Buccal oscillation and lung ventilation in a semi-aquatic turtle, Platysternon megacephalum

Movements of the hyobranchial apparatus in reptiles and amphibians contribute to many behaviors including feeding, lung ventilation, buccopharyngeal respiration, thermoregulation, olfaction, defense and display. In a semi-aquatic turtle, Platysternon megacephalum, x-ray video and airflow measurements from blowhole pneumotachography show no evidence that above water hyobranchial movements contribute to lung inflation, as in the buccal or gular pump of amphibians and some lizards. Instead, hyobranchial movements produce symmetrical oscillations of air into and out of the buccal cavity. The mean tidal volume of these buccal oscillations is 7.8 times smaller than the mean tidal volume of lung ventilation (combined mean for four individuals). Airflow associated with buccal oscillation occurs in the sequence of inhalation followed by exhalation, distinguishing it from lung ventilation which occurs as exhalation followed by inhalation. No fixed temporal relationship between buccal oscillation and lung ventilation was observed. Periods of ventilation often occur without buccal oscillation and buccal oscillation sometimes occurs without lung ventilation. When the two behaviors occur together, the onset of lung ventilation often interrupts buccal oscillation. The initiation of lung ventilation was found to occur in all phases of the buccal oscillation cycle, suggesting that the neural control mechanisms of the two behaviors are not coupled. The pattern of occurrence of both buccal oscillation and lung ventilation was found to vary over time with no obvious effect of activity levels.     

Partial liquid ventilation improves gas exchange and increases EELV in acute lung injury

Gas exchange is improved during partial liquidventilation with perfluorocarbon in animal models of acute lung injury.The specific mechanisms are unproved. We measured end-expiratory lung volume (EELV) by null-point body plethysmography in anesthetized sheep.Measurements of gas exchange and EELV were made before and after acutelung injury was induced with intravenous oleic acid to decrease EELVand worsen gas exchange. Measurements of gas exchange and EELV wereagain performed after partial liquid ventilation with 30 ml/kg ofperfluorocarbon and compared with gas-ventilated controls. Oxygenationwas significantly improved during partial liquid ventilation, and EELV(composite of gas and liquid) was significantly increased, comparedwith preliquid ventilation values and gas-ventilated controls. Weconclude that partial liquid ventilation may directly recruitconsolidated alveoli in the lung-injured sheep and that this may be onemechanism whereby gas exchange is improved.

     

A perfluorochemical loss/restoration (L/R) system for tidal liquid ventilation

Tidal liquid ventilation is the transport of dissolved respiratory gases via volume exchange of perfluorochemical (PFC) liquid to and from the PFC-filled lung. All gas-liquid surface tension is eliminated, increasing compliance and providing lung protection due to lower inflation pressures. Tidal liquid ventilation is achieved by cycling fluid from a reservoir to and from the lung by a ventilator. Current approaches are microprocessor-based with feedback control. During inspiration, warmed oxygenated PFC liquid is pumped from a fluid reservoir/gas exchanger into the lung. PFC fluid is conserved by condensing (60-80% efficiency) vapor in the expired gas. A feedback-control system was developed to automatically replace PFC lost due to condenser inefficiency. This loss/restoration (L/R) system consists of a PFC-vapor thermal detector (+/- 2.5%), pneumatics, amplifiers, a gas flow detector (+/- 1%), a PFC pump (+/- 5%), and a controller. Gravimetric studies of perflubron loss from a flask due to evaporation were compared with experimental L/R results and found to be within +/- 1.4%. In addition, when L/R studies were conducted with a previously reported liquid ventilation system over a four-hour period, the L/R system maintained system perflubron volume to within +/- 1% of prime volume and 11.5% of replacement volume, and the difference between experimental PFC loss and that of the L/R system was 1.8 mL/hr. These studies suggest that the PFC L/R system may have significant economic (appropriate dosing for PFC loss) as well as physiologic (maintenance of PFC inventory in the lungs and liquid ventilator) impact on liquid ventilation procedures.     

