Effects of recombinant Clara cell secretory protein (rhCC10) on inflammatory-related matrix metalloproteinase activity in a preterm lamb model of neonatal respiratory distress.

OBJECTIVE: To test the hypothesis that recombinant Clara cell secretory protein (rhCC10) instillation would foster improved lung function, acute structural preservation, and attenuation of matrix metalloproteinase (MMP) activity in a surfactant-deficient, mechanically ventilated lung. DESIGN: Interventional laboratory study. SETTING: An academic medical research facility in the northeastern United States. SUBJECTS: Sedated, ventilated premature lambs. INTERVENTIONS: Preterm lambs (n = 18; 126 +/- 3 days gestation) were instrumented, ventilated, and treated with 100 mg/kg exogenous surfactant. Lambs were randomized to receive 0, 0.5, or 5.0 mg/kg rhCC10 (n = 6 per group) and were ventilated for 4 hrs. MEASUREMENTS AND MAIN RESULTS: Posttreatment, lung function and cardiopulmonary stability were monitored for the ventilation period and then animals were killed for in vitro surfactant function analysis, lung histomorphometry, and analysis of MMP-2, -7, and -9 as well as their tissue inhibitors (TIMP)-1 and -2. Ventilation efficiency and pulmonary compliance were improved in the 5.0-mg/kg rhCC10 group by 4 hrs. Lung expansion was variable in the apical regions only. MMP-2 quantity was greater in the apical than the base lung regions of rhCC10-treated groups, and rhCC10 decreased MMP-7 in the base of the lung. CONCLUSIONS: These data suggest that improved lung function in the surfactant-treated preterm lamb following intratracheal rhCC10 may be related to the reduction of proteolytic activity of MMP-7.     

Safety and efficacy of intratracheal recombinant human Clara cell protein in a newborn piglet model of acute lung injury

Despite the widespread use of exogenous surfactant, acute and chronic lung injury continues to be a major cause of morbidity in preterm infants. CC10 is a protein produced by Clara cells that inhibits phospholipase A2 and has anti-inflammatory and antifibrotic properties. We studied whether intratracheal (IT) recombinant human Clara cell protein (rhCC10) could safely minimize lung injury in a newborn piglet model of acute lung injury. Twenty-nine newborn piglets were given Survanta and then ventilated for 48 h receiving the following: room air (group 1); 100% O2 (group 2); or 100% O2 and 25, 5, or 1 mg/kg (groups 3, 4, and 5, respectively) of IT rhCC10 (diluted to 2 mL/kg with saline) at time 0. Laboratory studies, oxygen ratios, static pressure-volume curves, bronchoalveolar lavage (for inflammatory markers), and histologic analyses were performed over the 48-h study period. Pulmonary compliance and oxygenation were significantly improved in animals receiving 5 mg/kg IT rhCC10 compared with room air and 100% O2 controls (p < 0.004 and p < 0.05, respectively, ANOVA). Reductions in inflammatory markers were seen in animals receiving rhCC10, although changes did not reach statistical significance. No significant toxicity was noted. rhCC10 appeared safe and improved pulmonary function in this newborn piglet model of hyperoxic lung injury. We speculate that rhCC10 may represent a promising therapy for the prevention of lung injury in preterm infants.     

Selective medicated (normal saline and exogenous surfactant) bronchoalveolar lavage in severe aspiration syndrome in children.

