Surfactant blocks lipopolysaccharide signaling by inhibiting both NFκB and PARP activation in experimental ARDS.

Surfactant plays an important role in lung homeostasis and is also involved in maintaining innate immunity within the lung. Lipopolysaccharide (LPS) is known to elicit acute proinflammatory responses in lung diseases such as acute respiratory distress syndrome and is responsible for the expression of the inducible isoform of nitric oxide synthase (iNOS). Because cells are exposed to low pH within the microenvironment of inflammatory lesions, the potential role of low environmental pH on iNOS expression was investigated. Low environmental pH-induced iNOS gene transcription involved the activation of nuclear factor-κB (NF-κB) transcription factor and IκB kinases. Here, we find that exposure of cells to low environmental pH increased both nitrite accumulation and activation of NF-κB-signaling pathway by Western blot and immunohistochemistry. In addition, treatment with surfactant prevents NF-κB translocation to the nucleus by preventing phosphorylation of IκBα, and its subsequent degradation by IKKα, and canceling low pH-induced nitrite accumulation. Surfactant also inhibited the LPS-induced PARP activation. Therefore, surfactant may regulate lung homeostasis by neutralizing acidic microenvironment in inflammatory lesions that leads to the upregulation of iNOS activity through the activation of NF-κB pathway and by PARP activation.

The apolipoprotein A-I mimetic peptide, ETC-642, reduces chronic vascular inflammation in the rabbit.

BACKGROUND: High-density lipoproteins (HDL) and their main apolipoprotein, apoA-I, exhibit anti-inflammatory properties. The development of peptides that mimic HDL apolipoproteins offers a promising strategy to reduce inflammatory disease. This study aimed to compare the anti-inflammatory effects of ETC-642, an apoA-I mimetic peptide, with that of discoidal reconstituted HDL (rHDL), consisting of full-length apoA-I complexed with phosphatidylcholine, in rabbits with chronic vascular inflammation. RESULTS: New Zealand White rabbits (n = 10/group) were placed on chow supplemented with 0.2% (w/w) cholesterol for 6-weeks. The animals received two infusions of saline, rHDL (8 mg/kg apoA-I) or ETC-642 (30 mg/kg peptide) on the third and fifth days of the final week. The infusions of rHDL and ETC-642 were able to significantly reduce cholesterol-induced expression of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the thoracic aorta (p < 0.05). When isolated rabbit HDL was pre-incubated with human coronary artery endothelial cells (HCAECs), prior to stimulation with TNF-α, it was found that HDL from ETC-642 treated rabbits were more effective at inhibiting the TNF-α-induced increase in ICAM-1, VCAM-1 and p65 than HDL isolated from saline treated rabbits (p < 0.05). There were, however, no changes in HDL lipid composition between treatment groups. CONCLUSIONS: Infusion of ETC-642 causes anti-inflammatory effects that are comparable to rHDL in an animal model of chronic vascular inflammation and highlights that apoA-I mimetic peptides present a viable strategy for the treatment of inflammatory disease.

Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome.