乌司他丁对机械通气致肺损伤大鼠肺组织CC16表达的影响

目的通过观察乌司他丁（UTI）对大潮气量机械通气大鼠肺组织Clara细胞分泌蛋白（CC16）表达的影响,探讨CC16在机械通气所致肺损伤（VILI）发病中作用以及UTI对VILI的干预作用。方法 24只雄性Wistar大鼠随机分为对照组、大潮气量组和UTI干预组,观察其肺组织病理学改变,测定肺组织中丙二醛（MDA）和BALF中总蛋白（TP）含量,采用逆转录聚合酶链反应（RT-PCR）法检测肺组织CC16 mRNA的表达,采用免疫组织化学染色法检测肺组织中CC16蛋白表达及Clara细胞计数。结果与对照组比较,大潮气量肺组织MDA的含量及BALF总蛋白含量明显升高（P〈0.01）,而肺细支气管上皮细胞CC16mRNA及其蛋白表达水平明显降低（P〈0.01）;与大潮气量组比较,UTI干预组大鼠肺组织中MDA的含量及BALF总蛋白含量明显降低（P〈0.01）,而肺细支气管上皮细胞CC16mRNA及其蛋白表达水平明显升高（P〈0.01）。结论大潮气量机械通气导致肺组织CC16 mRNA及其蛋白表达水平降低在VILI发病中起重要作用,乌司他丁不但能促进Clara细胞分泌CC16而抑制肺组织炎症反应,还能抑制脂质过氧化物的产生,对VILI有一定保护作用。     

Anti-inflammatory effects of clarithromycin in ventilator-induced lung injury

Background

Mechanical ventilation can promote lung injury by triggering a pro-inflammatory response. Macrolides may exert some immunomodulatory effects and have shown significant benefits over other antibiotics in ventilated patients. We hypothesized that macrolides could decrease ventilator-induced lung injury.

Methods

Adult mice were treated with vehicle, clarithromycin or levofloxacin, and randomized to receive mechanical ventilation with low (12 cmH₂O, PEEP 2 cmH₂O) or high (20 cmH₂O, ZEEP) inspiratory pressures for 150 minutes. Histological lung injury, neutrophil infiltration, inflammatory mediators (NFκB activation, Cxcl2, IL-10) and levels of adhesion molecules (E-selectin, ICAM) and proteases (MMP-9 and MMP-2) were analyzed.

Results

There were no differences among groups after low-pressure ventilation. Clarithromycin significantly decreased lung injury score and neutrophil count, compared to vehicle or levofloxacin, after high-pressure ventilation. Cxcl2 expression and MMP-2 and MMP-9 levels increased and IL-10 decreased after injurious ventilation, with no significant differences among treatment groups. Both clarithromycin and levofloxacin dampened the increase in NFκB activation observed in non-treated animals submitted to injurious ventilation. E-selectin levels increased after high pressure ventilation in vehicle- and levofloxacin-treated mice, but not in those receiving clarithromycin.

Conclusions

Clarithromycin ameliorates ventilator-induced lung injury and decreases neutrophil recruitment into the alveolar spaces. This could explain the advantages of macrolides in patients with acute lung injury and mechanical ventilation.     

High tidal volume ventilation induces NOS2 and impairs cAMP- dependent air space fluid clearance

Tidal volume reduction during mechanical ventilation reduces mortality in patients with acute lung injury and the acute respiratory distress syndrome. To determine the mechanisms underlying the protective effect of low tidal volume ventilation, we studied the time course and reversibility of ventilator-induced changes in permeability and distal air space edema fluid clearance in a rat model of ventilator-induced lung injury. Anesthetized rats were ventilated with a high tidal volume (30 ml/kg) or with a high tidal volume followed by ventilation with a low tidal volume of 6 ml/kg. Endothelial and epithelial protein permeability were significantly increased after high tidal volume ventilation but returned to baseline levels when tidal volume was reduced. The basal distal air space fluid clearance (AFC) rate decreased by 43% (P < 0.05) after 1 h of high tidal volume but returned to the preventilation rate 2 h after tidal volume was reduced. Not all of the effects of high tidal volume ventilation were reversible. The cAMP-dependent AFC rate after 1 h of 30 ml/kg ventilation was significantly reduced and was not restored when tidal volume was reduced. High tidal volume ventilation also increased lung inducible nitric oxide synthase (NOS2) expression and air space total nitrite at 3 h. Inhibition of NOS2 activity preserved cAMP-dependent AFC. Because air space edema fluid inactivates surfactant and reduces ventilated lung volume, the reduction of cAMP-dependent AFC by reactive nitrogen species may be an important mechanism of clinical ventilator-associated lung injury.     

