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At least 199 records · Page 11Linked to original sources

PubMed2001

Therapeutic time-window of a group IIA phospholipase A2 inhibitor in rabbit acute lung injury: correlation with lung surfactant protection.

OBJECTIVE: We attempted to determine whether group IIA secretory phospholipase A2 (sPLA2-IIA) blockade after the onset of lung injury exerted therapeutic efficacy in the treatment of oleic acid (OA)-induced acute lung injury by using S-5920/LY315920Na, a novel specific inhibitor of sPLA2-IIA, with special interest in the changes of lung surfactant. DESIGN: Prospective animal study. SETTING: University laboratory. SUBJECTS: Forty Japanese white rabbits. INTERVENTIONS: The rabbits, under anesthesia, were endotracheally intubated and mechanically ventilated and then were divided into the following groups: OA + vehicle groups, intravenous infusion of OA for the first 2 hrs (0.1 mL x kg(-1) x hr(-1)) with the addition of vehicle (1 or 2 hrs after OA administration, each n = 9, total 18 rabbits); OA + S-5920/LY315920Na groups, treated identically to the OA control with the addition of S-5920/LY315920Na (1 mg/kg bolus followed by infusion at 0.5 mg x kg(-1) x hr(-1)) after OA (1 or 2 hrs after OA administration, each n = 9, total 18 rabbits); saline control groups, treated with saline instead of OA with the addition of vehicle (1 hr after OA administration, 4 rabbits). Arterial blood gas, lung mechanics, lung inflammation, lung surfactant phospholipids, and production of inflammatory mediators in the lung were measured. MEASUREMENTS AND MAIN RESULTS: Treatment with S-5920/LY315920Na 1 hr after OA infusion, but not 2 hrs after infusion, significantly attenuated the lung injury, as estimated by hypoxemia, decreased lung compliance, pulmonary edema, and vascular permeability. The therapeutic efficacy was similar to that found in our previous pretreatment study. The treatment after 1 hr dramatically inhibited OA-induced surfactant degradation in the bronchoalveolar lavage fluid (BALF), without affecting the concentrations of thromboxane A2, leukotriene B4, and interleukin-8 in BALF. The degree of surfactant degradation in BALF paralleled well with the severity of the lung injury. Furthermore, recombinant human sPLA2-IIA reproduced the similar hydrolysis pattern of isolated surfactant in vitro, which was inhibited by S-5920/LY315920Na. CONCLUSIONS: Our results indicate that therapeutic blockade of sPLA2-IIA ameliorated lung dysfunction via protection of surfactant degradation in an animal model of acute lung injury, and they suggest a new strategy in treating clinical acute lung injury.

Acetates↗

PubMed2005

The effects of diethylcarbamazine on the ultrastructure of lung cells in vivo.

The pulmonary surfactant synthesis is disturbed in experimentally induced asthma, as are the intracellular storage capacity and its physical activity. These alterations may also be present in chronic asthmatic patients, and therefore the dysfunction of the pulmonary surfactant system may play an important role in the pathophysiology of asthma. Some clinical reports have described favorable results with the use of diethylcarbamazine (DEC) in patients with bronchial asthma showing that DEC is effective in terminating acute attacks of bronchial asthma. The present study aimed to analyze the ultrastructural alterations of lung cells after treatment in vivo with diethylcarbamazine. After 12 days of treatment with DEC, when compared with control samples, type II pneumocytes showed active nuclei with abundant euchromatin and evident nucleoli, and a substantially greater number of mature secretion vesicle. On the other hand, type I pneumocytes showed no morphological alterations. After DEC treatment, lung macrophages also presented several characteristics of cellular activation such as nuclei with a prominence of euchromatin and central nucleoli as well as an abundance of early and late endossomes distributed throughout the cytoplasm. These results confirm that DEC exerts a role in the activation of important pulmonary cellular pathways, which are probably related to the clinical improvement of asthma symptoms after DEC treatment.

Animals↗

PubMed1992

Cerebroelectrical depression following surfactant treatment in preterm neonates.