BACKGROUND: Respiratory distress syndrome (RDS) is a significant cause of morbidity and mortality in preterm infants. RDS is caused by a deficiency, dysfunction, or inactivation of pulmonary surfactant. Numerous surfactants of either animal extract or synthetic design have been shown to improve outcomes. New surfactant preparations that include peptides or whole proteins that mimic endogenous surfactant protein have recently been developed and tested. OBJECTIVES: To assess the effect of administration of synthetic surfactant containing surfactant protein mimics compared to animal derived surfactant extract on the risk of mortality, chronic lung disease, and other morbidities associated with prematurity in preterm infants at risk for or having RDS. SEARCH STRATEGY: Standard search methods of the Cochrane Neonatal Review Group were used. The search included MEDLINE (1966 - May 2007) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) in all languages. In addition, published abstracts of the Society of Pediatric Research were searched electronically. For abstract books that did not include key words, the search was limited to the relevant sections on pulmonary and neonatology. The bibliography cited in each publication was obtained and searched in order to identify additional relevant articles. SELECTION CRITERIA: Randomized and quasi-randomized controlled clinical trials were considered for this review. Studies that enrolled preterm infants or low birth weight infants at risk for or having RDS who were treated with either a synthetic surfactant containing surfactant protein mimics or an animal-derived surfactant preparation were included for this review. Studies that either attempted to treat or prevent respiratory distress syndrome were included. DATA COLLECTION AND ANALYSIS: Primary outcome measures, including mortality, chronic lung disease and multiple secondary outcome measures were abstracted by the reviewers. Statistical analysis was performed using Review Manager software. Categorical data was analyzed using relative risk, risk difference, and number needed to treat. 95% confidence intervals reported. A fixed effects model was used for the meta-analysis. Heterogeneity was assessed using the I-squared statistic. MAIN RESULTS: Two studies were identified that compared protein containing synthetic surfactants to animal derived surfactant preparations. In a meta-analysis of these two studies, infants who received protein containing synthetic surfactant compared to animal derived surfactant extract did not demonstrate significantly different risks of prespecified primary outcomes: mortality at 36 weeks [typical RR 0.81 (95% CI 0.64, 1.03)], chronic lung disease at 36 weeks [typical RR 0.99 (95% CI 0.84, 1.18)], or the combined outcome of mortality or chronic lung disease at 36 weeks [typical RR 0.96 (95% CI 0.82, 1.12)]. There were also no differences in any of the secondary outcomes regarding complications of prematurity between the two surfactant groups with the exception of necrotizing enterocolitis. A decrease in the risk of necrotizing enterocolitis was noted in infants who received protein containing synthetic surfactants compared to animal derived surfactant extract [typical RR 0.60 (95% CI 0.42, 0.86)]. However, this was a secondary outcome in both of the primary studies and there was moderate heterogeneity between the studies. AUTHORS' CONCLUSIONS: In two trials of protein containing synthetic surfactants compared to animal derived surfactant extract, no statistically different clinical differences in death and chronic lung disease were noted. Further well designed studies of adequate size and power will be needed to confirm and refine these findings.

Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome.

BACKGROUND: Respiratory distress syndrome (RDS) is a significant cause of morbidity and mortality in preterm infants. RDS is caused by a deficiency, dysfunction, or inactivation of pulmonary surfactant. Numerous surfactants of either animal extract or synthetic design have been shown to improve outcomes. New surfactant preparations that include peptides or whole proteins that mimic endogenous surfactant protein have recently been developed and tested. OBJECTIVES: To assess the effect of administration of synthetic surfactant containing surfactant protein mimics compared to animal derived surfactant extract on the risk of mortality, chronic lung disease, and other morbidities associated with prematurity in preterm infants at risk for or having RDS. SEARCH STRATEGY: Standard search methods of the Cochrane Neonatal Review Group were used. The search included MEDLINE (1966 - May 2007) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) in all languages. In addition, published abstracts of the Society of Pediatric Research were searched electronically. For abstract books that did not include key words, the search was limited to the relevant sections on pulmonary and neonatology. The bibliography cited in each publication was obtained and searched in order to identify additional relevant articles. SELECTION CRITERIA: Randomized and quasi-randomized controlled clinical trials were considered for this review. Studies that enrolled preterm infants or low birth weight infants at risk for or having RDS who were treated with either a synthetic surfactant containing surfactant protein mimics or an animal-derived surfactant preparation were included for this review. Studies that either attempted to treat or prevent respiratory distress syndrome were included. DATA COLLECTION AND ANALYSIS: Primary outcome measures, including mortality, chronic lung disease and multiple secondary outcome measures were abstracted by the reviewers. Statistical analysis was performed using Review Manager software. Categorical data was analyzed using relative risk, risk difference, and number needed to treat. 95% confidence intervals reported. A fixed effects model was used for the meta-analysis. Heterogeneity was assessed using the I-squared statistic. MAIN RESULTS: Two studies were identified that compared protein containing synthetic surfactants to animal derived surfactant preparations. In a meta-analysis of these two studies, infants who received protein containing synthetic surfactant compared to animal derived surfactant extract did not demonstrate significantly different risks of prespecified primary outcomes: mortality at 36 weeks [typical RR 0.81 (95% CI 0.64, 1.03)], chronic lung disease at 36 weeks [typical RR 0.99 (95% CI 0.84, 1.18)], or the combined outcome of mortality or chronic lung disease at 36 weeks [typical RR 0.96 (95% CI 0.82, 1.12)]. There were also no differences in any of the secondary outcomes regarding complications of prematurity between the two surfactant groups with the exception of necrotizing enterocolitis. A decrease in the risk of necrotizing enterocolitis was noted in infants who received protein containing synthetic surfactants compared to animal derived surfactant extract [typical RR 0.60 (95% CI 0.42, 0.86)]. However, this was a secondary outcome in both of the primary studies and there was moderate heterogeneity between the studies. AUTHORS' CONCLUSIONS: In two trials of protein containing synthetic surfactants compared to animal derived surfactant extract, no statistically different clinical differences in death and chronic lung disease were noted. In general, clinical outcomes between the two groups were similar. Further well designed studies of adequate size and power will help confirm and refine these findings.