An in vitro investigation of the inflammatory response to the strain amplitudes which occur during high frequency oscillation ventilation and conventional mechanical ventilation

Children randomised in the neonatal period to high frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CMV) in the United Kingdom Oscillation study (UKOS) had superior lung function at 11 to 14 years of age. During HFOV, much smaller tidal volumes, but a higher mean airway distending pressure is delivered, hence, a possible explanation for a volume dependent effect on long term lung function could be an increase in inflammation in response to higher tidal volumes and strains. We tested that hypothesis by assessing interleukin-6 (IL-6) and -8 (IL-8) release from A549 alveolar analogue cells following biaxial mechanical strain applied at 0.5 Hz occurring during conditions mimicking strain during CMV (5–20% strain) and conditions mimicking strain during HFOV (17.5% ± 2.5% strain) for up to 4 h. Cyclic strain of 5–20%, occurring during CMV, increased levels of both IL-6 and IL-8 compared to unstrained controls, while 17.5% ± 2.5% strain, occurring during HFOV, was associated with significantly lower levels of IL-6 (46.31 ± 2.66 versus 56.79 ± 3.73 pg/mL) and IL-8 (1340.2 ± 74.9 versus 2522 ± 248 pg/mL) secretion compared to conditions occurring during CMV at four hours. These results may provide a possible explanation for the superior lung function in 11–14-year-old children who had been supported in the neonatal period by HFOV.     

不同潮气量机械通气对大鼠肺组织HMGB1表达的影响

目的观察不同潮气量机械通气大鼠肺组织高迁移率族蛋白1（HMGB1） mRNA及其蛋白的表达水平,探讨HMGB1在呼吸机相关性肺损伤（VILI）发病中的作用。方法24只雄性Wister大鼠随机分为对照组、小潮气量组和大潮气量组,分别采用原位分子杂交技术和免疫组织化学染色法检测肺组织HMGB1 mRNA及其蛋白的表达水平。结果与对照组和小潮气量组比较,大潮气量组大鼠肺组织HMGB1 mRNA及其蛋白表达水平明显升高（均P〈0.01）,小潮气量组与对照组各项指标比较差异无统计学意义（P〉0.05）。结论大潮气量机械通气可诱导肺组织HMGB1 mRNA及其蛋白高表达;HMGB1分泌增多导致肺组织炎症反应扩大,可能是呼吸机相关性肺损伤（VILI）发生的重要因素之一。     

Neural organization of the ventilatory activity in the frog,Rana catesbeiana. I

In order to elucidate the neural basis for lung ventilation in the frog, we have investigated the efferent neural activity to oropharyngeal muscles in the decerebrate, paralyzed, unanesthetized bullfrog, Rana catesbeiana. Efferent motor output was recorded from the mandibular branch of the trigeminal (Vmd), the laryngeal branch of the vagus (Xl), and the main and sternohyoid branches of the hypoglossal nerve (Hm and Hsh, respectively). Two types of rhythmic bursting outputs were observed: (1) a high-frequency, low-amplitude, reciprocal oscillation between Vmd, a buccal levator nerve, and Hsh, a buccal depressor nerve; and (2) a low-frequency, high amplitude, synchronous bursting of Vmd, Hm, Hsh, and Xl. The first type is inferred to represent fictive oropharyngeal ventilation. The second type of burst was divided into four intervals: (a)augmenting acitivity of Hsh; (b) activation of Xl with continued activation of Hsh; (c) activation of Vmd and Hm (a buccal levator nerve), continued activation of Xl, and termination of Hsh activity; and (d) waning activity in Vmd and Hm associated with a prominent second wave in Xl. This coordinated activity is inferred to represent fictive pulmonary ventilation because the neurograms in these four intervals correspond closely EMGs and neurograms recorded in the intact frog during the four phases of pulmonary ventilation, namely, buccal depression, pulmonary expiration, pulmonary inspiration, and glottal closure. Hypercapnia, vagotomy, and cutaneus pinching enhanced the high-amplitude, low-frequency rhythm, but not the low-amplitude, high-frequency oscillation. Lung inflation generally inhibited the former and not the latter, but in some cases lung inflation stimulated pulmonary ventilation. We conclude that oropharyngeal and pulmonary ventilation of the frog are produced by one or, possibly, two intrinsically active generators. 1994 John Wiley & Sons, Inc.     

