均升高,除GRP78蛋白质表达量无明显变化外,其余各差异均有统计学意义。结论：低氧高二氧化碳诱导的肺动脉高压大鼠肺血管重塑可能与肺动脉平滑肌细胞增殖过度及凋亡过少有关;ERS相关因子（JNK、caspase-12和CHOP）参与低氧高二氧化碳性肺动脉高压的调控。