OBJECTIVE: To study the ability of volume-controlled ventilation and medicated (normal saline plus surfactant) bronchoalveolar lavage in aspiration to reduce the duration of intubation and improve gas exchange. DESIGN:: Randomized controlled clinical trial. SETTING: Pediatric intensive care unit. PATIENTS: Twenty children, 1 month to 16 yrs old, who were intubated and mechanically ventilated, were randomized within 6 hrs of aspiration to receive volume-controlled ventilation plus medicated bronchoalveolar lavage (treatment group) or the same ventilation and bronchosuction (control group). INTERVENTIONS: Volume-controlled ventilation and positive end-expiratory pressure (10-12 cm H2O) were applied. Medicated bronchoalveolar lavage was performed using five aliquots of 5 mL of saline plus 10 mg/mL Curosurf (porcine surfactant, Chiesi Pharmaceutical SpA, Parma, Italy) in infants, five boluses of 10 mL of saline plus 5 mg/mL Curosurf in children, and four boluses of 25 mL of saline with 2.4 mg/mL Curosurf in adolescents for each affected lobe. One hour after bronchoalveolar lavage, 240 mg of Curosurf was administered locally. MEASUREMENTS AND MAIN RESULTS: All patients survived. In the treatment group, days of intubation were 4.6 (+/-1.07), oxygenation index and Pao2/Fio2 improved significantly at 24 hrs, and statistical reduction in tidal volume mL/kg was observed from 36 hrs. In the control group, days of intubation were 11.8 (+/-3.22) (p < .0001), no improvement in oxygenation was noted, and pneumonia was observed in seven children (70%). CONCLUSIONS: Even though this was an unblinded small clinical trial and low tidal volume strategy was not employed at an early stage after lung injury, there is some evidence that bronchoalveolar lavage with normal saline and surfactant may have clinical value in treating severe aspiration syndrome in children. More clinical studies are warranted to overcome study limitations and potential bias.     

Surfactant lavage decreases systemic interleukin‐1β production in meconium aspiration syndrome

Background: Surfactant lavage has been used to remove meconium debris in meconium aspiration syndrome (MAS), but the influence of surfactant lavage on pro‐inflammatory cytokines and cellular apoptosis is unclear. The aim of this study was to investigate the response of pro‐inflammatory cytokine and the influence on alveolar cellular apoptosis using therapeutic bronchoalveolar lavage with diluted surfactant to treat MAS. Methods: Twelve newborn piglets were anesthetized, intubated via tracheostomy, and artificially ventilated. MAS was induced by intratracheal instillation of 3–5 mL/kg of 20% human meconium. The piglets were then randomly assigned to a surfactant lavage group (n= 6) or a control group (n= 6). Piglets in the lavage group received bronchoalveolar lavage with 30 mL/kg diluted surfactant (5 mg/mL) in two aliquots. Cardiopulmonary parameters were monitored continuously. Serum was obtained hourly to measure concentrations of pro‐inflammatory cytokines, including interleukin (IL)‐Iβ, IL‐6, and tumor necrosis factor α. Lung tissue was histologically examined after experiments, and terminal deoxynucleotidyl transferase‐mediated nick‐end labeling assay for apoptotic cell death was also performed. Results: The animals in the lavage group displayed significantly better gas exchange and lower serum concentrations of IL‐1β than the animals in the control group (P < 0.05). The number of apoptotic cells in lung tissues was significantly lower in the lavage group than the control group, and also in the nondependent than the dependent site. Conclusion: Therapeutic surfactant lavage improves oxygenation, decreases production of systemic pro‐inflammatory cytokine IL‐1β, and alleviates the severity of lung cell apoptosis in newborn piglets with experimentally‐induced MAS.     

The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome

Clara cell 10-kD protein (CC10) is a potent anti-inflammatory protein that is normally abundant in the respiratory tract. CC10 is deficient and oxidized in premature infants with poor clinical outcome (death or the development of bronchopulmonary dysplasia). The safety, pharmacokinetics, and anti-inflammatory activity of recombinant human CC10 (rhCC10) were evaluated in a randomized, placebo-controlled, double-blinded, multicenter trial in premature infants with respiratory distress syndrome. A total of 22 infants (mean birth weight: 932 g; gestational age: 26.9 wk) received one intratracheal dose of placebo (n = 7) or 1.5 mg/kg (n = 8) or 5 mg/kg (n = 7) rhCC10 within 4 h of surfactant treatment. Pharmacokinetic analyses demonstrated that the serum half-life was 11.6 (1.5 mg/kg group) and 9.9 h (5 mg/kg group). Excess circulating CC10 was eliminated via the urine within 48 h. rhCC10-treated infants showed significant reductions in total cell count (p < 0.0002), neutrophil counts (p < 0.001), and total protein concentrations (p < 0.01) and tended to have decreased IL-6 (p < 0.07) in tracheal aspirate fluid collected over the first 3 d of life. Infants in all three groups showed comparable growth. At 36 wk postmenstrual age, five of seven infants were still hospitalized and two of seven infants were receiving oxygen in the placebo group compared with two of seven hospitalized and one of seven receiving oxygen in the 1.5-mg/kg group and four of six hospitalized and three of six receiving oxygen in the 5-mg/kg group. A single intratracheal dose of rhCC10 was well tolerated and had significant anti-inflammatory effects in the lung. Multiple doses of rhCC10 will be investigated for efficacy in reducing pulmonary inflammation and ameliorating bronchopulmonary dysplasia in future studies.     