肺保护性通气策略对老年患者腹腔镜结直肠癌手术的氧合功能及血浆炎症介质水平的影响

目的:探讨肺保护通气策略对老年患者行腹腔镜结直肠癌根治术肺部氧合功能及血清炎症介质水平的影响。方法:选择50例行择期腹腔镜结直肠癌根治术老年患者,ASA分级(美国麻醉医师协会体格情况评估分级)Ⅰ~Ⅱ级、年龄≥60岁,采用随机数字表法将其分为两组:VCV组和PCV组。在围术期行全麻机械通气中,VCV组采用容量通气模式,潮气量为8 m L/kg,PCV组采用肺保护通气,潮气量为6 m L/kg及5 cm H2O呼气末正压通气(positive end expiration pressure,PEEP),同时气腹后每30 min给予一次手法肺复张。记录患者气腹前5 min(T0)、气腹后5 min(T1)、气腹后30 min(T2)、气腹后60 min(T3)、气腹后120 min(T4)、气腹停止10 min后(T5)的呼吸力学指标、血流动力学指标于T0、T4、离开苏醒室时抽取血气,计算氧合指数(OI)值,于术前一天、T4、术后一天抽取静脉血,检测血浆CRP、IL-6的值。结果:与VCV组比较,PCV组在T4、T5时刻气道压降低,T4、T5肺顺应性增高(P<0.05)。两组患者血流动力学指标无明显差异。PCV组在离开苏醒室时氧合指数较高(P<0.05);PCV组在术后一天时刻IL-6和CRP值较低(P<0.05)。结论:肺保护性通气策略可以提高老年患者肺部氧合功能,减少炎症介质释放,减轻肺损伤。     

The effect of conductive ventilation heterogeneity on diffusing capacity measurement.

It has long been assumed that the ventilation heterogeneity associated with lung disease could, in itself, affect the measurement of carbon monoxide transfer factor. The aim of this study was to investigate the potential estimation errors of carbon monoxide diffusing capacity (Dl(CO)) measurement that are specifically due to conductive ventilation heterogeneity, i.e., due to a combination of ventilation heterogeneity and flow asynchrony between lung units larger than acini. We induced conductive airway ventilation heterogeneity in 35 never-smoker normal subjects by histamine provocation and related the resulting changes in conductive ventilation heterogeneity (derived from the multiple-breath washout test) to corresponding changes in diffusing capacity, alveolar volume, and inspired vital capacity (derived from the single-breath Dl(CO) method). Average conductive ventilation heterogeneity doubled (P < 0.001), whereas Dl(CO) decreased by 6% (P < 0.001), with no correlation between individual data (P > 0.1). Average inspired vital capacity and alveolar volume both decreased significantly by, respectively, 6 and 3%, and the individual changes in alveolar volume and in conductive ventilation heterogeneity were correlated (r = -0.46; P = 0.006). These findings can be brought in agreement with recent modeling work, where specific ventilation heterogeneity resulting from different distributions of either inspired volume or end-expiratory lung volume have been shown to affect Dl(CO) estimation errors in opposite ways. Even in the presence of flow asynchrony, these errors appear to largely cancel out in our experimental situation of histamine-induced conductive ventilation heterogeneity. Finally, we also predicted which alternative combination of specific ventilation heterogeneity and flow asynchrony could affect Dl(CO) estimate in a more substantial fashion in diseased lungs, irrespective of any diffusion-dependent effects.     

Effect of ventilation rate on instilled surfactant distribution in the pulmonary airways of rats.