During surfactant treatment of respiratory distress syndrome, 23 premature newborns were investigated with continuous amplitude-integrated electroencephalography (cerebral function monitors). Simultaneously, arterial blood pressure and transcutaneous blood gas values were recorded. A short (less than 10 minutes) but significant decrease in cerebral activity was seen in almost all neonates immediately after the surfactant instillation, in spite of an improved pulmonary function. In 21 of 23 neonates, a transient fall in mean arterial blood pressure of 9.3 mm Hg (mean) occurred coincidently with the cerebral reaction. Neonates in whom intraventricular hemorrhage developed tended to have lower presurfactant mean arterial blood pressure (P greater than .05), but they had a significantly lower mean arterial blood pressure after surfactant instillation (P less than .05). No other differences were found between neonates in whom intraventricular hemorrhage developed and those without intraventricular hemorrhage. The present findings demonstrate that an acute cerebral dysfunction may occur after surfactant instillation. In some vulnerable neonates with arterial hypotension and severe pulmonary immaturity, the fall in mean arterial blood pressure may increase the risk of cerebral complications and could be related to an unchanged rate of intraventricular hemorrhage after surfactant treatment.

Biological Products↗

PubMed2006

The future of surfactant therapy during ALI/ARDS.

The importance of pulmonary surfactant in maintaining normal lung function, and the observations that alterations in endogenous surfactant contribute to the lung dysfunction associated with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), provide a rationale for administering exogenous surfactant in this setting. The results of clinical trials have been variable, however, in part due to the various surfactant preparations used, the different delivery and dosing methods employed, and the types of patients targeted for this therapy. Based on the insight gained from these studies, ongoing trials have modified these factors to optimize outcome, including one trial that is focusing on patients with direct lung insults such as pneumonia and aspiration. The future of surfactant therapy may well take advantage of the recently described host defense functions of this material. Based on extensive in vitro data as well as in vivo animal studies demonstrating the anti-inflammatory and antibacterial functions of various surfactant components, administration of surfactant earlier in the course of the disease, when lung inflammation is present but before severe lung dysfunction occurs, may prove to be optimal. This review discusses both the biophysical and host defense functions of surfactant in the context of novel therapeutic approaches for patients with ALI/ARDS.

Animals↗

PubMed2000

Function and composition of pulmonary surfactant and surfactant-derived fatty acid profiles are altered in young adults with cystic fibrosis.

STUDY OBJECTIVES: To determine whether chronic lung inflammation in young adult patients with cystic fibrosis (CF) alters the composition and function of surfactant and surfactant components in bronchoalveolar secretions. DESIGN: A prospective, descriptive study. SETTING: An adult CF center in a tertiary health-care center. PARTICIPANTS: Thirteen normal volunteer (NV) subjects recruited via local advertising and 15 CF patients recruited from the CF center. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We performed BAL and measured surfactant-associated protein A (SP-A) via enzyme-linked immunosorbent assay in BAL fluid (BALF), and quantitated total phospholipid, phospholipid subclass, and fatty acid subclass content of extracted BALF. We also determined the protein and phospholipid content, SP-A content, and functional characteristics of surfactant isolated from BALF via high-speed centrifugation. The phospholipid-to-protein ratio (milligram/milligram) of surfactant isolated by centrifugation (mean +/- SEM) was 1.01 +/- 0.07 for NV subjects and 2.62 +/- 0.42 for CF patients (p = 0.0001). Minimal surface tension was < 1 dyne.s.cm(-5) in all samples from NV subjects, but 21.9 +/- 0.73 dyne.s.cm(-5) for surfactant from CF patients. Immunoblotting of isolated surfactant revealed a marked decrease in SP-A for CF patients, compared to NV subjects. However, mean concentrations of SP-A in BALF that had not been subjected to high-speed centrifugation to isolate surfactant were not significantly different for CF patients (4.7 +/- 0.8 microgram/mL) vs NV subjects (4.6 +/- 0.2 microgram/mL). Additionally, phospholipid-to-protein ratios (0.32 +/- 0.04 for NV subjects vs 0.10 +/- 0.02 for CF patients; p < 0.0001) in extracted uncentrifuged BALF, and SP-A-to-protein ratios (microgram/milligram) in BALF were significantly depressed (74 +/- 8 for NV subjects vs 16 +/- 3 for CF patients; p < 0.0001). The phospholipid and fatty acid subclass profiles of extracted CF BALF vs NV BALF revealed a decreased mean phosphatidylcholine-to-sphingomyelin ratio (20.7 +/- 10.0 vs 55.2 +/- 8.7; p = 0.002), increased oleic acid content (12.1 +/- 2.3 nmol/mL vs 3.2 +/- 0.9 nmol/mL; p < 0.01), and increased arachidonic acid content (2.2 +/- 0.5 nmol/mL vs 0.6 +/- 0.3 nmol/mL; p < 0.05) for CF patients. CONCLUSIONS: Altered phospholipid-to-protein ratios and phospholipid subclasses, altered surfactant-derived fatty acid profiles, high minimal surface tension, and decreased association of SP-A with lipid components of isolated surfactant indicate that surfactant components are considerably altered and dysfunctional in lower respiratory tract secretions of CF patients. Surfactant composition and function are altered in CF, and the pattern of phospholipid and surfactant-derived fatty acid subclass alterations in CF are characteristic of ongoing lung injury and may depress surfactant function.