CC10 reduces inflammation in meconium aspiration syndrome in newborn piglets

Complications from meconium aspiration syndrome (MAS) remain significant despite a variety of therapeutic interventions. Clara cell protein (CC10) is a novel anti-inflammatory agent that can also inhibit phospholipase A2 (PLA2) (an important component of meconium). The present study examined whether administration of recombinant human CC10 (rhCC10) would reduce inflammation and improve lung function in a piglet model of MAS. Following meconium instillation, piglets exhibited significant physiologic dysfunction that improved significantly after surfactant administration. Analysis of tracheal aspirates revealed significant increases in both tumor necrosis factor (TNF) alpha and interleukin (IL)-8 after meconium instillation. rhCC10-treated animals had significantly lower TNF-alpha levels at 24 h (561 +/- 321 versus 1357 +/- 675 pg/mL, p < 0.05) compared with saline controls. There were no differences between rhCC10-treated and untreated groups with respect to other measured physiologic variables or inflammatory markers, including secretory PLA2 activity. Histologic analyses revealed marked inflammatory infiltrates and thickened alveolar walls, but no significant differences among rhCC10 and control animals. Newborn piglets with MAS have significant physiologic dysfunction, marked inflammatory changes and histologic abnormalities, which was partially counteracted by a single dose of exogenous surfactant and rhCC10.     

Effects of an intratracheally delivered anti-inflammatory protein (rhCC10) on physiological and lung structural indices in a juvenile model of acute lung injury

BACKGROUND: Mechanical ventilation results in acute lung trauma that can stimulate processes that alter lung development. Activation of matrix metalloproteinases (MMPs) and their tissue-produced inhibitors (TIMPs) is initiated by the inflammatory response to mechanical ventilation and are involved in breakdown of the basement membrane and parenchymal modeling. OBJECTIVES: The aim of this study was to test the hypothesis that rhCC10, a lung anti-inflammatory mediator, would foster improved lung function, structural preservation, and a reduction in net MMP activity in a juvenile model of acute lung injury. METHODS: Twenty-four juvenile rabbits were saline-lavage-injured and treated with 100 or 25 mg/kg surfactant (Survanta, Ross Labs) with or without rhCC10 (Claragen, Inc.; n=6 per group). Animals were ventilated for 4 h, then euthanized for in vitro surfactant function analysis, lung histomorphometry, and analysis of MMP-2, MMP-7, and MMP-9 and TIMPs 1 and 2 in the lung. RESULTS: Apical lung expansion, reduced with the lower dose of surfactant, was partially restored with the addition of rhCC10. Alveolar septal wall thickness was reduced (p<0.05) with low-dose surfactant plus rhCC10 compared to high-dose surfactant alone. Increased within-group variance in MMP-2 and MMP-9 proteolytic activity was found with the low-dose surfactant and was abolished with rhCC10. MMP-7 was reduced (p<0.05) with rhCC10 administration, independent of surfactant dose. CONCLUSIONS: Intratracheal administration of the anti-inflammatory rhCC10 resulted in preserved lung structure and MMP/TIMP profile after 4 h of mechanical ventilation, in a surfactant dose-dependent manner.     

