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PubMed2001

Phospholipase A2 is present in meconium and inhibits the activity of pulmonary surfactant: an in vitro study.

UNLABELLED: Atelectasis, a major contributor to pulmonary dysfunction in meconium aspiration syndrome (MAS), is produced by bronchiolar obstruction and surfactant inactivation. It has been shown that substances in meconium, e.g. fatty acids, inhibit surfactant activity. However, the role of the enzyme phospholipase A2 (PLA2), which hydrolyses surfactant in adult respiratory distress syndrome (ARDS), has not yet been studied. Our objective was to investigate whether PLA2 is present in meconium and inhibits pulmonary surfactant activity in vitro. Therefore, the presence of PLA2 activity in meconium, collected from 10 newborns, was measured by the formation of lysophosphatidylcholine after incubation of meconium with radioactively labelled dipalmitoylphosphatidylcholine. Meconium was fractionated by Sephadex G-100 column chromatography and the fractions were assayed for PLA2 activity. Also, their effect on the surface tension of surfactant (Curosurf) was measured using a pulsating bubble surfactometer (PBS). PLA2 activity was present in all meconium samples. Addition of meconium to surfactant significantly increased surface tension (mean +/- SD: 1.7 +/- 1.6 mN/m to 24.3 +/- 6.7 mN/m, p = 0.0001) and only the addition of the PLA2 containing fraction from meconium to surfactant also significantly increased surface tension (mean 1.7 +/- 1.6 mN/m to 19.0 +/- 3.58 mN/m, p < 0.0001). CONCLUSION: PLA2 is present in meconium and inhibits the activity of pulmonary surfactant in vitro. Therefore, PLA2 in meconium may contribute to surfactant inactivation and alveolar atelectasis in MAS.

Biological Products↗

PubMed2004

In vivo clearance of surfactant lipids during acute pulmonary inflammation.

BACKGROUND: A decrease in pulmonary surfactant has been suggested to contribute to the lung dysfunction associated with pulmonary inflammation. A number of studies have implicated surfactant clearance as a possible mechanism for altered pool sizes. The objective of the current study was to specifically investigate the mechanisms of surfactant clearance in a rodent model of acute pulmonary inflammation. METHODS: Inflammation was induced by intrapulmonary instillation of lipopolysaccharide (LPS: 100 microg/kg). Lipid clearance was assessed at 18 and 72 hours post-LPS instillation by intratracheal administration of radiolabel surfactant-like liposomes 2 hours prior to isolation and analysis of inflammatory cells and type II cells. RESULTS: At both 18 and 72 hours after LPS instillation there was significantly less radioactivity recovered in the lavage fluid compared to respective control groups (p < 0.05). At both time points, the number of cells recovered by lavage and their associated radioactivity was greater compared to control groups (p < 0.01). There was no difference in recovery of radioactivity by isolated type II cells or other cells obtained from enzymatic digestion of lung tissue. CONCLUSION: These results show that increased clearance of surfactant lipids in our model of acute pulmonary inflammation is primarily due to the inflammatory cells recruited to the airspace and not increased uptake by alveolar type II cells.

Acute Disease↗

PubMed2003

Lysophosphatidylcholine-induced myocardial damage is inhibited by pretreatment with poloxamer 188 in isolated rat heart.