Adult↗

PubMed1996

Surfactant treatment before reperfusion improves the immediate function of lung transplants in rats.

An impaired function of alveolar surfactant can cause lung transplant dysfunction early after reperfusion. In this study it was investigated whether treatment with surfactant before reperfusion improves the immediate function of lung transplants and whether an improved transplant function was associated with an increase in alveolar surfactant components. Left lungs with 6-h (n = 8) or prolonged 20-h ischemia (n = 10) were transplanted syngeneically in rats. In both ischemia groups half of the lung transplants were treated with surfactant just before reperfusion. Lung function was measured during reperfusion for 1 h. Thereafter, the rats were killed and bronchoalveolar lavage was performed to measure alveolar surfactant components. We found that surfactant treatment improved the immediate function of lung transplants in parallel with a higher amount of total surfactant phospholipids, a higher percentage of the heavy subtype of surfactant, a normalized percentage of phosphatidylcholine, and a higher amount of endogenous surfactant protein A (SP-A). We conclude that surfactant treatment before reperfusion does improve the immediate lung transplant function in rats in association with an increase in alveolar surfactant components. More particularly, the amount of (endogenous) SP-A is thought to be crucial for the efficacy of surfactant treatment after lung transplantation.

Animals↗

PubMed2002

The role of exogenous surfactant in the treatment of acute lung injury.

A number of conditions, such as pneumonia, trauma, or systemic sepsis arising from the gut, may result in the acute respiratory distress syndrome (ARDS). Because of its significant morbidity and mortality, ARDS has been the focus of extensive research. One specific area of interest has been the investigation of the role of the surfactant system in the pathophysiology of this disease. Several studies have demonstrated that alterations of surfactant contribute to the lung dysfunction associated with ARDS, which has led to investigations into the use of exogenous surfactant as a therapy for this syndrome. Clinical experience with surfactant therapy has been variable owing to a number of factors including the nature of the injury at the time of treatment, the specific surfactant preparation utilized, the dose and delivery method chosen, the timing of surfactant administration over the course of the disease, and the mode of ventilation used during and after surfactant administration.

Animals↗

PubMed2006

[Value of surfactant replacement therapy in the treatment of acute respiratory distress syndrome].

Acute respiratory distress syndrome (ARDS) is a common, devastating clinical problem arising from a number of conditions, such as pneumonia, trauma or sepsis. Because of its significant mortality and morbidity, ARDS has been in the focus of extensive experimental and clinical research. Since there is little doubt that alterations of the surfactant system contribute to lung dysfunction and the onset of ARDS, several clinical studies examined the therapeutic safety and efficacy of a surfactant replacement therapy. Clinical experience with exogenous surfactant has proven inconsistent as a therapeutic modality for adult patients with ARDS. This is mainly due to a number of confounding factors, e.g. severity of injury at the time of treatment, dosing regimes and delivery methods used in different trials. However, current data suggest that patients with direct ARDS (e.g. pneumonia, aspiration) could benefit from surfactant replacement therapy rather than patients with indirect ARDS (e.g. sepsis, trauma). Although surfactant replacement therapy has been shown to significantly reduce mortality in neonates with ARDS, there has been no large randomised clinical trial showing that exogenous surfactant improves outcome in adults with respiratory failure. Therefore, surfactant therapy cannot be recommended for routine clinical use in adult patients and has to be considered as a last resort treatment.

