Surfactant treatment for ventilation-induced lung injury in rats: effects on lung compliance and cytokines

The objective of this study was to determine if exogenous surfactant therapy could prevent the harmful effects of ventilation at high tidal volumes without positive end-expiratory pressure (PEEP). Rats were randomized to either a nontreated control group (8 mL/kg 4 cm H2O PEEP), a nontreated injuriously ventilated group (20 mL/kg 0 cm H2O PEEP) or a treatment group of either 50 mg/kg, 50 mg/kg + 5% surfactant-associated protein A, 100 mg/kg exogenous surfactant followed by injurious ventilation. Isolated lungs from animals in all 5 groups were ventilated in a humidified box at 37 degrees C for 2 hours. Pressure-volume curves and light microscopy showed that surfactant treatment reduced the ventilation-induced lung injury (VILI). Inflammatory cytokines (tumor necrosis factor-alpha [TNFalpha], interleukin [IL]-1beta, and IL-6) in the lavage were significantly higher in injuriously ventilated lungs compared to the control group. However the 3 treatment groups had cytokine concentrations that were similar to the injuriously ventilated group. We conclude that surfactant treatment is beneficial in preventing VILI; however, it does not prevent the release of inrflammatory cytokines during mechanical ventilation.     

Phosphoinositide 3-OH kinase inhibition prevents ventilation-induced lung cell activation

In acute respiratory distress syndrome patients, protective ventilation strategies reduce mortality and proinflammatory mediator levels. It has been suggested that some of the side effects of mechanical ventilation are caused by the excessive release of mediators capable of causing pulmonary inflammation and tissue destruction (biotrauma). Selective inhibition of this process might be used to minimize the side effects of artificial mechanical ventilation. This study was designed to identify the cell types and specific signaling mechanisms that are activated by ventilation with increased pressure/volume (overventilation). In isolated perfused mouse lungs, overventilation caused nuclear translocation of nuclear factor-kappaB (NF-kappaB) and enhanced expression of interleukin-6 mRNA in alveolar macrophages and alveolar epithelial type II cells. The phosphoinositide 3-OH kinase inhibitor Ly294002 prevented nuclear translocation of NF-kappaB and the subsequent release of interleukin-6 and macrophage inflammatory protein-2alpha in overventilated but not in endotoxic lungs. Similar results were obtained in rats in vivo, where Ly294002 prevented NF-kappaB activation by overventilation but not by endotoxin. These findings show that alveolar macrophages and alveolar epithelial type II cells contribute to the ventilation-induced release of proinflammatory mediators and that selective inhibition of this process is possible without inhibiting the activation of NF-kappaB by endotoxin.     

Apoptosis and proliferation in lungs of ventilated and oxygen-treated preterm infants.

Apoptosis and proliferation and the effect of exogenous surfactant on these processes were investigated in the lungs of mechanically ventilated/oxygen-treated preterm infants with respiratory distress syndrome and stillborn foetuses. Apoptotic and proliferation indices were determined in lung tissue sections from 27 ventilated/oxygen-treated preterm infants and 29 stillborn foetuses. The effect of exogenous surfactant on apoptosis and proliferation was studied in 16 ventilated preterm infants; 11 untreated infants served as control. Apoptotic and proliferating cells were identified by double labelling combining terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end-labelling or Ki-67 with cell marker proteins. Pathways to cell death were explored by immunolabelling of cleaved caspases-3, -8 and -9. In the lungs of ventilated/oxygen-treated preterm infants, the numbers of apoptotic and proliferating cells increased significantly compared to the respective numbers in the lungs of stillborn foetuses. Apoptosis was detected in alveolar epithelial cells, whereas epithelial, endothelial and smooth muscle cells proliferated. Surfactant treatment reduced apoptosis induced by ventilation/oxygen-treatment; however, the decrease was not significant. Caspases-8 and -9 do not contribute to ventilation-induced apoptosis, whereas caspase-3 is involved. In conclusion, ventilation/oxygen-treatment induces epithelial cell apoptosis and proliferation of epithelial, endothelial and smooth muscle cells in the lungs of preterm infants.     