Lysophosphatidylcholine (LPC) accumulates in myocardial tissues and coronary sinus during ischemia, and plays important role in the development of ischemia-reperfusion injury and ischemic ventricular arrhythmia. The aim of this study was to examine whether pretreatment of poloxamer 188 (P-188), a nonionic and non-toxic surfactant, can prevent the cardiac dysfunction induced by exogenous LPC perfusion in Langendorff perfused rat heart model. LPC (6 microM) significantly (p < 0.05) decreased heart rate (HR) and left ventricular developed pressure (LVDP) from 274.3 +/- 23.2 to 175.0 +/- 42.9/min and from 115.9 +/- 11.3 to 26.7 +/- 7.1 mmHg, respectively. The LPC-induced reduction of HR and LVDP did not recover by washout of LPC. Pretreatment with P-188 (1 mM for 30 min) inhibited completely the LPC-induced decreases of HR and LVDP. The pretreatment with P-188 also prevented the LPC-induced increases of left ventricular end-diastolic pressure (LVEDP) and GOT release, significantly (p < 0.05). The coronary perfusion pressure (CPP) rose (p < 0.01) by the LPC perfusion from 71.9 +/- 5.3 to 121.9 +/- 13.0 mmHg, significantly, but pretreatment of P-188 did not affect the LPC-induced vasoconstriction. Our results suggest that exogenous LPC causes irreversible cardiac injury by the sarcolemmal membrane disruption followed by Ca overload, and this LPC-induced cardiac injury, probably, can be prevented by the pretreatment with poloxamer 188.

Animals↗

PubMed1982

Factors regulating lamellar body volume density of type II pneumocytes in excised dog lungs.

Pulmonary arterial occlusion (PAO) produces multiple alterations in the physiological/biochemical environment of lung cells as well as dysfunction of the lung's surfactant system, which is considered to play a significant role in mediating lung injury. The present studies were performed using 66 excised dog lungs to evaluate the impact of alterations in ventilation, substrate availability, alveolar CO2 tension, hydrogen ion and bicarbonate concentrations, and temperature and neural denervation on the lamellar body (LB) volume density of type II pneumocytes. Ventilating excised nonperfused dog lungs with room air (0% CO2) for 4 h at 38 degrees C resulted in severe reductions (68-77%) in LB volume density. Supplementing inspired gas with 5% CO2 prevented LB depletion, while ventilation with 2.5% CO2 moderated the severity of depletion to 17-27% of control. Ventilation with 10% CO2 tended to increase LB volume density by increasing the number of LBs per cell, whereas reductions in LB volume density predominantly resulted from a decrease in LB size. The level of ventilation had no significant effect on LB volume density independent of inspired CO2 concentration. Reducing temperature to 5 degrees C prevented LB depletion. Lung perfusion with autologous whole blood failed to moderate the severity of LB depletion during room air ventilation despite the increased availability of metabolic substrates for cellular metabolism. Adding hydrochloric acid to maintain physiologically normal hydrogen ion concentrations in the perfusing blood had a small effect in ameliorating the severity of LB depletion. These results indicate that alveolar CO2 tension and bicarbonate concentration are major factors regulating the LB content of type II pneumocytes and suggest an important link between the gas exchange and phospholipid metabolic functions of the lung.

Animals↗

PubMed1997

Alterations of the endogenous surfactant system in septic adult rats.

Sepsis is the most common factor leading to the acute respiratory distress syndrome (ARDS) and is associated with the highest mortality rate. It has been suggested that the pulmonary surfactant system is altered and contributes to the lung dysfunction associated with ARDS. The objective of this study was to characterize the lung injury, specifically the endogenous surfactant system in septic adult rats. Sepsis was induced in male Sprague-Dawley rats by cecal ligation and perforation and resulted in significant increases in heart rates, respiratory rates, and lactate levels along with positive blood cultures in septic animals compared with a sham control group. Two distinct septic groups were developed, a septic group and a sepsis with lung injury (septic+LI) group. The septic group had no significant differences in oxygenation compared with the sham group, whereas the septic+LI group had significantly lower PaO2 and higher A-a gradient values compared to both the sham and septic groups. The total surfactant pool size was significantly lower in the septic+LI group compared with the sham group. The small surfactant aggregate to large surfactant aggregate ratio was significantly lower in the septic group and was further reduced in the septic+LI group. There were also significantly higher levels of surfactant protein A (SP-A) in both septic and septic+LI groups compared to the sham group. These results demonstrated that the endogenous surfactant system was altered in systemic sepsis without lung dysfunction and is further altered when a lung injury is present.