Liquid can be instilled into the pulmonary airways during medical procedures such as surfactant replacement therapy, partial liquid ventilation, and pulmonary drug delivery. For all cases, understanding the dynamics of liquid distribution in the lung will increase the efficacy of treatment. A recently developed imaging technique for the study of real-time liquid transport dynamics in the pulmonary airways was used to investigate the effect of respiratory rate on the distribution of an instilled liquid, surfactant, in a rat lung. Twelve excised rat lungs were suspended vertically, and a single bolus (0.05 ml) of exogenous surfactant (Survanta, Ross Laboratories, Columbus, OH) mixed with radiopaque tracer was instilled as a plug into the trachea. The lungs were ventilated with a 4-ml tidal volume for 20 breaths at one of two respiratory rates: 20 or 60 breaths/min. The motion of radiodense surfactant was imaged at 30 frames/s with a microfocal X-ray source and an image intensifier. Dynamics of surfactant distribution were quantified for each image by use of distribution statistics and a homogeneity index. We found that the liquid distribution depended on the time to liquid plug rupture, which depends on ventilation rate. At 20 breaths/min, liquid was localized in the gravity-dependent region of the lung. At 60 breaths/min, the liquid coated the airways, providing a more vertically uniform liquid distribution.     

Extended high-frequency partial liquid ventilation in lung injury: gas exchange, injury quantification, and vapor loss.

High-frequency oscillatory ventilation with perflubron (PFB) reportedly improves pulmonary mechanics and gas exchange and attenuates lung injury. We explored PFB evaporative loss kinetics, intrapulmonary PFB distribution, and dosing strategies during 15 h of high-frequency oscillation (HFO)-partial liquid ventilation (PLV). After saline lavage lung injury, 15 swine were rescued with high-frequency oscillatory ventilation (n = 5), or in addition received 10 ml/kg PFB delivered to dependent lung [n = 5, PLV-compartmented (PLV(C))] or 10 ml/kg distributed uniformly within the lung [n = 5, PLV(U)]. In the PLV(C) group, PFB vapor loss was replaced. ANOVA revealed an unsustained improvement in oxygenation index in the PLV(U) group (P = 0.04); the reduction in oxygenation index correlated with PFB losses. Although tissue myeloperoxidase activity was reduced globally by HFO-PLV (P < 0.01) and regional lung injury scores (lung injury scores) in dependent lung were improved (P = 0.05), global lung injury scores were improved by HFO-PLV (P < 0.05) only in atelectasis, edema, and alveolar distension but not in cumulative score. In our model, markers of inflammation and lung injury were attenuated by HFO-PLV, and it appears that uniform intrapulmonary PFB distribution optimized gas exchange during HFO-PLV; additionally, monitoring PFB evaporative loss appears necessary to stabilize intrapulmonary PFB volume.     

Pulmonary diffusing capacity in the presence of ventilation inhomogeneity

A model has been developed to quantify the effectiveness of alveolar-capillary transport in the presence of ventilation inhomogeneity. The exhalation dynamics of carbon monoxide (CO), argon (Ar), and lung volume from a single-breath experiment are analyzed simultaneously. A membrane transport coefficient (MTCO) that does not vary with lung volume is evaluated by a two-stage optimization procedure and related to diffusing capacity. Also, the model allows for a decrease in membrane transport rate associated with reduced lung volume. The model is tested by simulation studies and experiments with human subjects having normal or diseased (mainly obstructed) lungs. The MTCO provides a clear distinction between normal and obstructed lungs with respect to alveolar-capillary transport, whereas the semilog slope of the Ar alveolar plateau characterizes the ventilation inhomogeneity. Only when the diffusing capacity is corrected by the Ar slope, DLCO(Ar), do the breathing maneuvers performed from different preinflation volumes (residual volume or functional residual capacity) yield the same results for lungs with ventilation inhomogeneity. The uncorrected DLCO overestimates the effectiveness of alveolar-capillary transport in the presence of ventilation inhomogeneity.     