Humans↗

PubMed1993

Cardiopulmonary bypass significantly reduces surfactant activity in children.

Lung injury remains an important problem after cardiopulmonary bypass. The contribution of altered surfactant concentration or activity to pulmonary dysfunction after cardiopulmonary bypass is unclear. Recent evidence indicates that alveolar surfactant exists in specific aggregate forms that differ with respect to density, phospholipid composition, and function. A transition from surface active, higher density, large aggregates of surfactant to lower density, small aggregates that possess reduced surface activity has been demonstrated after experimental lung injury. The purpose of the present study was to examine surfactant aggregate fractions before and after bypass in children. Twelve acyanotic patients, aged 2 to 12 years, underwent intraoperative pulmonary function testing followed by bronchoalveolar lavage before incision and approximately 1 hour after termination of cardiopulmonary bypass. Saturated phosphatidylcholine pool sizes and total protein content of the small- and large-aggregate fractions of bronchoalveolar lavage fluid were determined. One hour after termination of cardiopulmonary bypass, the ratio of saturated phosphatidylcholine in small-aggregate as compared with that in large-aggregate fractions increased (mean +/- standard error) from 0.19 +/- 0.03 to 0.37 +/- 0.07 (p < 0.02), as did the ratio of saturated phosphatidylcholine to protein in the small-aggregate fraction (from 0.04 +/- 0.01 to 0.08 +/- 0.02, p < 0.05). Reductions in forced vital capacity (-19% +/- 5%), inspiratory capacity (-15% +/- 3%), and small airway flow rates (-32% +/- 6%) were also observed after bypass. These changes were accompanied by a fivefold increase in alveolar polymorphonuclear leukocyte content. The present study suggests that cardiopulmonary bypass of moderate duration in relatively healthy children is associated with surfactant changes that are similar in type and magnitude to those observed in experimental lung injury.

Bronchoalveolar Lavage Fluid↗

PubMed2026

CRISPR screening identifies DTX4 governing alveolar macrophage cholesterol efflux in pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain incompletely defined. Here, through a genome-wide CRISPR screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify DTX4 as a pivotal regulator of cholesterol efflux in AMs. In mice, AAV-mediated silencing of DTX4 led to excessive AM lipid accumulation, exacerbated proteinosis, increased lung opacities, and deteriorated pulmonary function. Similarly, DTX4 depletion in primary AMs impaired cholesterol efflux and promoted intracellular lipid deposition. Conversely, AM-specific overexpression of DTX4 in the Csf2ra-/- PAP model markedly alleviated lipid accumulation, mitigated alveolar proteinosis, restored lung densities, and rescued pulmonary function. Mechanistically, DTX4 stabilizes the GM-CSF receptor via an E3-independent interaction to sustain JAK2/STAT5 signaling, which reciprocally maintains DTX4 transcription. This positive-feedback loop drives PPARγ expression, and its disruption in PAP impairs cholesterol efflux, a defect partially reversible by ectopic PPARγ expression. Collectively, our findings identify DTX4 as a central orchestrator of AM cholesterol efflux and surfactant homeostasis, positioning it as a promising therapeutic target for PAP.

Animals↗

PubMed1996

Effect of lung contusion on surfactant composition in multiple-trauma patients.