改良的保护性肺通气策略对婴幼儿体外循环术后急性呼吸窘迫综合征的疗效

目的:探讨改良“保护性肺通气策略”的可行性,并评价其对婴幼儿体外循环术后急性呼吸窘迫综合征(ARDS)的治疗效果。方法:对17例先天性心脏病术后合并ARDS的婴幼儿采用新的通气模式:(1)低潮气量(6～8ml/kg);(2)高PEEP(6～12cmH_2O);(3)限制气道峰压(<30～35cmH_2O);(4)高呼吸频率(25～40次/分钟);(5)适当允许高碳酸血症(PaCO_2≤60mmHg)。同时注重液体限制、体位疗法等辅助措施,并在部分危重患儿及时应用外源性肺表面活性物质和(或)一氧化氮。结果:术后平均应用呼吸机时间12.73天。与以往同类病例的治疗结果相比,本组患儿无死亡,并发症发生率降低,无明显后遗症,近远期随访均满意。结论:在改良的保护性肺机械通气的基础上,辅以液体限制、外源性肺表面活性物质、一氧化氮等综合治疗手段,可以明显提高体外循环术后ARDS的治疗效果。     

Different effects of surfactant and inhaled nitric oxide in modulation of inflammatory injury in ventilated piglet lungs

Septic acute lung injury (ALI) causes high morbidity and mortality in intensive care service as a result of biotrauma and dysfunction in the lungs and other organ systems. We hypothesized that surfactant and/or inhaled nitric oxide (iNO) may have different effects in modulation of inflammatory injury in septic ALI. Twenty-four healthy, 6-9 kg piglets were anesthetized, and intraperitoneally injected with Escherichia coli, followed by a low tidal volume ventilation until sepsis and ALI developed within 4-6 h. They were then randomly treated in groups (n=6 each) as: control (C), inhaled NO at 10 ppm (NO), surfactant at 100mg/kg (Surf), or both surfactant and iNO (SNO). A normal control group (N) was sham-injected and similarly ventilated. Over the 24 h of treatment period, both Surf, and SNO groups had significantly improved PaO2/FiO2, dynamic compliance and resistance of respiratory system. At 24h, the best alveolar aeration and least protein leakage, the lowest wet-to-dry lung weight ratio and lung injury score were found in SNO. Activity of nuclear factor kappa B (NF-kappaB) and myeloperoxidase, interleukin 8 mRNA expression and melondialdehyde were significantly increased, and IL-10 mRNA decreased, in lung tissue of the C group, but were significantly altered in the SNO group, and moderately altered in either NO or Surf group. We conclude that the effects of lung protection by surfactant and/or iNO in this model may be different in modulation of inflammatory cytokine mRNA expression and activity of NF-kappaB, and iNO did not have adverse effects.     

Mechanical ventilation-induced air-space enlargement during experimental pneumonia in piglets

Mechanical ventilation-induced air-space enlargement was investigated in a porcine model of multifocal pneumonia. Following the intrabronchial inoculation of Escherichia coli, 9 piglets (22 +/- 2 kg) were ventilated with a tidal volume (VT) of 15 ml/kg for 43 +/- 15 h. Five noninoculated piglets ventilated for 60 h with the same VT served as control animals. Following death, the lungs were fixed and lung morphometry was assessed. In inoculated animals, unventilated infected and normally ventilated noninfected pulmonary lobules coexisted. In normally ventilated lung regions (1) emphysema-like lesions were present, (2) mean alveolar area and mean linear intercept were significantly greater in inoculated than in control animals, and (3) the degree of alveolar distension correlated with the decrease in respiratory compliance. In unventilated lung areas (1) pseudocysts were frequent, (2) alveolar edema was rare, (3) bronchiolectasis was frequent, (4) mean bronchiolar area was greater in inoculated than in control animals, and (5) the degree of bronchiolar distension correlated with the increase in inspiratory plateau pressure. In conclusion, in piglets with severe bronchopneumonia, air-space enlargement rather than pulmonary edema was the major feature of mechanical ventilation-induced lung barotrauma and resembled lesions previously reported in critically ill patients ventilated using high inspiratory pressures.     