根际通气状况对盐胁迫下棉花幼苗生长的影响

以溶液培养的棉花(Gossypium hirsutum)幼苗为材料,测定了不同盐胁迫程度和不同通气状况下棉花幼苗株高、根系体积、根系和茎叶生物量以及灰分含量的变化,以探索根际通气状况对盐胁迫下棉花生长的影响。结果表明,盐胁迫抑制棉花植株生长,表现为植株变矮、叶面积减小和干物质积累下降;根际环境通气不良也会导致棉花幼苗生长受抑制、干物质积累下降和矿质元素吸收减少等。进一步比较盐胁迫和根际通气状况及两者组合作用对棉苗生长的影响,发现盐胁迫对株高和总生物量的影响较大,而根际通气状况对根系体积、根系生物量、根冠比和矿质元素吸收的影响较大。总体表现为:盐胁迫对茎叶生长的不利影响较大,而根际通气状况对根系生长的不利影响较大。同时,在根际环境通气良好的条件下,不同程度盐胁迫导致的棉花幼苗株高、根系体积、叶面积、根系生物量和总生物量的变化程度远小于根际环境通气不良条件下的变化程度。实验结果表明,根际环境通气良好可以减弱盐胁迫对棉花生长发育的抑制作用,而根际环境通气不良则会加重盐胁迫的不利影响。     

Comparison of gas and liquid ventilation: clinical, physiological, and histological correlates.

To differentiate the effects of gas and liquid ventilation on cardiopulmonary function during early development, we compared the clinical, physiological, and histological profiles of gas- and liquid-ventilated preterm lambs (n = 16; 108-116 days gestation). Immediately after cesarean section delivery, ventilation commenced using gas delivered by a volume ventilator (n = 9) or liquid perfluorochemical (n = 7) delivered by a mechanically assisted liquid ventilation system. Pulmonary gas exchange, acid-base status, vital signs, and respiratory compliance were assessed during the 3-h protocol; sections of the lungs were obtained for histological analyses when the animals were killed. Six of nine gas-ventilated lambs expired from respiratory failure before 3 h, with the remaining animals experiencing severe respiratory insufficiency, pneumothoraces, and cardiovascular deterioration. Six of seven liquid-ventilated lambs survived with good gas exchange and cardiovascular stability and without fluorothorax; one experienced ventricular fibrillation before 1 h and expired despite pulmonary stability. Respiratory compliance was significantly greater in the liquid- than in the gas-ventilated lambs. Histological analyses of gas-ventilated lungs demonstrated nonhomogeneous lung expansion, with thick-walled gas exchange spaces containing proteinaceous exudate, hemorrhage, and hyaline membranes. In contrast, liquid-ventilated lungs appeared clear, with thin-walled and uniformly expanded gas exchange spaces that were free of hyaline membranes and luminal debris. Morphometric analyses demonstrated that surface area and gas exchange index were greater in the liquid- than in the gas-ventilated lambs. These results indicate that elimination of surface active forces by liquid ventilation during early development provides more effective gas exchange with less barotrauma compared with gas ventilation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sustained Inflation at Birth Did Not Alter Lung Injury from Mechanical Ventilation in Surfactant-Treated Fetal Lambs

Background

Sustained inflations (SI) are used with the initiation of ventilation at birth to rapidly recruit functional residual capacity and may decrease lung injury and the need for mechanical ventilation in preterm infants. However, a 20 second SI in surfactant-deficient preterm lambs caused an acute phase injury response without decreasing lung injury from subsequent mechanical ventilation.

Hypothesis

A 20 second SI at birth will decrease lung injury from mechanical ventilation in surfactant-treated preterm fetal lambs.

Methods

The head and chest of fetal sheep at 126±1 day GA were exteriorized, with tracheostomy and removal of fetal lung fluid prior to treatment with surfactant (300 mg in 15 ml saline). Fetal lambs were randomized to one of four 15 minute interventions: 1) PEEP 8 cmH₂O; 2) 20 sec SI at 40 cmH₂O, then PEEP 8 cmH₂O; 3) mechanical ventilation with 7 ml/kg tidal volume; or 4) 20 sec SI then mechanical ventilation at 7 ml/kg. Fetal lambs remained on placental support for the intervention and for 30 min after the intervention.