Analysis of Variance↗

PubMed2000

Use of stable isotope labeling technique and mass isotopomer distribution analysis of [(13)C]palmitate isolated from surfactant disaturated phospholipids to study surfactant in vivo kinetics in a premature infant.

Pulmonary surfactant is a complex mixture of phospholipids and proteins which lowers surface tension and maintains alveolar expansion at end expiration. Developmental and genetic disruption of pulmonary surfactant metabolism leads to respiratory distress in newborns. Stable isotope labeling of metabolic precursors of disaturated phospholipids, the most abundant and specific component of pulmonary surfactant, permits the measurement of the kinetics of surfactant metabolism in vivo. We measured [U-(13)C(6)]glucose incorporation into palmitic acid derived from disaturated surfactant phospholipids. A 24 h infusion of [U-(13)C(6)]glucose (140 mg kg(-1)) was administered to a premature infant who required mechanical ventilation for respiratory distress syndrome; tracheal aspirate samples were obtained at the start of the infusion and at regular intervals for the next 70 h. Each tracheal aspirate sample was incubated with osmium tetroxide to isolate disaturated surfactant phospholipids. Methyl esters of the fatty acids in the disaturated phospholipids were prepared and the enrichment of [(13)C]methyl palmitate was measured by gas chromatography/mass spectrometry (GC/MS) and gas chromatography/combination/isotope ratio mass spectrometry (GC/C/IRMS). Mass isotopomer distribution analysis (MIDA) was used to calculate the fractional synthetic rate (FSR) of palmitate synthesized from acetate. With both GC/MS and GC/C/IRMS, palmitate (13)C enrichment was first detected 12.3 h after the start of the tracer infusion. The enrichment increased in a linear fashion, reached a peak at 47 h and remained constant in the remainder of the samples. The FSR of palmitate from acetate was 5.2% per day. Stable isotope techniques and MIDA will provide insights into the kinetics of surfactant metabolism in newborns with respiratory dysfunction.

Carbon Isotopes↗

PubMed2003

Endogenous surfactant metabolism in newborn infants with and without respiratory failure.

Studies using stable isotopically labeled glucose and palmitate as precursors of pulmonary surfactant synthesis have demonstrated slow surfactant turnover in premature infants with respiratory distress syndrome (RDS). However, only limited data about surfactant turnover are available for term infants. Because acetate is a direct precursor of de novo synthesized surfactant fatty acid, we measured [1-13C1]acetate incorporation into surfactant of term infants without respiratory dysfunction (control group), preterm infants with RDS, and term infants with primary respiratory failure to determine whether stable isotopically labeled acetate would yield similar results to previous studies of preterm infants with RDS and, furthermore, would distinguish normal from abnormal surfactant turnover. Despite similar amounts of phospholipids and acetate precursor enrichment, the control group had higher fractional synthetic rate and shorter half-life of clearance than preterm infants with RDS, (fractional synthetic rate, 15.4 +/- 2.4 versus 2.2 +/- 0.4%/d, p < 0.001; half-life of clearance, 27 +/- 3 versus 105 +/- 11 h, p < 0.001). Term infants with severe respiratory failure had a lower fractional synthetic rate than those with mild disease (2.9 +/- 0.6 versus 13.8 +/- 3.5%/d, p = 0.014) and a reduced amount of phospholipids recovered from tracheal aspirates (54 +/- 17 versus 300 +/- 28 nmol, severe versus mild disease, respectively, p < 0.001). The amount of phospholipids in tracheal aspirates correlated inversely with disease severity, (r = -0.75, p = 0.01). We conclude that normal surfactant turnover in term infants is faster than in preterm infants with RDS. Surfactant turnover in term infants with severe respiratory failure is similar to that of preterm infants with RDS, suggesting either delayed maturity of the surfactant system or disruption from the underlying disease process.