Lucinactant: in neonatal respiratory distress syndrome.

Lucinactant, formerly known as KL(4) surfactant, is a novel synthetic lung surfactant containing phospholipids and an engineered peptide, sinapultide, which is designed to mimic the actions of human surfactant protein B. It has been developed for use in the prevention or treatment of respiratory distress syndrome (RDS), a common problem in premature infants, which results from a deficiency or degradation of pulmonary surfactant. Lucinactant is administered intratracheally soon after birth as a replacement surfactant. In the pivotal randomized, double-blind, prophylaxis trial in premature infants, the incidence of RDS at 24 hours after birth was significantly lower in lucinactant recipients than in recipients of colfosceril palmitate, a synthetic non-protein-containing surfactant. RDS-related mortality at 14 days was significantly lower in lucinactant recipients than in recipients of colfosceril palmitate or beractant, a bovine-derived surfactant. In another randomized, double-blind, prophylaxis trial in premature infants, the rate of survival without bronchopulmonary dysplasia at 28 days of age in lucinactant recipients was not inferior to that in recipients of poractant alfa, a porcine-derived surfactant. Lucinactant was generally well tolerated. Adverse events were transient and related to the administration procedure. There were no differences in the incidences of complications of prematurity between lucinactant and the other surfactants.

Colfosceril palmitate. A review of the therapeutic efficacy and clinical tolerability of a synthetic surfactant preparation (Exosurf Neonatal) in neonatal respiratory distress syndrome.

Colfosceril palmitate (dipalmitoylphosphatidylcholine) is the primary surface-active agent of natural lung surfactant and the major constituent of exogenous surface replacement preparations. Exogenous surfactants derived from either natural (i.e. animal and human) or synthetic sources are indicated for the prophylaxis and treatment of neonatal respiratory distress syndrome. One of the synthetic surfactants, Exosurf Neonatal, is the focus of this review. This preparation is composed of colfosceril palmitate plus cetyl alcohol and tyloxapol, which facilitate rapid spreading and adsorption of the surface-active agent at the air-alveolar interface. For review purposes, this preparation is referred to only as colfosceril palmitate. Comparative trials with air placebo have shown that colfosceril palmitate improves clinical outcome in infants weighing greater than 700g at birth by reducing mortality and increasing the number of infants who survive without bronchopulmonary dysplasia. It also reduces the number of deaths from respiratory distress syndrome and decreases the incidence of air leak events such as pulmonary interstitial emphysema and pneumothorax. Although colfosceril palmitate itself is very well tolerated and does not increase the incidence of most complications of prematurity or of respiratory distress syndrome, its use is associated with a higher incidence of apnoea of prematurity and pulmonary haemorrhage compared with air placebo, possibly because of earlier extubation of surfactant-treated infants following an improved clinical course and decreased pulmonary vascular resistance secondary to improved ventilation, respectively. Colfosceril palmitate thus has an established efficacy in the prophylaxis and treatment of premature infants with respiratory distress syndrome. Ongoing trials may identify whether prophylactic or rescue administration of the surfactant preparation is the preferred approach and whether different dosage regimens or different administration techniques impart greater therapeutic efficacy. Importantly, it also remains to be determined whether any of the available surfactant preparations, including Exosurf Neonatal, will provide distinct therapeutic advantages over the others.