Production of inflammatory cytokines in ventilator-induced lung injury: a reappraisal

We investigated the production of proinflammatory cytokines by the lung during high mechanical stretch in vivo. To do this, we subjected rats to high-volume (42 ml/kg tidal volume [VT]) ventilation for 2 h. The animals developed severe pulmonary edema and alveolar flooding, with a high protein concentration in bronchoalveolar lavage fluid (BALF). The animals' BALF contained no tumor necrosis factor (TNF)-alpha, negligible amounts of interleukin (IL)-1beta, and less than 300 pg/ml of the chemokine macrophage inflammatory protein (MIP)-2, an amount similar to that found in rats ventilated with 7 ml/kg VT. Systemic cytokine levels were below the detection threshold. Because isolated lungs have been shown to produce high levels of proinflammatory cytokines when ventilated with a similarly high VT for the same duration (Tremblay, et al. J Clin Invest 1997;99:944-952), we reconsidered this specific issue. We ventilated isolated, unperfused rat lungs for 2 h with 7 ml/kg or 42 ml/kg VT, or maintained them in a statically inflated state. Negligible amounts of TNF-alpha were found in the BALF whatever the ventilatory condition applied. The BALF IL-1beta concentration was slightly elevated and higher in lungs ventilated with 42 ml/kg VT than in those ventilated with 7 ml/kg VT or in statically inflated lungs (p < 0.05). The BALF MIP-2 concentration was moderately elevated in all isolated lungs (200 to 300 pg/ml), and was slightly higher (p < 0.05) in lungs ventilated with 42 ml/kg VT. After lipopolysaccharide (LPS) challenge, high levels of TNF-alpha, IL-1beta, and MIP-2 were found in the animals' plasma before the lungs were removed. Negligible amounts of TNF-alpha and IL-1beta were retrieved from the BALF of statically inflated lungs. The concentrations of TNF-alpha and IL-1beta were higher in the BALF of ventilated lungs (p < 0.001). The TNF-alpha level did not differ with the magnitude of VT, whereas the level of IL-1beta was significantly higher in BALF of lungs ventilated with 42 ml/kg VT (p < 0.01). The MIP-2 concentrations were similar for the two ventilatory conditions. These results suggest that ventilation that severely injures lungs does not lead to the release of significant amounts of TNF-alpha or IL-1beta by the lung in the absence of LPS challenge but may increase lung MIP-2 production.     

Effect of ventilation strategy and surfactant on inflammation in experimental pneumonia.

This study explored, the inflammatory response during experimental pneumonia in surfactant-depleted animals as a function of ventilation strategies and surfactant treatment. Following intratracheal instillation of Group B streptococci (GBS), surfactant-depleted piglets were treated with conventional (positive-end expiratory pressure (PEEP) of 5 cmH2O, tidal volume 7 mL x kg(-1)) or open lung ventilation. During the latter, collapsed alveoli were recruited by applying high peak inspiratory pressures for a short period of time, combined with high levels of PEEP and the smallest possible pressure amplitude. Subgroups in both ventilation arms also received exogenous surfactant. Conventionally ventilated healthy animals receiving GBS and surfactant-depleted animals receiving saline served as controls. In contrast with both control groups, surfactant-depleted animals challenged with GBS and conventional ventilation showed high levels of interleukin (IL)-8, tumour necrosis factor (TNF)-alpha and myeloperoxidase in bronchoalveolar lavage fluid after 5 h of ventilation. Open lung ventilation attenuated this inflammatory response, but exogenous surfactant did not. Systemic dissemination of the inflammatory response was minimal, as indicated by low serum levels of IL-8 and TNF-alpha. In conclusion, the current study indicates that the ventilation strategy, but not exogenous surfactant, is an important modulator of the inflammation during Group B streptococci pneumonia in mechanically ventilated surfactant-depleted animals.     