Acetates↗

PubMed2001

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.

Animals↗

PubMedDate not supplied

Congenital alveolar proteinosis in the Netherlands: a report of five cases with immunohistochemical and genetic studies on surfactant apoproteins.

Congenital alveolar proteinosis is a recently described cause of lung dysfunction and respiratory distress in term neonates. In several cases a deficiency or insufficiency of surfactant apoprotein B (SP-B) has been caused by a frameshift mutation in the gene encoding SP-B. Five full-term children in three unrelated families from The Netherlands are reported. Immunohistochemistry demonstrated large amounts of surfactant proteins A and C (SP-A and SP-C) and precursors in alveolar cells and in intra-alveolar material. Results were positive for antibovine SP-B antibody but negative for antipig SP-B1 antibody, most probably reflecting differences in the antibody specificity. The findings suggest abnormal SP-B function. In two sibs, no pre-SP-C was demonstrated in the alveoli, although it was found in considerable amounts in alveolar cells. One such case has previously been reported. In two families, the parents were heterozygous for the 121 ins 2 mutation in the SP-B gene. Our findings suggest that congenital alveolar proteinosis may result from abnormalities in one or more of the surfactant proteins.

Fatal Outcome↗

PubMed1992

Acute ozone-induced lung injury in rats: structural-functional relationships of developing alveolar edema.

As part of a study on the effects of acute ozone stress on the lung surfactant system, we correlated morphometric, biochemical, and functional indices of lung injury using male rats exposed to 3 ppm ozone for 1, 2, 4, and 8 hr. Evaluation of lung mechanics, using the Pulmonary Evaluation and Diagnostic Laboratory System, revealed a significant decrease in dynamic lung compliance (ml/cmH2O/kg) from a control value of 0.84 +/- 0.02 (SEM) to 0.72 +/- 0.04 and 0.57 +/- 0.06 at 4 and 8 hr, respectively. At 2 hr there was a transient increase in PaO2 to 116 torr (control = 92 torr) followed by a decrease at 4 hr (65 torr) and 8 hr (55 torr). Morphometry of lung tissue, fixed by perfusion of fixative via the pulmonary artery at 12 cm H2O airway distending pressure, demonstrated an increase in the area of the intravascular compartment at 8 hr, in association with a 65 and 39% replacement of the alveolar area by fluid in ventral and dorsal lung regions, respectively. There was a positive correlation (r = 0.966) between alveolar edema and transudated proteins in lavage fluid. A stepwise multiple regression model, with edema as the dependent variable, suggested that pulmonary vasodilatation, hypoxemia, and depletion of surfactant tubular myelin in lavage fluid were indices for predicting alveolar edema. In a second model, with lavage protein concentration as the dependent variable, decreasing dynamic compliance and hypoxemia were predictors of progressive, intraalveolar transudation of plasma proteins. The above structural-functional relationships support the concept that ozone-induced high-protein alveolar edema is pathogenetically linked to pulmonary hyperemia, deficiency of surfactant tubular myelin, and associated lung dysfunctions.

Animals↗

PubMed2025

Lentiviral-mediated gene complementation rescues pathogenic ABCA3 variants.