Lung inflammatory responses to intratracheal interleukin-1alpha in ventilated preterm lambs

Interleukin-1alpha is an early response proinflammatory cytokine that has been associated with chorioamnionitis and preterm labor, brain injury, and bronchopulmonary dysplasia. However, IL-1alpha also can increase expression of surfactant proteins and induce lung maturation in the preterm fetus. We measured the effects of IL-1alpha given by intratracheal instillation (IT) and compared the responses with injection of i.v. IL-1alpha in surfactant-treated and ventilated premature lambs. IT recombinant ovine IL-1alpha at doses of 5 and 50 microg/kg caused a similar large recruitment of neutrophils into the bronchoalveolar lavage fluid. The neutrophils expressed CD11b, CD14, and CD44, but did not produce increased amounts of H(2)O(2). Cells from the bronchoalveolar lavage fluid had increased expression of proinflammatory cytokines, which also were increased in mRNA from lung tissue. The IT IL-1alpha also suppressed the expression of surfactant protein-C mRNA. Systemic effects were decreased neutrophils in blood, decreased lung function, increased heart rate, and hypotension or death in the 50 microg/kg IL-1alpha IT group and only decreased neutrophils in the blood in the 5 microg/kg IL-1alpha IT group. The i.v. IL-1alpha caused no lung inflammation or injury but did result in severe neutropenia and hypotension leading to early death. IT IL-1alpha can cause intense lung inflammation and systemic shock in ventilated preterm lungs.     

Chest position and pulmonary deposition of surfactant in surfactant depleted rabbits.

AIMS--To investigate the correlation between chest position and the distribution of surfactant in the lungs of surfactant depleted rabbits, to corroborate current guidelines on the intratracheal instillation of exogenous surfactant in newborns. METHODS--Twelve tracheotomised rabbits, depleted of pulmonary surfactant by saline bronchoalveolar lavage, were given intratracheal 99m Technetium labelled Exosurf in three positions (prone, right side down, and left side down) (n = 4 in each group). They were monitored for 10 minutes using dynamic gamma scintigraphy monitoring. Instillation completed, the lateral lying animals were turned to the opposite side to determine whether redistribution of the surfactant had taken place. The amount of radiolabelled surfactant deposited at the peripheral, central, dorsal and ventral parts of the lungs was then estimated by gamma counting of the lung sections at necropsy. RESULTS--Both gamma scintigraphy and gamma counting showed similar rates and total amount of surfactant accumulation in both lungs of the prone animals. In the lateral lying animals surfactant accumulated at a significantly faster rate in the dependent lungs: the amount of surfactant deposition was three to 14-fold that in the raised lungs (p = 0.017; nested ANOVA). Changing the chest position immediately after instillation did not redistribute the surfactant. In all three groups of animals there was no significant difference in deposition between the peripheral, central, ventral and dorsal parts of the lungs. CONCLUSIONS--Pulmonary distribution of intratracheally instilled surfactant is largely determined by gravity, and changing the chest position after instillation does not result in any redistribution of the surfactant. During the instillation of exogenous surfactant to newborn infants, keeping the chest in the horizontal position may therefore result in the most even distribution of the surfactant in the two lungs. Further deposition studies are required to evaluate the validity of the current recommendations on surfactant administration.     

Effect of inhaled corticosteroid on pulmonary injury and inflammatory mediator production after cardiopulmonary bypass in children.