Ventilatory strategies in patients with sepsis and respiratory failure

Patients with sepsis may require mechanical ventilation due to the acute respiratory distress syndrome (ARDS). It has become increasingly accepted that mechanical ventilation can contribute to lung injury in these patients. The modern concept of ventilator-induced lung injury is described in the context of alveolar over-distention (volutrauma), alveolar de-recruitment (atelectrauma), and biochemical injury and inflammation to the lung parenchyma (biotrauma). To avoid over-distention lung injury, the tidal volume should be set at 6 mL/kg predicted body weight and plateau pressure should be limited to 30 cm H₂O. This has been shown to afford a survival benefit. Although setting positive end-expiratory pressure (PEEP) to zero is likely harmful during mechanical ventilation of patients with ARDS, evidence is lacking for a survival benefit if a high PEEP level is set compared with a modest level of PEEP. Although adjunctive measures such as recruitment maneuvers, prone position, and inhaled nitric oxide may improve oxygenation, evidence is lacking that these measures improve survival.     

Surfactant protein A recruits neutrophils into the lungs of ventilated preterm lambs

We tested the effects of surfactant protein A (SP-A) on inflammation and surfactant function in ventilated preterm lungs. Preterm lambs of 131 d gestation were ventilated for 15 min to initiate a mild inflammatory response, and were then treated with 100 mg/ kg recombinant human SP-C surfactant or with the same surfactant supplemented with 3 mg/kg ovine SP-A. Addition of SP-A to the SP-C surfactant did not change lung function. After 6 h of ventilation, cell numbers in the alveolar wash were 4.9 times higher in SP-A + SP-C-surfactant-treated animals. Cellular infiltrates consisted of neutrophils that produced less hydrogen peroxide than did cells from SP-C-surfactant-treated animals. Expression of adhesion molecules CD11b and CD44 was significantly greater after SP-A treatment, whereas the expression of CD14 was unchanged. Messenger RNAs (mRNAs) for the proinflammatory cytokines interleukin (IL)-1beta, IL-6, and IL-8, but not tumor necrosis factor-alpha, were increased in SP-A-treated lungs. Surfactant protein mRNAs and protein leakage into alveolar washes were not altered by SP-A, indicating that SP-A treatment produces no evidence of lung injury. The present study identifies an unanticipated role of SP-A in neutrophil recruitment in the lungs of preterm lambs.     

Surfactant reduces extravascular lung water and invasion of polymorphonuclear leukocytes into the lung in a piglet model of airway lavage

Acute respiratory distress syndrome (ARDS) in newborns and young infants is linked with an inflammatory response of the lungs which affects the capillary-alveolar permeability, epithelial integrity and type I and II pneumocyte function. Abundant extravascular lung water with a high protein content inactivates surfactant together with the enzymatic action of polymorphonuclear leukocytes (PMNL). We asked if a decrease in extravascular lung water and a reduction in lung infiltration with PMNL could be achieved by surfactant administration (Curosurf) within 6 h of mechanical ventilation when given in a newborn piglet model of repeated airway lavage. Improvements in gas exchange and lung mechanics were predominantly caused by resorption of extravascular lung water rather than by the reopening of alveolar atelectases. PMNL were significantly reduced in the bronchoalveolar lavage fluid after 6 h of mechanical ventilation. However, acute phase cytokines (IL-6, TNF-alpha) remained unchanged, except for IL-8 which increased after administration of surfactant. We conclude that the decrease in extravascular lung water and in infiltration with PMNL following surfactant administration is accomplished within 6 h through mechanisms different from attenuation of pro-inflammatory cytokines. Surfactant treatment for newborn and infant ARDS might therefore improve fluid overload and atelectasis and reduce PMNL infiltration.     