The ATP-binding cassette subfamily A member 3 (ABCA3) protein on the limiting membrane of lamellar bodies in alveolar type 2 (AT2) cells transports phospholipids required for pulmonary surfactant assembly. ABCA3 deficiency results from biallelic pathogenic variants in ABCA3 and causes progressive neonatal respiratory failure or childhood interstitial lung disease (chILD). Supportive/compassionate care or lung transplantation are the only current definitive treatments for ABCA3 deficiency and progressive respiratory failure. Complementing dysfunctional ABCA3 by gene addition has therapeutic potential. Previous studies show that repairing or complementing ABCA3 in induced pluripotent stem cell (iPSC)-derived AT2 cells rescues lamellar body morphology and surfactant phospholipid composition. Pathogenic variants disrupt ABCA3 function through altered protein trafficking (type 1) or by impaired phospholipid transport (type 2) into lamellar bodies. Here we tested ABCA3 gene complementation using a human pulmonary epithelial cell line (A549) with a genomically silenced ABCA3 locus (ABCA3 KO). From this line, additional cell lines that stably express individual ABCA3 variant cDNA constructs from a single genomic locus were tested: L101P (type 1), E292V (type 2), E690K (type 2), or wild-type ABCA3. Lentiviral-mediated ABCA3 delivery to each cell line partially rescued localization to LAMP3+ vesicles, lamellar body-like structure morphology, and cell proliferation. A functional assay measuring NF-κB signaling suggested that ABCA3 complementation ameliorated aberrant inflammatory signaling in E292V or E690K (type 2) mutant lines, but not in L101P (type 1) or knockout lines. These studies highlight the therapeutic potential of gene addition as well as differences between ABCA3 pathogenic variants that may influence genetic therapy outcomes.

ABCA3 deficiency↗

PubMed1991

Ductal shunting and effective systemic blood flow following single dose surfactant treatment in the premature baboon with hyaline membrane disease.

We studied the hemodynamic effects of using natural surfactant in premature baboons with hyaline membrane disease (HMD). Study animals (n = 5) received a single dose of surfactant immediately after delivery and control animals (n = 8) did not. Using microspheres at 3, 8, and 23 h we found no significant differences in left ventricular output, effective systemic flow, systemic-to-pulmonary patent ductus arteriosus (PDA) shunting, or in cerebral or renal organ blood flow. However, both groups had large PDA shunts (fraction of LVO to lungs greater than 0.40-0.55 at 3 and 8 h) resulting in low systemic perfusion (less than 80 ml/min/kg). Single dose surfactant did not improve the myocardial dysfunction and low cerebral and renal blood flow which occur during treatment for HMD.

Animals↗

PubMed1995

Epithelial dysfunction in acute lung injury.

More than a quarter century has passed since Ashbaugh and colleagues postulated that abnormalities of surfactant are causally related to the abrupt and severe organ dysfunction that occurs in individuals with acute lung injury (ALI). In this time, much progress has been made in expanding our understanding of the normal functions of the alveolar epithelium and how these functions may be disrupted in the context of ALI. Alveolar epithelial cells are a key structural component of the spatial separation of gas and plasma, essential for normal gas exchange in the lung. In addition, alveolar epithelial cells synthesize, secrete, and take up surfactant, which, by reducing surface tension, is a key determinant of intra-alveolar pressure. Surfactant is qualitatively and quantitatively abnormal in lung injury due to changes in synthesis, secretion, intra-alveolar metabolism, and biophysical inhibition by protein and lipid inhibitors. Alveolar epithelial cells also subserve additional host defense functions, such as modulation of lymphocyte, macrophage, and neutrophil function; production of prostanoids, complement proteins, and nitric oxide; and display of major histocompatibility complex II molecules and intracellular adhesion molecule-1. Although the physiologic and pathogenic significance of some these functions is not absolutely clear, they are of potential relevance in the context of lung injury, wherein they may participate in the process of alveolar injury and repair.

Acute Disease↗

PubMed1984

Synthesis of lung surfactant-associated glycoproteins by A549 cells: description of an in vitro model for human type II cell dysfunction.