OBJECTIVE: The aim of this study was to investigate alterations of the surfactant system in multiple-trauma patients (MTP) with lung contusion and the influence of single- or multiple-organ dysfunction syndrome (OF/MOF) on the surfactant system. SETTING: University hospital, trauma-intensive care unit. DESIGN: Prospective, nonrandomized study. METHODS: MTP with an Injury Severity Score > 19 points have been recorded prospectively since 1992. Bronchoalveolar lavages were obtained daily either until day 14 or extubation. Three groups of MTP were compared: noL: MTP, no lung contusion (n = 14); LuCo-: MTP, lung contusion, no OF/MOF (n = 17); LuCo+: MTP, lung contusion, with OF/MOF (n = 10). Also, surfactant samples of 11 healthy volunteers (Con) were investigated and compared with MTP. All data were presented as mean +/- SEM. Statistical analysis were performed using programs of SPSS 6.0.1. (univariate ANOVA, Fisher's Exact Test, p < = 0.05). RESULTS: There were no differences in sex and age. Injury Severity Score was significantly impaired in group LuCo+ (44 +/- 4), compared with groups noL (31 +/- 3) and LuCo- (34 +/- 3). Group noL showed no statistical differences for lung function, total protein, and total phospholipid content of the bronchoalveolar lavage compared with group LuCo-. Furthermore, the relative content of phosphatidylcholine and phosphatidylglycerol in total phospholipids and surfactant-associated protein A were not significantly altered compared with group LuCo-. Lung function in group LuCo+ was significantly impaired and led to hypoxemia on the day of trauma. Total protein content and total phospholipids were significantly elevated in group LuCo+ compared with groups noL and LuCo- on the first day. Also, the relative content of phosphatidylcholine was significantly increased in group LuCo+ up to day 4, compared with groups noL and LuCo-. In comparison with groups noL and LuCo-, a significant decrease of the relative content of phosphatidylglycerol was obtained in group LuCo+ up to day 7. The surfactant-associated protein A was increased in group LuCo+ during the whole observation time, compared with the other groups. CONCLUSIONS: Multiple trauma leads to alterations in the surfactant system. The composition of surfactant was not further influenced by lung contusion alone. Only MTP with OF/MOF during the intensive care unit treatment showed significant alterations in surfactant composition and a decrease in lung function.

Adolescent↗

PubMed1997

Nebulized surfactant for experimentally induced otitis media with effusion.

Eustachian tube dysfunction frequently results in clinical evidence of otitis media with effusion (OME). Surface active substances, surfactants, are hypothesized to play a role in normal eustachian tube function. Recent work in a rodent model has demonstrated improved eustachian tube function with topical application of surfactants to the middle ear. A novel, noninvasive, and clinically practical method of delivering surfactant to the eustachian tube was studied in a gerbil model of OME. Otitis media with effusion was experimentally induced in 20 gerbils by transtympanic inoculation of heat-killed Streptococcus pneumoniae. This represents a well established model for creating a serous effusion in the gerbil that significantly increases eustachian tube opening pressure. Effusion developed in 27 of 40 ears (67.5%) after inoculation. An inhaled nebulized surfactant was used to treat the animals with microscopically confirmed OME in one or both ears. The treatment period was 5 days. Eustachian tube opening studies were performed on both affected and nonaffected animals. Successful eustachian tube opening pressures were obtained in 30 of 36 ears (83.3%). The mean opening pressure for ears without effusion (healthy ears) was 42.8 mmHg. The mean opening pressure for ears with effusion in animals treated with nebulized surfactant was 41.4 mmHg. The difference between these mean values was not statistically significant (t = 0.32; p > 0.50). This pilot study suggests that inhaled nebulized surfactant may be efficacious in treating eustachian tube dysfunction when manifested in disorders such as OME.

Administration, Inhalation↗

PubMed1994

Surfactant disposition in rats with monocrotaline-induced pneumotoxicity.

Monocrotaline (MCT)-treated rats exhibit airways and gas exchange abnormalities which precede development of sustained pulmonary hypertension (Lai et al., 1991). Because the density of type II pneumocytes is reduced in MCT-treated rat lungs (Wilson and Segall, 1990), decreased abundance or activity of type II pneumocyte-derived surfactant may contribute to pulmonary dysfunction. On the other hand, since the remaining type II pneumocytes undergo an apparent hypertrophic response, it is possible that they compensate for the reduction in population density by elaborating more surfactant or surfactant with enhanced surface activity. As an initial means of discriminating between these possibilities, the amount, surface activity, and synthesis rate of surfactant was examined in rats at 1, 2, and 3 weeks after MCT administration. The amounts of surfactant phospholipid and protein recovered in bronchoalveolar lavage fluid did not differ substantially between control and MCT-treated rats at any time post MCT administration. Similarly, neither the initial rate of surface tension reduction nor the maximum reduction in surface tension differed between surfactant preparations recovered from control and MCT-treated rats. The rate of surfactant synthesis in lung explants, as determined by incorporation of [3H]glycerol into phospholipid, also was not different between MCT-treated and control rats at any time after MCT administration. MCT treatment failed to alter the distribution of [3H]glycerol into surfactant phospholipid. Collectively, these data indicate that airways abnormalities in MCT-treated rats cannot be ascribed to a reduction in the abundance or the activity of surfactant. Furthermore, in light of previous studies indicating that the density of type II pneumocytes is reduced in MCT pneumotoxicity, the present findings suggest that surfactant regulatory pathways must undergo a compensatory response that preserves normal functional status.