Chronic lung injury in preterm lambs. Disordered respiratory tract development

The cause of chronic lung disease of early infancy, often called bronchopulmonary dysplasia (BPD), remains unclear, partly because large-animal models that reliably reproduce BPD have not been available. We developed a model of BPD in lambs that are delivered prematurely and ventilated for 3 to 4 wk after birth to determine whether the histopathology of chronic lung injury in premature lambs mimics that which occurs in preterm infants who die with BPD, and to compare two ventilation strategies to test the hypothesis that differences in tidal volume (VT) influence histopathologic outcome. The two ventilation strategies were slow, deep ventilation (20 breaths/min, 15 +/- 2 ml/kg body weight VT; n = 5) or rapid, shallow ventilation (60 breaths/min, 6 +/- 1 ml/kg body weight VT; n = 5). Lambs were delivered at 125 +/- 4 d gestation (term = 147 d), treated with surfactant, and mechanically ventilated with sufficient supplemental oxygen to maintain normal arterial oxygenation (60 to 90 mm Hg). Quantitative histologic analysis revealed lung structural abnormalities for both groups of experimental lambs compared with lungs of control term lambs that were < 1 d old (matched for developmental age; n = 5) or 3 to 4 wk old (matched for postnatal age; n = 5). Compared with control lambs, chronically ventilated preterm lambs had pulmonary histopathology characterized by nonuniform inflation patterns, impaired alveolar formation, abnormal abundance of elastin, increased muscularization of terminal bronchioles, and inflammation and edema. Slow, deep ventilation was associated with less atelectasis, less alveolar formation, and more elastin when compared with rapid, shallow ventilation. We conclude that prolonged mechanical ventilation of preterm lambs disrupts lung development and produces pulmonary histopathologic changes that are very similar to those that are seen in the lungs of preterm infants who die with BPD. This chronic lung disease is not prevented by surfactant replacement at birth, does not appear to require arterial hyperoxia, and is influenced by VT.     

Effects of ventilation with different positive end-expiratory pressures on cytokine expression in the preterm lamb lung

Ventilator-induced lung injury increases proinflammatory cytokines in the adult lung. We asked if positive end-expiratory pressure (PEEP) affects proinflammatory cytokine mRNA expression in the preterm lung. Preterm lambs at 129 +/- 3 d gestation were treated with 100 mg/kg recombinant human surfactant protein-C surfactant and ventilated for 2 or 7 h with 0, 4, or 7 cm H(2)O of PEEP. Unventilated fetal lambs were used as controls. Within 2 h of ventilation, alveolar total protein and activated neutrophils were increased and expression of mRNAs for the proinflammatory cytokines interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) was increased in lung tissue of all ventilated animals relative to unventilated controls. Alveolar protein and neutrophils were higher for 0 and 7 PEEP animals than 4 PEEP animals. IL-1beta, IL-6, and IL-8 mRNAs were significantly elevated in animals ventilated with 0 PEEP compared with 4 PEEP. The percentage fractional area of collapsed alveoli was significantly higher for 0 PEEP compared with 4 and 7 PEEP groups. Mechanical ventilation increased the expression of proinflammatory mediators in surfactant-treated preterm lungs and the use of 4 PEEP minimized this response.     

Inhibition of granulocyte activation by surfactant in a 2-yr-old female with meningococcus-induced ARDS.

Activated polymorphonuclear neutrophils (PMNs) play a crucial role in acute respiratory distress syndrome (ARDS) via extracellular release of reactive cell products such as elastase. Surfactant has proved valuable in restoring lung function in ARDS. The significance of its immunomodulatory properties with respect to this effect has not yet been clarified. The aim of the present study was to determine the anti-inflammatory effects of surfactant administration in an infant with ARDS. During the acute phase of ARDS in a 2-yr-old female, levels of PMN-derived elastase complexed with alpha1-protease inhibitor (E-alpha1PI) were measured in both arterial and central venous blood samples obtained simultaneously. The results were correlated with oxygen demand and plasma concentrations of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) after endotracheal administration of surfactant (Alveofact 60 mg x kg x body weight(-1)). In the present case, for the first time, a higher E-alpha1PI concentration was detected in arterial blood (4.51 mg x L(-1)) than in central venous blood (2.28 mg x L(-1)). After administration of surfactant, these concentrations and the arteriovenous difference decreased, indicating that during ARDS, most PMN degranulation takes place in the pulmonary vascular bed and is inhibited by surfactant administration. Simultaneously, TNF-alpha and IL-6 plasma concentrations decreased within hours and lung function was restored. This local inhibition of polymorphonuclear neutrophil activation by exogenous surfactant may play a key role in the early improvement in lung function after surfactant administration.     