Immunocytochemical, ultrastructural, and biochemical approaches were used in a series of in vitro and in vivo experiments designed to identify characteristic changes reflecting differentiated type II cell function of A549 cells. Monolayers of A549 cells and A549 clones were maintained in culture for up to 3 weeks. Using an immunoperoxidase (PAP) technique, we demonstrated that variable proportions of A549 cells and of cells in several A549 clones reacted specifically with antibodies to high molecular weight (greater than 400,000) human surfactant-associated glycoproteins (HSAG). The cells of one clone, A549-C12, were consistently negative for HSAG, but their lamellar bodies were similar in appearance and distribution to those found in a PAP-positive clone, A549-C11, as well as in A549 cells. In addition, both C11 and C12 clones displayed time-dependent, divergent differentiation predominantly toward type II epithelium and nonciliated bronchiolar and bronchial cells. Surfactant isolated from either C11 or C12 cells revealed reduced content of disaturated phosphatidylcholine and phosphatidylglycerol when compared to human surfactant; however, a 95,000-dalton peptide immunologically related to HSAG was identified in surfactant from C11 cells but not from the PAP-negative C12 clone. Tumor xenografts produced in athymic (nude) mice following inoculation with cells from C11 and C12 clones exhibited prominent immunoperoxidase staining involving most tumor cells. Cell lines derived from these xenografts (T-11 and T-12) were also enriched in PAP-positive cells. Immunoelectron microscopy indicated that HSAG was localized in the rough endoplasmic reticulum, multivesicular bodies (MVB), intermediate MVB-lamellar forms, and abnormal pleomorphic inclusions. Moreover, two HSAG peptides, both larger than the 34,000-dalton peptide subunit found in normal human surfactant, were present in cells and media from monolayers of the T-11 cell line. We conclude that A549 cells synthesize "defective" HSAG and that the synthesis may be modulated by host factors. The results indicate that appropriate A549 clones can be used effectively as model systems for selected type II cell dysfunctions.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed1989

Bacteremia-induced suppression of alveolar surfactant production.

Sepsis is characterized by Adult Respiratory Distress Syndrome (ARDS)-like pulmonary dysfunction largely attributed to alveolar capillary endothelial cell injury which causes increased microvascular permeability and interstitial edema formation. In addition, quantitative and qualitative abnormalities of the pulmonary surfactant system may be important features of some clinical and experimental lung injuries. This study was designed to investigate the relationship of bacteremia and endotoxemia to pulmonary surfactant production in vivo. A technique for estimation of pulmonary surfactant phospholipid synthesis measuring incorporation of a stable isotope precursor [( 2-13C]acetate) into dipalmitoylphosphatidylcholine (DPPC) in alveolar lavage fluid was developed. Male 350 g Sprague-Dawley rats had placement of central venous catheters. After overnight recovery, sublethal bacteremia (Escherichia coli, 1 x 10(8) organisms, iv) and sublethal endotoxemia (Difco; 10 mg/kg, iv) were induced. Both were associated with lung microvascular permeability increases consistent with capillary endothelial injury. Eight-hour infusions of [2-13C]acetate were given. After sacrifice, bronchoalveolar washings and lung tissue were obtained and [2-13C] incorporation into lavage and lung DPPC was measured by gas chromatography mass spectroscopy. Endotoxin-treated animals had a 21.5% reduction in label incorporation into DPPC [1.215 +/- 0.145 APE (%) sham versus 0.954 +/- 0.144 APE (%) experimental, P greater than 0.05] and bacteremic animals had a 56.9% diminution of [2-13C]acetate incorporation [1.215 +/- 0.145 APE (%) sham versus 0.524 +/- 0.56 APE (%) experimental, P less than 0.05]. Bacteremia-induced dysfunction of alveolar type II epithelial cells manifested as diminished alveolar surfactant phospholipid production may be a contributing factor to sepsis-induced respiratory failure.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2001

[Surfactant replacement therapy]