Animals↗

PubMed2005

Circulating surfactant protein-B levels increase acutely in response to exercise-induced left ventricular dysfunction.

1. As a result of its enormous surface area and necessary thinness for gas exchange, the alveolocapillary barrier is vulnerable to mechanical disruption from raised pulmonary microvascular pressure (Pmv). 2. Because surfactant protein-B (SP-B) leaks into the blood stream from the alveoli in response to alveolocapillary barrier damage and exercise leads to increased Pmv, we sought to determine whether exercise results in increased plasma SP-B. Moreover, in the setting of exercise-induced left ventricular dysfunction, the consequent increase in left heart filling pressure and, therefore, P(mv) would be expected to further increase plasma SP-B levels. 3. Twenty consecutive subjects referred for treadmill exercise stress echocardiography (ESE) had venous blood sampled immediately before and after ESE for batch atrial natriuretic peptide (ANP) and SP-B assay. Echocardiographic measures of pulmonary haemodynamics (pulmonary artery flow acceleration time (pafAT) and right ventricular outflow tract velocity time integral (rVTI)) were also taken pre- and post-exercise. 4. Although circulating ANP levels increased following exercise (P < 0.001), there was no change in circulating SP-B levels in the entire cohort. 5. Ten subjects had a positive ESE for ventricular dysfunction. Although circulating ANP was increased post-exercise in both the negative and positive ESE groups (P < 0.05 and P < 0.01, respectively), circulating SP-B only increased post-exercise in the positive ESE group (P < 0.05). Echocardiographic parameters supported an increment in P(mv) in the cohort with exercise-induced left ventricular dysfunction because this group had an increase in pafAT (P < 0.05; reflecting pulmonary artery pressure) and no change in rVTI. 6. Physical exertion associated with a Bruce protocol ESE is insufficient to increase circulating SP-B, despite evidence of increased left atrial and pulmonary vascular pressure. However, in the setting of exercise-induced myocardial dysfunction, there is a detectable increase in circulating SP-B. 7. The exaggerated increase in pulmonary vascular pressure in exercise-induced myocardial dysfunction may result in increased SP-B leakage from the alveoli into the circulation by altering the integrity of the alveolocapillary barrier to protein.

Atrial Natriuretic Factor↗

PubMed2002

Accelerated arteriolar gas embolism reabsorption by an exogenous surfactant.

BACKGROUND: Cerebrovascular gas embolism can cause profound neurologic dysfunction, and there are few treatments. The authors tested the hypothesis that an exogenous surfactant can be delivered into the bloodstream to alter the air-blood interfacial mechanics of an intravascular gas embolism and produce bubble conformations, which favor more rapid bubble absorption. METHODS: Microbubbles of air were injected into the rat cremaster microcirculation after intravascular administration of either saline (control, n = 5) or Dow Corning Antifoam 1510US (surfactant, n = 5). Embolism dimensions and dynamics were directly observed after entrapment using intravital microscopy. RESULTS: To achieve embolization, the surfactant group required twice as many injections as did controls (3.2 +/- 1.3 vs. 1.6 +/- 0.9; P < 0.05). There was no difference in the initial lodging configuration between groups. After bubble entrapment, there was significantly more local vasoconstriction in the surfactant group (24.2% average decrease in diameter) than in controls (3.4%; P < 0.05). This was accompanied by a 92.7% bubble elongation in the surfactant group versus 8.2% in controls (P < 0.05). Embolism shape change was coupled with surfactant-enhanced breakup into multiple smaller bubbles, which reabsorbed nearly 30% more rapidly than did parent bubbles in the control group (P < 0.05). CONCLUSIONS: Intravascular exogenous surfactant did not affect initial bubble conformation but dramatically increased bubble breakup and rate of reabsorption. This was evidenced by both the large shape change after entrapment and enhancement of bubble breakup in the surfactant group. These dynamic surfactant-induced changes increase the total embolism surface area and markedly accelerate bubble reabsorption.