The development of surfactant replacement therapy and the various types of replacement surfactants.

This overview has been intended to ease the reader who is not familiar with the surfactant replacement field into this area. The discussion of various surfactants should help in the clarification of terminology use by different authors and provides a perspective for the following articles, which deal more completely with many of the issues raised in this article.

Biophysical behavior of lung surfactant: implications for respiratory physiology and pathophysiology.

The major emphasis of this article has been the complex, multicomponent system of surfactants that are required for proper pulmonary mechanics and function in the mammalian lung. Although LS was discovered over 30 years ago, and soon after was linked directly with neonatal RDS, it has taken a significant time for researchers to develop a fundamental understanding of the pulmonary surfactant system, and its actions and roles in respiratory physiology. Nonetheless, knowledge about LS has increased greatly over the past decade, and it is now clear that exogenous surfactant replacement therapy for infants with RDS provides a substantial clinical advantage for these patients. Indeed, the therapy is life-saving in many very small premature infants, and as experience accrues, and therapy is optimized, this advance is clearly a major step forward in neonatology. Perhaps the most prominent theme that has been presented throughout the discussion here is that pulmonary surfactant research must take advantage of interdisciplinary descriptions and cross-correlations for accurate and rapid progress. One positive feature of prior work on lung surfactant replacement and RDS is that its difficulty has forced investigators toward a level of understanding that is sound enough to extend LS research into related fields, such as lung injury and ARDS. These areas have their own complications, including a much more diverse pathology and injury progressions than found with neonatal RDS. In fact, if defining the role of lung surfactant in ARDS (and developing replacement therapy for it) had been the goal of investigators before considering neonatal RDS, it is difficult to imagine a positive outcome. The situation now, however, is one where it is realistic to think of recognizing when and how LS effects will occur in different ARDS lung injuries, so that surfactant replacement will have the best opportunity to help mitigate their progressive pathology. In dealing with ARDS, it is well to remember that there are a variety of complicating factors, since lung injuries vary with animal age and species, and according to the level and duration of exposure. For example, in the hyperoxic injury described in the previous section there was clearly significant LS involvement. However, had animals been subjected to a lower level of oxygen (eg, 60%), even for a comparatively long time (eg, 21 days), the entire pathologic pattern would have been altered, as demonstrated, for example, by Holm et al.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of inhaled nitric oxide and surfactant treatment on lung function and pulmonary hemodynamics in bronchoalveolar-lavage-induced respiratory failure.

Our aim was to study whether inhaled nitric oxide (iNO) moderates respiratory failure induced by bronchoalveolar lavage (BAL) without severe pulmonary hypertension. The following successive treatments, interrupted by 20-30-min rest periods, were given to piglets: iNO (20 ppm for 20 min), exogenous surfactant, iNO, Nomega-nitro-L-arginine methyl ester (L-NAME), and iNO. The controls inhaled NO first after L-NAME. Lung mechanics and hemodynamics were measured serially. The pulmonary to systemic arterial pressure ratio decreased during iNO and tended to increase after its discontinuation. In contrast, the iNO-induced decreases in severity of respiratory failure were not reversible during the rest periods. In a second experiment, iNO/placebo and surfactant containing (3)H-labeled dipalmitoyl phosphatidylcholine were given to rabbits. The surfactant aggregates and the surface activity from postmortem BAL, and extravascular lung water, were studied. Inhaled NO improved the surface activity and increased the large surfactant aggregates. There was no detectable decrease in extravascular lung water. The results suggest that a low dose of iNO has a beneficial effect on the gas exchange that is in part unrelated to its effect on the pulmonary vasculature.

Economic outcomes of colfosceril palmitate rescue therapy in infants weighing 1250g or more with respiratory distress syndrome: results from a randomised trial.