Results

SI recruited a mean volume of 6.8±0.8 mL/kg. SI did not alter respiratory physiology during mechanical ventilation. Heat shock protein (HSP) 70, HSP60, and total protein in lung fluid similarly increased in both ventilation groups. Modest pro-inflammatory cytokine and acute phase responses, with or without SI, were similar with ventilation. SI alone did not increase markers of injury.

Conclusion

In surfactant treated fetal lambs, a 20 sec SI did not alter ventilation physiology or markers of lung injury from mechanical ventilation.     

Activation of calpains mediates early lung neutrophilic inflammation in ventilator-induced lung injury

Lung inflammatory responses in the absence of infection are considered to be one of primary mechanisms of ventilator-induced lung injury. Here, we determined the role of calpain in the pathogenesis of lung inflammation attributable to mechanical ventilation. Male C57BL/6J mice were subjected to high (28 ml/kg) tidal volume ventilation for 2 h in the absence and presence of calpain inhibitor I (10 mg/kg). To address the isoform-specific functions of calpain 1 and calpain 2 during mechanical ventilation, we utilized a liposome-based delivery system to introduce small interfering RNAs targeting each isoform in pulmonary vasculature in vivo. Mechanical ventilation with high tidal volume induced rapid (within minutes) and persistent calpain activation and lung inflammation as evidenced by neutrophil recruitment, production of TNF-α and IL-6, pulmonary vascular hyperpermeability, and lung edema formation. Pharmaceutical calpain inhibition significantly attenuated these inflammatory responses caused by lung hyperinflation. Depletion of calpain 1 or calpain 2 had a protective effect against ventilator-induced lung inflammatory responses. Inhibition of calpain activity by means of siRNA silencing or pharmacological inhibition also reduced endothelial nitric oxide (NO) synthase (NOS-3)-mediated NO production and subsequent ICAM-1 phosphorylation following high tidal volume ventilation. These results suggest that calpain activation mediates early lung inflammation during ventilator-induced lung injury via NOS-3/NO-dependent ICAM-1 phosphorylation and neutrophil recruitment. Inhibition of calpain activation may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury.     

The role of ventilation frequency in airway reopening

Inhomogeneously compliant lungs need special treatment during ventilation as they are often affected by respiratory insufficiency which is frequently caused by a regional collapse of the airways. To treat respiratory insufficiency atelectatic areas have to be recruited. Beside conventional mechanical ventilation, high-frequency oscillatory ventilation (HFOV) is an efficient method for airway reopening. Using a transparent in-vitro model of the human lung the influence of varying frequencies on the reopening behavior of atelectatic regions is investigated for volume controlled ventilation. The experiments show that higher ventilation frequencies at constant tidal volume enhance the probability of successful reopening of collapsed lung regions and thus, lead to a more homogeneous distribution of air within the lung. This effect can be attributed (i) to larger flow velocities and thus larger pressure losses in the free pathways as the ventilation frequency increases and (ii) to higher inertia effects. In consequence, the static pressure in the branches above the atelectatic regions increases until it reaches a level at which recruitment is achieved.     

Regional ventilation during spontaneous breathing and mechanical ventilation in dogs

We evaluated the effects of the different patterns of chest wall deformation that occur with different body positions and modes of breathing on regional lung deformation and ventilation. Using the parenchymal marker technique, we determined regional lung behavior during mechanical ventilation and spontaneous breathing in five anesthetized recumbent dogs. Regional lung behavior was related to the patterns of diaphragm motion estimated from X-ray projection images obtained at functional residual capacity (FRC) and end inspiration. Our results indicate that 1) in the prone and supine positions, FRC was larger during mechanical ventilation than during spontaneous breathing; 2) there were significant differences in the patterns of diaphragm motion and regional ventilation between mechanical ventilation and spontaneous breathing in both body positions; 3) in the supine position only, there was a vertical gradient in lung volume at FRC; 4) in both positions and for both modes of breathing, regional ventilation was nonlinearly related to changes in lobar and overall lung volumes; and 5) different patterns of diaphragm motion caused different sliding motions and differential rotations of upper and lower lobes. Our results are inconsistent with the classic model of regional ventilation, and we conclude that the distribution of ventilation is determined by a complex interaction of lung and chest wall shapes and by the motion of the lobes relative to each other, all of which help to minimize distortion of the lung parenchyma.