Absorption↗

PubMed1995

Pulmonary surfactant subfractions in patients with the acute respiratory distress syndrome.

Changes in the surfactant system have been observed in patients with acute respiratory distress syndrome (ARDS). These alterations in surfactant are thought to contribute to lung dysfunction in this disease. In this report we describe the changes in surfactant subfractions in bronchoalveolar wash obtained from five patients with established ARDS compared with five non-ARDS patients. Our results show that, in addition to the changes in surfactant composition and yield reported previously, the ratio of small to large surfactant aggregates is significantly increased in patients with ARDS compared with non-ARDS patients (0.48 +/- 0.09 versus 0.20 +/- 0.05 respectively [p < 0.05]). This increased ratio was associated with a decreased level of SP-A in the large aggregate fraction. We suggest that this increased ratio represents a marker for surfactant alterations in ARDS that is independent of lavage technique and can be measured in a very small surfactant sample.

Adult↗

PubMed2005

A surfactant protein C precursor protein BRICHOS domain mutation causes endoplasmic reticulum stress, proteasome dysfunction, and caspase 3 activation.

BRICHOS is a domain found in several proteins consisting of approximately 100 amino acids with sequence and structural similarities. Mutations in BRICHOS domain have been associated with both degenerative and proliferative diseases in several nonpulmonary organs, although the pathogenic mechanisms are largely undefined. Recently, several mutations in surfactant protein C (SP-C) mapping to the BRICHOS domain located within the proprotein (proSP-C) have been linked to interstitial lung diseases. In vitro expression of one of these BRICHOS mutants, the exon 4 deletion (hSP-CDeltaexon4), promotes a dominant-negative perinuclear aggregation of the protein. The present study characterizes the trafficking behavior and pathogenic consequences resulting from hSP-CDeltaexon4 expression. Time-lapse and co-localization microscopy studies demonstrated enhanced green fluorescent protein (EGFP)/hSP-CDeltaexon4 expression in calnexin-positive (endoplasmic reticulum [ER]) compartment with subsequent time- and concentration-dependent development of ubiquitinated perinuclear inclusion bodies followed by apoptosis. Compared with controls, EGFP/hSP-CDeltaexon4 promoted upregulation of multiple ER stress species, activated caspase 3, and induced annexin V binding. Furthermore, in GFP-u cells, hSP-CDeltaexon4 directly inhibited proteasome activity. These results support a model whereby proSP-C BRICHOS mutations induce a dynamic toxic gain-of-function, causing apoptotic cell death both by early ER accumulation leading to an exaggerated unfolded protein response and by enhanced deposition of cellular aggregates associated with proteasome dysfunction.

Amino Acid Sequence↗

PubMed2000

YM-40461, a potent surfactant secretagogue, improves mucociliary clearance in SO2-exposed guinea pigs.

The effects of the new pulmonary surfactant secretagogue YM-40461, 1-(2-dimethylaminoethyl)-1-(3,4,5-trimethoxyphenyl) urea, on tracheal mucociliary transport (MCT) were assessed using guinea pigs with acute bronchitis. Acute bronchitis was induced by SO2 gas exposure (400 ppm for 3 h). MCT velocity was measured by means of the dye gelatin technique. YM-40461 at doses of 1-10 mg/kg, p.o. induced recovery of MCT function, with an ED50 value of 2.4 mg/kg. Maximal recovery (78.0+/-12.5%) was observed 2 h in the animals treated with 10 mg/kg of YM-40461. Ambroxol and bromhexine showed less effect on the MCT dysfunction than YM-40461. An artificial surfactant (Surfacten) also aided recovery. YM-40461 at a dose of 10 mg/kg, p.o. significantly improved surfactant production without affecting mucus secretion. These results show that YM-40461 ameliorates MCT dysfunction caused by SO2 exposure by activation of pulmonary surfactant secretion.

Animals↗