An analysis of the economic data from a multicentre, randomised, placebo-controlled clinical trial of colfosceril palmitate in infants with neonatal respiratory distress syndrome (NRDS) and birthweights of 1250g or more is presented. Two 5 ml/kg (67.5 mg/kg) doses of a synthetic surfactant (colfosceril palmitate) or air placebo were administered to 1237 infants who were receiving mechanical ventilation and had an arterial/alveolar oxygen tension ratio of less than 0.22. In addition to the clinical end-points for safety and efficacy, data were collected on length of hospital stay, days in the neonatal intensive care unit, days on mechanical ventilation, days on oxygen, and hospital charges until the child reached 1-year adjusted age. One-year adjusted age is attained when the time elapsed since birth is equal to 365 days plus the number of days of prematurity. Rescue treatment with synthetic surfactant therapy has been shown to reduce the incidence of complications of NRDS. Growth and development of infants who received colfosceril palmitate therapy in the study and survived to 1-year adjusted age were equivalent to those of the survivors in the air placebo group. For the cohort of treated infants, colfosceril palmitate reduced the average length of stay at 2 levels of care needed during both the initial hospitalisation (a reduction of 8 days overall and 5 days in intensive care) and all first year hospitalisations (a reduction of 9 days overall and 5 days in intensive care). Total hospital charges for the initial hospitalisation and through 1-year adjusted age for a hypothetical cohort of 100 infants treated with colfosceril palmitate were less than those for a comparable cohort in the air placebo group. The results would, therefore, suggest that rescue therapy with colfosceril palmitate in infants with NRDS and birthweights over 1250g can result in substantial reductions in hospital resource utilisation and charges in addition to the clinical benefits associated with its use.

Randomized trial of artificial surfactant (ALEC) given at birth to babies from 23 to 34 weeks gestation.

Artificial surfactant (ALEC) composed of dipalmitoylphosphatidylcholine and unsaturated phosphatidylglycerol in a ratio of 7:3 (w/w) and a dose of 50-100 mg was suspended in 1 ml of cold saline and used at birth as a prophylaxis against the respiratory distress syndrome and its complications in a two centre randomized prospective trial involving 341 babies from 23 to 34 weeks gestation regardless of their antenatal problems. The surfactant had little effect in babies above 29 weeks gestation and was most beneficial in babies under 30 weeks gestation (67 controls and 69 surfactant treated babies). In this subgroup the artificial surfactant significantly reduced the inspired oxygen and peak ventilator pressure requirements during the first 96 h, the incidence of intraventricular haemorrhages from 40% to 19% (P less than 0.01), the overall mortality from 36% to 17% (P less than 0.02), the mortality due to RDS from 31% to 9% (P less than 0.01), the need for more than 28 days oxygen from 37% to 21% (P = 0.05) and the use of pancuronium in ventilated babies from 52% to 27% (P less than 0.01). There were no apparent side effects. This protein free, artificial surfactant should be a useful addition to the therapy of babies under 30 weeks gestation to reduce the severity of their RDS and the incidence of serious complications.

Kinetics of surfactant in respiratory diseases of the newborn infant.

Deficiency or dysfunction of pulmonary surfactant plays a critical role in the pathogenesis of respiratory diseases in the newborn. We describe the studies made by applying two recently developed methods to measure surfactant kinetics. The first allows the measurement of endogenous surfactant phosphatidylcholine (PC) synthesis and kinetics by a constant intravenous infusion of glucose or fatty acids labeled with stable isotope 13C. The second method consists of endotracheal administration of a tracer dose of 13C-labeled dipalmitoyl-phosphatidylcholine (DPPC) to measure disaturated-phosphatidylcholine (DSPC) half-life and apparent pool size. We present the results of surfactant kinetics in some of the respiratory diseases of the newborn infant.

The lubricating ability of biomembrane models with dipalmitoyl phosphatidylcholine and gamma-globulin.