OBJECTIVE: To determine whether inhaled steroid administration after cardiopulmonary bypass will attenuate pulmonary inflammation and improve lung compliance and oxygenation. DESIGN: Randomized, prospective, double-blind, placebo-controlled clinical trial. SETTING: Children's Hospital of Michigan, intensive care unit. PATIENTS: Thirty-two children <2 yrs of age with congenital heart disease requiring cardiopulmonary bypass. INTERVENTIONS: Participants were randomly assigned to one of two groups. Group 1 (n = 16) received an inhaled steroid, Budesonide (0.25 mg/2 mL), and group 2 (n = 16) received an inhaled placebo (2 mL of inhaled 0.9% saline). The nebulizations were given at the end of cardiopulmonary bypass, 6 hrs after cardiopulmonary bypass, and 12 hrs after cardiopulmonary bypass. Two hours after each nebulization, bronchoalveolar lavage for interleukin-6 and interleukin-8 was collected. MEASUREMENTS AND MAIN RESULTS: The concentrations of interleukin-6 and interleukin-8 in the bronchoalveolar lavage increased in both groups after cardiopulmonary bypass. Interleukin-6 peaked 2 hrs after cardiopulmonary bypass and was decreasing by 14 hrs after cardiopulmonary bypass. However, administration of corticosteroid did not affect the production of interleukin-6 when compared with the placebo group (378 +/- 728 vs. 287 +/- 583 pg/mL pre-cardiopulmonary bypass, 1662 +/- 1410 vs. 1584 +/- 1645 pg/mL at the end of cardiopulmonary bypass, 2601 +/- 3132 vs. 3677 +/- 4935 pg/mL 2 hrs after cardiopulmonary bypass, and 1792 +/- 3100 vs. 1283 +/- 1344 pg/mL 14 hrs after cardiopulmonary bypass; p > .05). Likewise, interleukin-8 in the lavage fluid was similar in both the placebo and steroid groups at all time points (570 +/- 764 vs. 990 +/- 1147 pg/mL pre-cardiopulmonary bypass, 1647 +/- 1232 vs. 1394 +/- 1079 pg/mL at the end of cardiopulmonary bypass, 1581 +/- 802 vs. 1523 +/- 852 pg/mL 2 hrs after cardiopulmonary bypass, and 1652 +/- 1069 pg/mL vs. 1808 +/- 281 pg/mL 14 hrs after cardiopulmonary bypass; p > .05). Lung compliance and oxygenation were similar in both groups. CONCLUSIONS: Cardiopulmonary bypass is associated with a pulmonary inflammatory response. Inhaled corticosteroid did not affect the pulmonary inflammatory response as measured by interleukin-6 and interleukin-8 concentrations in the lung lavage after cardiopulmonary bypass. Pulmonary mechanics and oxygenation were not improved by the use of inhaled corticosteroid.     

Short-term distribution kinetics of intratracheally administered exogenous lung surfactant.

The short-term distribution kinetics of exogenous surfactant distribution after intratracheal instillation was investigated in surfactant-deficient neonatal piglets during assisted conventional mechanical ventilation and by high-frequency jet ventilation using exogenous calf lung surfactant extract (CLSE) labeled with 99mTc. Surfactant deficiency was induced by repeated bronchoalveolar lavage in piglets (1.2 +/- 0.4 kg, 1.4 +/- 0.7 d of age), and the short-term distribution kinetics of instilled, labeled CLSE were followed by gamma radioscintigraphy. Animals ventilated by either conventional mechanical ventilation or high-frequency jet ventilation showed similar improvement in arterial/alveolar oxygen ratios after surfactant replacement therapy (0.47 +/- 0.03 prelavage, 0.09 +/- 0.01 postlavage, 0.36 +/- 0.06 postsurfactant). This correlated directly with dynamic radioscintigraphic results showing that instilled CLSE began to distribute to the lungs within 5 s, and was present in substantial amounts in standardized symmetrical lung fields (central, right, and left; upper and lower) within 20 s of tracheal instillation. Subsequent measurements over 30 min showed continued presence of radiolabeled CLSE in all five areas of the lung, with no significant difference between conventional mechanical ventilation and high-frequency jet ventilation animals. Static (5-min) analyses at the end of this period showed that surfactant had distributed relatively symmetrically with 30% of the CLSE located in central regions, 40% in the upper lobes, and 30% in the lower lobes. In contrast, piglets receiving 99mTc in saline showed nonuniform distribution with multiple filling defects noted throughout the lungs. The rapid kinetics and ventilation independence of CLSE distribution suggest that surfactant spreading phenomena after tracheal instillation may facilitate the delivery of exogenous surfactant into aerated lungs in therapeutic applications.     