Na,K-ATPase gene transfer increases liquid clearance during ventilation-induced lung injury

Mechanical ventilation with high tidal volumes (HVT) downregulates alveolar Na,K-ATPase function and impairs lung liquid clearance. We hypothesized that overexpression of Na,K-ATPase in the alveolar epithelium could counterbalance these changes and increase clearance in a rat model of mild ventilation-induced lung injury. We used a surfactant-based system to deliver 4 x 10(9) plaque-forming units of E1a-/E3- recombinant adenovirus containing either a rat beta1 Na,K-ATPase subunit cDNA (adbeta1) or no cDNA (adnull) to rat lungs 7 days before ventilation with a VT of approximately 40 ml/kg (peak airway pressure of less than 35 cm H2O) for 40 minutes. Lung liquid clearance and Na, K-ATPase activity and protein abundance were increased in HVT adbeta1-infected lungs as compared with sham and adnull-infected HVT lungs. These results suggest that Na,K-ATPase subunit gene overexpression in the alveolar epithelium increases Na,K-ATPase function and lung liquid clearance in a model of HVT. We provide here the first evidence that using a genetic approach improves active Na+ transport and thus liquid clearance in the setting of mild ventilation-induced lung injury.     

Active immunization induces lung hyperresponsiveness in the guinea pig. Pharmacologic modulation and triggering role of the booster injection

In order to investigate whether bronchopulmonary hyperresponsiveness represents a unique property of sensitized lungs, we examined the responses of lungs from either actively sensitized, passively sensitized, or nonsensitized (control) guinea pigs to in vitro bronchoconstriction (BC) and release of thromboxane (TX) B2, 6-keto-PGF1 alpha, and histamine induced by platelet-activating factor (PAF-acether) or leukotriene (LT) D4. Guinea pigs were actively sensitized with 10 micrograms of either ovalbumin or Dermatophagoides farinae extract in AI(OH)3 injected intraperitoneally twice at a 2-wk interval. Seven days after the second injection (booster injection), the lungs were removed, ventilated, and perfused via the pulmonary artery with Krebs solution containing 2.5 g/L bovine serum albumin. In lungs from actively sensitized animals, BC was induced by significantly lower doses of PAF-acether and LTD4 than those required to elicit the same response in control preparations. In addition, sensitized lungs released more TxB2, 6-keto-PGF1 alpha, and histamine in response to PAF-acether and LTD4 than did control lungs. Increased mediator release was also observed upon challenge of lungs from actively sensitized animals with arachidonic acid and histamine. Lungs from guinea pigs passively sensitized with serum from actively sensitized animals did not exhibit increased responsiveness to PAF-acether as compared to control lungs. The hyperresponsiveness induced after booster injection of the antigen occurred concomitantly with an increase in the homocytotropic antibody titer (as measured by passive cutaneous anaphylaxis) and persisted for 3 months after sensitization, when the levels of circulating antibodies and lung response to antigen challenge returned to control values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intratracheal endotoxin causes systemic inflammation in ventilated preterm lambs

Intratracheal endotoxin causes acute inflammation in the adult lung, and injurious styles of mechanical ventilation can result in systemic inflammation derived from the lungs. We asked how ventilated premature and near-term lungs responded to intratracheal endotoxin and if systemic inflammation occurred. Lambs delivered at 130 d gestational age (GA) were treated with surfactant or surfactant plus endotoxin (0.1 mg/kg or 10 mg/kg) (Escherichia coli, serotype O55:B5) and were ventilated for 6 h. Both endotoxin doses resulted in impaired gas exchange and systemic inflammation in the preterm lambs. Lambs at 141 d GA (term 146 d) were given either 10 mg/kg intratracheal endotoxin, 10 mg/kg endotoxin plus high tidal volume ventilation for the first 30 min of life, or 5 microg/kg endotoxin given intravenously. Endotoxin alone (10 mg/kg) caused lung inflammation but no systemic effects after 6 h of ventilation. Lambs given 10 mg/kg endotoxin plus high tidal volume ventilation or 5 microg/kg endotoxin intravenously had decreased gas exchange and systemic inflammation. Endotoxin was detected in the plasma of lambs at 130 d GA but not at 141 d GA. Inflammation in the lungs was more severe in preterm animals. Mechanical ventilation of the endotoxin-exposed preterm lung resulted in systemic effects at a low endotoxin dose and without high tidal volume ventilation.     