Two kinds of friction tests were conducted to investigate the lubricating effect of the injection of amphiphilies on the osteoarthritic joint. The effects of the addition of L alpha-dipalmitoyl phosphatidyl-choline (L alpha-DPPC) riposomes and gamma-globulin in a saline solution of sodium hyaluronate (HA) were evaluated through pendulum friction tests. The frictional characteristics of pig shoulder joints were confirmed to depend on the viscosity of the lubricants only in the physiologically low load condition and in the condition immediately after loading. Detergent (polyoxyethylene p-t-octylphenyl ether) was successfully used to remove adsorbed films from the articular surfaces. The friction coefficient of natural synovial joints was significantly increased in a mode of mixed lubrication with the HA solution of 0.2 g/dl by the treatment of the surface with the detergent. The addition of L alpha-DPPC riposomes or gamma-globulin significantly improved the boundary lubricating ability of the articular surfaces treated with the detergent, depending on the quantity of those additives. It appears that the L alpha-DPPC riposomes and gamma-globulin can form protective films on the articular surfaces like a biomembrane. Moreover, the reciprocating frictional behaviour in sliding pairs of pig articular cartilages and glass plates was studied in order to elucidate the tribological role of those constituents in the boundary lubricating film on the articular surface. Pig synovial fluid and water solutions of HA were used as lubricants. The synovial fluid had superior lubricating ability compared to the HA solution of equivalent viscosity under a physiologically high load condition. This fact seems to be responsible for the boundary lubricating ability of constituents other than hyaluronic acid. Langmuir-Blodgett (LB) films of L alpha-DPPC on the glass plate were kept at a low and stable friction coefficient, depending on the number of film layers. In conditions of mixed films with L alpha-DPPC and gamma-globulin, the frictional behaviour was improved by increasing the quantity of gamma-globulin. A model is proposed in which the effective adsorbed films are composed of proteins, phospholipids and other conjugated constituents on the articular surfaces to be accurate in describing the boundary lubricating mechanism. The mechanism is controlled by hydrophobic groups in those amphiphilies.

The potential of liposomes as dental drug delivery systems.

The potential of liposomes as a drug delivery system for use in the oral cavity has been investigated. Specifically targeting for the teeth, the in vitro adsorption of charged liposomal formulations to hydroxyapatite (HA), a common model substance for the dental enamel, has been conducted. The experiments were performed in human parotid saliva to simulate oral-like conditions. It was observed, however, that precipitation occurred in tubes containing DPPC/DPTAP or DPPC/DPPG-liposomes in parotid saliva with no HA present, indicating that constituents of parotid saliva reacted with the liposomes. The aggregation reactions of liposome-parotid saliva mixtures were examined by turbidimetry and by atomic force microscopy. Negatively charged DPPC/DPPS and DPPC/PI-liposomes were additionally included in these experiments. The initial turbidity of positive DPPC/DPTAP-liposomes in parotid saliva was very high, but decreased markedly after 30 min. AFM images showed large aggregates of micelle-like globules known to be present in saliva. The turbidity of the various negatively charged liposome and parotid saliva mixtures stayed relatively constant throughout the measuring time; however, their initial turbidities were different; mixtures with DPPC/DPPG-liposomes were the most turbid and DPPC/DPPA-liposomes the least. Pyrophosphate (PP) was added to the various liposome-parotid saliva mixtures to examine the effect of Ca(2+) on the interactions. The effect of PP treatment of the negatively charged liposome-parotid saliva mixtures was most pronounced with DPPC/DPPG-liposome mixtures where it caused a sudden drop in turbidity. For positive DPPC/DPTAP liposome and parotid saliva mixtures, the effect of PP was minimal. These experiments showed that saliva constituents may interact with liposomes. An appropriate liposomal drug delivery system intended for use in the oral cavity seems to be dependent on the liposomal formulation. Based on the present results, negatively charged DPPC/DPPA-liposomes seem to be most suitable for use in the oral cavity as they were found to be the least reactive with the components of parotid saliva.

Exogenous surfactant therapy for ARDS.

Regardless of the cause, a common pathophysiological feature of patients with acute respiratory distress syndrome is a dysfunction of the endogenous surfactant system. Although exogenous surfactant therapy has proven to be an effective treatment for neonatal respiratory distress syndrome, no similar current effective therapy exists for patients with acute respiratory distress syndrome. This is mainly due to the complexity of the lung injury that is involved with this disorder. Results from clinical trials, to date, have failed to show an improvement in patient survival after administration of exogenous surfactant; however, ongoing and future research efforts suggest that this therapy may eventually be feasible.