Bronchoalveolar lavage with pulmonary surfactant/dextran mixture improves meconium clearance and lung functions in experimental meconium aspiration syndrome

Surfactant lung lavage is a promising approach in the treatment of meconium aspiration syndrome (MAS). We hypothesise that the enrichment of modified natural surfactant with dextran will enhance meconium clearance from the airspaces during lung lavage and improve lung function in experimental MAS. Human meconium (30 mg/ml; 4 ml/kg) was instilled into the tracheal cannula of anaesthetised and paralysed adult rabbits to induce respiratory failure. The animals were then lavaged with saline (Sal), surfactant without (Surf) and with dextran (Surf+dex). Lung lavage (10 ml/kg in three portions) was performed with diluted surfactant (Curosurf(R), 10 mg/ml, 100 mg/kg) without or with dextran (3 mg/mg of surfactant phospholipids) or saline and the animals were conventionally ventilated with 100% O(2) for an additional hour. Lung functions were measured prior to and after meconium instillation, and 10, 30 and 60 min after lavage. The recovery of meconium in bronchoalveolar lavage (BAL) fluid was quantified. More meconium solids was recovered in the surfactant-lavaged than in the saline-lavaged groups (Surf: 12.4 +/- 3.9% and Surf+dex: 17.5 +/- 3.5% vs. Sal: 4.8 +/- 1.0%; both P < 0.01). Moreover, more meconium solids was obtained by Curosurf/dextran than by Curosurf-only lavage (P < 0.05). In the Surf group, the values for PaO(2)/FiO(2) were significantly higher than in the controls (at 60 min: 24.5 +/- 4.2 kPa vs.9.1 +/- 2.2 kPa, P < 0.01). An additional increase in oxygenation was seen in the Surf+dex group (at 60 min: 34.2 +/- 8.1 kPa, P vs. Surf group <0.01). The lung-thorax compliance was higher in the Surf+dex group in comparison with the Sal and Surf groups (at 60 min: 9.6 +/- 0.9 vs.7.6 +/- 1.2, P < 0.01 and 8.0 +/- 0.7 ml/kPa/kg, P < 0.05). The enrichment of Curosurf with dextran improves meconium clearance and lung functions in surfactant-lavaged rabbits with meconium aspiration.     

Lavage administration of dilute recombinant surfactant in acute lung injury in piglets

In an acute lung injury model, we previously observed reversal of pulmonary dysfunction with natural surfactant administered by lavage (dose = 18 mg/kg phospholipid). The present study questioned whether a lower dose of phospholipid would be effective if a recombinant preparation rather than natural surfactant were used. Acute lung injury was induced by repeated saline lung lavage in ventilated, sedated, and paralyzed piglets. Three concentrations of recombinant surfactant were studied (low phospholipid, 1 mg/mL; medium phospholipid, 4 mg/mL; high phospholipid, 13.5 mg/mL). Control piglets received no surfactant. Thirty-five milliliters per kilogram of surfactant was administered by gravity, followed by passive drainage of excess fluid. All treatment groups retained similar volumes (4.7+/-0.3 mL/ kg), corresponding to phospholipid doses of 4+/-0.4, 22+/-3, and 67+/-4 mg/kg in low, medium, and high-dose groups, respectively. Treatment groups showed significant improvement in Pao2 compared with controls. Other parameters different from controls were found in only the medium and high-dose groups. All surfactant-treated groups showed improvement over time in Pao2, Paco2, lung resistance mean airway pressure, functional residual capacity, and dynamic compliance. These data support the statement that whereas there is a dose response to exogenous surfactant, the effective dose of recombinant surfactant in acute lung injury may be as low as 4 mg/kg phospholipid when administered by lavage.     

Exudative lung injury is associated with decreased levels of surfactant proteins in a rat model of meconium aspiration