Exogenous surfactant restores lung function but not peripheral immunosuppression in ventilated surfactant-deficient rats

The authors have previously shown that mechanical ventilation can result in increased pulmonary inflammation and suppressed peripheral leukocyte function. In the present study the effect of surfactant therapy on pulmonary inflammation and peripheral immune function in ventilated surfactant-deficient rats was assessed. Surfactant deficiency was induced by repeated lung lavage, treated rats with surfactant or left them untreated, and ventilated the rats during 2 hours. Nonventilated rats served as healthy control group. Expression of macrophage inflammatory protein (MIP)-2 was measured in bronchoalveolar lavage (BAL), interleukin (IL)-1beta, and heat shock protein 70 (HSP70) were measured in total lung homogenates. Outside the lung phytohemagglutinin (PHA)-induced lymphocyte proliferation, interferon (IFN)-gamma and IL-10 production, and natural killer activity were measured in splenocytes. After 2 hours of mechanical ventilation, expression of MIP-2, IL-1beta, and HSP70 increased significantly in the lungs of surfactant-deficient rats. Outside the lung, mitogen-induced proliferation and production of IFN-gamma and IL-10 reduced significantly. Only natural killer cell activity remained unaffected. Surfactant treatment significantly improved lung function, but could not prevent increased pulmonary expression of MIP-2, IL-1beta, and HSP70 and decreased peripheral mitogen-induced lymphocyte proliferation and IFN-gamma and IL-10 production in vitro. In conclusion, 2 hours of mechanical ventilation resulted in increased lung inflammation and partial peripheral leukocyte suppression in surfactant-deficient rats. Surfactant therapy ameliorated lung function but could not prevent or restore peripheral immunosuppression. The authors postulate that peripheral immunosuppression may occur in ventilated surfactant deficient patients, which may enhance susceptibility for infections.     

Effects of high-frequency oscillation on endogenous surfactant in an acute lung injury model.

This study evaluated the effects of high-frequency oscillation (HFO) and conventional mechanical ventilation (CMV) on gas exchange and the pulmonary surfactant system in an acute lung injury model. Following induction of lung injury with N-nitroso-n-methylurethane, adult rabbits were anesthetized and randomized to one of the following ventilatory strategies: HFO for 120 min, CMV for 120 min, HFO for 60 min, followed by CMV for 60 min, CMV for 60 min followed by HFO for 60 min or CMV for 60 min. Separate animals were ventilated using CMV with a lower tidal volume and a positive end-expiratory pressure level that was increased throughout the experimental period. Oxygenation was significantly greater in animals ventilated with HFO compared with animals ventilated with CMV. The proportion of surfactant in large aggregate forms was significantly greater following ventilatory support with HFO compared with CMV. Surfactant aggregate conversion was also significantly lower during HFO compared with CMV. We conclude that in our model of acute lung injury, HFO was a superior mode of ventilation and reduced the conversion of alveolar surfactant large aggregates into small aggregate forms, resulting in a greater percentage of large aggregate forms in the alveolar space.     

Effects of mechanical ventilation of isolated mouse lungs on surfactant and inflammatory cytokines.

Mechanical ventilation of the lung is an essential but potentially harmful therapeutic intervention for patients with acute respiratory distress syndrome. The objective of the current study was to establish and characterize an isolated mouse lung model to study the harmful effects of mechanical ventilation. Lungs were isolated from BalbC mice and randomized to either a nonventilated group, a conventionally ventilated group (tidal volume 7 mL x kg(-1), 4 cm positive endexpiratory pressure (PEEP)) or an injuriously ventilated group (20 mL x kg(-1), 0 cm PEEP). Lungs were subsequently analysed for lung compliance, morphology, surfactant composition and inflammatory cytokines. Injurious ventilation resulted in significant lung dysfunction, which was associated with a significant increase in pulmonary surfactant, and surfactant small aggregates compared to the other two groups. Injurious ventilation also led to a significantly increased concentration of interleukin-6 and tumour necrosis factor-a in the lavage. It was concluded that the injurious effects of mechanical ventilation can effectively be studied in isolated mouse lung, which offers the potential of studying genetically altered animals. It was also concluded that in this model, the lung injury is, in part, mediated by the surfactant system and the release of inflammatory mediators.