OBJECTIVE: To analyze and update information about surfactant therapy replacement in newborns with lung diseases. SOURCES: Literature review, including textbooks, meta-analyses, prospective, randomized controlled trials, retrospective assessments and case studies. Literature was reviewed based on the authors clinical and scientific experience regarding surfactant replacement therapy in neonatal lung diseases. SUMMARY OF THE FINDINGS: Surfactant replacement therapy for the neonatal respiratory distress syndrome improves respiratory function, and reduces the need for oxygen supplementation and pressure support ventilation, in addition to minimizing the air leak syndrome. However, the use of surfactant did not prevent the occurrence of other intercurrent diseases such as patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, and bronchopulmonary dysplasia. The surfactant treatment decreased neonatal mortality up to 40%. The effectiveness of exogenous surfactant on other respiratory diseases with surface film dysfunction, such as meconium aspiration syndrome, pneumonia, acute respiratory distress syndrome and congenital diaphragmatic hernia has not yet been widely accepted. CONCLUSIONS: Surfactant replacement is now considered the standard treatment for newborns with respiratory distress syndrome. We hope that, in the future, new synthetic surfactant preparations will be more effective in treating other infant respiratory diseases.

Journal Article↗

PubMed1998

Lavage administration of dilute surfactants after acute lung injury in neonatal piglets.

Exogenous surfactant therapy is not standard in the acute respiratory distress syndrome (ARDS) because of a lack of proven benefit. Nonuniform surfactant distribution after either bolus or aerosol administration may be an important factor limiting response. In a previous study of acute lung injury, we demonstrated that lavage administration of Exosurf (13.5 mg phospholipid/ml) was both effective and distributed uniformly in the lungs. Since the endogenous surfactant pool is much smaller than the typical dose of exogenous surfactant administered, we hypothesized that dilute surfactant preparations (4-4.5 mg phospholipid/ml) administered by lung lavage would be equally effective in reversing pulmonary dysfunction in a piglet model of acute lung injury. We compared three dilute surfactants: Infasurf (n = 5), KL4-Surfactant (n = 6), and Exosurf (n = 5) with controls (n = 6) and undiluted Exosurf (13. 5 mg phospholipid/ml; n = 6). All dilute surfactant preparations were effective in improving oxygenation and other parameters of pulmonary function. Surfactant administered by lavage resulted in uniform lung distribution. We conclude that dilute surfactants administered by lung lavage are effective in reversing pulmonary dysfunction after acute lung injury. We speculate that doses in the range of 20-40 mg phospholipid/kg may be adequate to improve lung function in ARDS when exogenously administered surfactant is uniformly distributed in the lung.

Animals↗

PubMed1995

Healthy lungs tolerate repetitive collapse and reopening during short periods of mechanical ventilation.

The possible occurrence of lung damage if alveolar units are allowed to collapse and reopen breath by breath during mechanical ventilation with normal tidal volumes was investigated. Anaesthetised, paralysed, open chest rabbits were subjected to either intrathoracic negative (NEEP; n = 6) or positive (PEEP; n = 6) end-expiratory pressure during volume controlled mechanical ventilation. Both experimental settings were preceded by a 30 min control period and followed by a 30 min recovery period during which a PEEP of 0.2 kPa was maintained. Pao2 and pulmonary compliance deteriorated significantly in the NEEP group during the experimental period and compared to ventilation with PEEP. Partial restoration of lung mechanics and blood gases was achieved during the recovery period. After an alveolar recruitment manoeuvre, this recovery was complete. Lung clearance studied by depositing an aerosol of technetium-99m-labelled diethylenetriamine pentaacetate (99mTc-DTPA) in the alveoli, was significantly faster during ventilation with NEEP compared to the PEEP group (P = 0.0002) as well as the control period (P = 0.0029). It did not recover completely during the recovery period but remained significantly faster. Light microscopic histology was normal in both groups with no evidence of inflammation or epithelial disruption. We conclude that previously healthy rabbit lungs show only a transient disturbance of lung mechanics and blood gases with repetitive collapse and re-expansion. The integrity of the alveolar microstructure is preserved. The disturbance in the alveolo-capillary permeability persists and may indicate surfactant related alveolo-capillary barrier dysfunction.

Animals↗