OBJECTIVE: Meconium aspiration syndrome remains a common cause of respiratory failure in neonates. The acute effects of meconium aspiration are inactivation of lung surfactant in vivo and in vitro. This study investigated the delayed effects of meconium on alveolar surfactant phospholipids and protein levels in spontaneously breathing animals. METHODS: Twenty-two adult rats were given 4.3 mg of dry weight human meconium after endotracheal intubation. Rats were briefly mechanically ventilated in room air, extubated, then killed after 16 (n = 6), 24 (n = 6), 48 (n = 6), and 72 hours (n = 4). Control animals received the same volume of normal saline (n = 7) or no meconium (n = 7). Bronchoalveolar lavage and tissue specimens were evaluated for inflammatory cells, total proteins, surfactant phospholipids, and surfactant proteins. RESULTS: Meconium caused exudative lung injury that was reflected in increased cell counts and proteins in alveolar lavage fluid. The peak injury occurred at 16 hours after instillation, whereas recovery occurred by 72 hours. Although total lavage fluid phospholipids did not change over time, phospholipid and dipalmitoyl phosphatidylcholine in large aggregates tended to decrease at 24 hours. Western blot analysis demonstrated time-dependent qualitative decreases in surfactant proteins A and B (SP-A, SP-B) in meconium-instilled animals compared with the controls. ELISA for SP-B confirmed the Western blot findings with total SP-B in large aggregate decreasing from 25 +/- 4 microg in controls to 6.6 +/- 0.8 microg at 24 hours of injury. CONCLUSIONS: Our study suggests that the exudative lung injury with meconium instillation is associated with decreased levels of SP-A and SP-B in the large aggregate fraction of lung surfactant. We speculate that decreased secretion and/or increased degradation accounts for lower levels of SP-B in bronchoalveolar lavage fluid.     

应用不同配方磷脂预防大鼠肺出血和肺水肿的研究

为了观察５种不同配方磷脂预防大鼠肺出血、肺水肿的效果，应用静脉注射肾上腺素制备大鼠肺水肿、肺出血模型。结果：多种配方均使支气管肺泡灌洗液总蛋白质的量下降；但大豆磷脂组不能使血脂质过氧化物值下降，该组及人工合成磷脂组均不能使肺指数下降。提示不同磷脂配方预防大鼠肺水肿、肺出血效果，依次为牛肺表面活性物质或人工合成磷脂＋牛肺表面活性物质蛋白质，大豆磷脂＋维生素Ｅ，人工合成磷脂，大豆磷脂。     

猪肺表面活性物质联合布地奈德混悬液气管内滴入治疗新生儿胎粪吸入综合征的疗效观察

目的探讨猪肺表面活性物质(PS)联合布地奈德混悬液气管内滴入治疗新生儿胎粪吸入综合征(MAS)的临床效果。方法采用前瞻性研究法,将70例MAS新生儿随机分成治疗组与对照组(n=35)。对照组常规给予气管内滴入PS(100 mg/kg)治疗,治疗组在此基础上加用布地奈德(0.25 mg/kg)治疗。结果治疗组在治疗后12 h需重复使用PS的比例明显低于对照组(P0.05)。治疗组在治疗后6 h、12 h、24 h动脉氧分压与吸入氧浓度比值(Pa O_2/Fi O_2)、经皮血氧饱和度(Tc Sa O_2)、动脉血氧分压(Pa O_2)、动脉血二氧化碳分压(Pa CO_2)的改善情况明显优于对照组(P0.05)。治疗后48 h胸片显示治疗组肺部炎症吸收明显优于对照组(P0.05);治疗组并发症的发生率明显低于对照组(P0.05),平均住院时间也较对照组明显缩短(P0.01)。结论与单用PS比较,PS联合布地奈德混悬液气管内滴入治疗新生儿MAS能更好改善血气指标和临床症状,缩短住院时间,减少并发症。     

Tracheal gas insufflation as a lung-protective strategy: physiologic, histologic, and biochemical markers.

OBJECTIVE: Conventional mechanical ventilation in acute lung failure potentiates lung injury, which can be assessed by physiologic, histologic, and biochemical markers. Thus, new ventilation strategies are directed at reducing lung injury. Tracheal gas insufflation has been shown to reduce endotracheal tube prosthetic deadspace and peak inspiratory pressure during conventional mechanical ventilation. Our objective was to use physiologic, histologic, and biochemical markers to test the hypothesis that tracheal gas insufflation in acute lung injury is lung protective. DESIGN: Animal experiment. SETTING: University setting. SUBJECTS: Juvenile rabbits (n = 12; 1.95 +/- 0.1 SE kg). INTERVENTIONS: Rabbits were anesthetized, instrumented, paralyzed, and ventilated with Fio(2) = 1.0. Lung injury was induced with repeated saline lavage (10 mL/kg per lavage until Pao(2) 相似文献   

Fibronectin in Bronchoalveolar Lavage Fluid and Plasma from Children with Chronic Inflammation of Lungs

ABSTRACT. Fibronectin/albumin ratios in plasma and in bronchoalveolar lavage fluid were evaluated in patients (1–6 years of age) with recurrent obstructive bronchitis and different interstitial lung diseases. These inflammatory reactions were characterized by increased influx of macrophages on the bronchoalveolar surface, but an increase in the proportion of lymphocytes or neutrophils was also detected in the group of patients with lymphocyte-macrophage or neutrophil-macrophage alveolitis. There was no considerable difference in plasma fibronectin concentrations obtained from healthy children and patients with moderate obstructive bronchitis and slight inflammation of the bronchial mucosa observed bronchoscopically. Levels of plasma fibronectin were elevated in patients with serious bronchial inflammation and different alveolitis, but they were within the normal range. A comparison of lavage fibronectin/albumin ratios with plasma fibronectin/albumin ratios with plasma fibronectin/albumin ratios indicated significant local production of fibronectin in subjects with serious bronchial inflammation and interstitial lung disorders. Fibronectin detected on the bronchoalveolar surface seems to be an important factor in mediating cell-to-cell interactions in the repair of the bronchoalveolar structures, and in tracing the activity of the inflammatory reactions not only in patients with interstitial lung diseases, but also in patients with serious chronic bronchial inflammation.     

Comparison of effects of perflubron and surfactant lung lavage on pulmonary gas exchange in a piglet model of meconium aspiration

In a piglet model of meconium aspiration we compared lavage with surfactant with that with perflubron (PFOB) and a control group. A human meconium suspension was instilled into piglets which were randomized in 3 (n = 6 each) groups. After lung injury, the control group was ventilated with high-frequency oscillatory ventilation (HFOV) without suctioning and lavage. A second group was lavaged with 10 ml/kg diluted surfactant, a third with 10 ml/kg pre-oxygenated PFOB. Thereafter, the animals of both groups were ventilated with HFOV. After lung injury by instillation of meconium, no further improvement in oxygenation was possible in animals of the control group and 3 piglets died during the ventilation. The subjects of the surfactant group improved promptly, and at the end of the study the arterial pO(2) was significantly better than immediately after injury as compared with the other groups. Lavage with PFOB had intermediate effects in gas exchange and oxygenation compared to surfactant lavage. No differences were observed in arterial blood pressure and heart rate as well as in histological lung injury score between all groups. Lavage with exogenous surfactant as well as with PFOB improve pulmonary gas exchange in a piglet model of meconium aspiration.     

Acute effects on systemic circulation after intratracheal instillation of Curosurf or Survanta in surfactant-depleted newborn piglets

Systemic vasodilatation in surfactant-depleted newborn piglets is induced by 200 mg/kg of modified porcine lung surfactant (Curosurf™). The aim of this investigation was to study whether this effect is dependent on dose and could further be induced by instillation of a bovine surfactant preparation (Survanta™). Twenty-two 3–5-d old piglets were subjected to repeated saline lung lavage and then randomized to one of three groups. Instillation of either Curosurf 100 mg/kg ( n = 8), Survanta 100 mg/kg ( n = 7) or Curosurf 200 mg/kg ( n = 7) was performed through the endotracheal tube. Systemic vascular resistance decreased 7 (± 4)%, 15 (± 12)% and 18 (± 6)% in the three groups, respectively ( p < 0:05 in all three groups). A significant difference between the high and low dose Curosurf groups was found ( p < 0:05), whereas no significant difference was seen between the Curosurf 100 mg group and the Survanta group. The decrease in vascular resistance was compensated by an increase in cardiac output, resulting in a stable mean arterial blood pressure. In conclusion, both Curosurf and Survanta induce a significant decrease in systemic vascular resistance in surfactant-depleted newborn piglets. A more pronounced effect was observed after 200 mg/kg than after 100 mg/kg of Curosurf.