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Results for “surfactant dysfunction”

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PubMed2004

Eosinophil cationic protein alters pulmonary surfactant structure and function in asthma.

BACKGROUND: Impaired surfactant function has been demonstrated in patients with asthma. Inhibitory proteins originating from plasma or inflammatory mediators are good candidates to contribute to this dysfunction. Eosinophils are potent effector cells in asthma, which, on activation, release inflammatory mediators, especially reactive granula proteins such as eosinophil cationic protein (ECP). OBJECTIVE: Because the potential role of ECP in the inhibition of surfactant function is not known, we tested the hypothesis of whether ECP levels in bronchoalveolar lavage fluid (BALF) of patients with asthma after segmental allergen provocation correlate to surfactant dysfunction. Furthermore, we tested the effect of purified ECP on surfactant function and structure in vitro. METHODS: Surfactant isolated from BALF of asthmatic patients was assessed for biophysical function with the Pulsating Bubble Surfactometer and the Capillary Surfactometer and correlated to ECP levels. Purified ECP and plasma proteins at various concentrations were incubated with natural surfactant. Surfactant function was studied with the Capillary Surfactometer, and surfactant structure was determined by electron microscopy. RESULTS: ECP is elevated in BALF from patients with asthma after allergen challenge compared with baseline. ECP levels after allergen challenge correlate well to surfactant dysfunction. In vitro, ECP induces a concentration-dependent inhibition of surfactant function that can be inhibited by antibodies against ECP. ECP is more potent compared with albumin or fibrinogen. Finally, ECP induces severe ultrastructural changes to surfactant vesicles that are more pronounced than changes induced by either fibrinogen or albumin. CONCLUSIONS: ECP contributes to surfactant dysfunction in asthma, which in turn could lead to airway obstruction.

Adult↗

PubMed2006

Probing perturbation of bovine lung surfactant extracts by albumin using DSC and 2H-NMR.

Lung surfactant (LS), a lipid-protein mixture, forms films at the lung air-water interface and prevents alveolar collapse at end expiration. In lung disease and injury, the surface activity of LS is inhibited by leakage of serum proteins such as albumin into the alveolar hypophase. Multilamellar vesicular dispersions of a clinically used replacement, bovine lipid extract surfactant (BLES), to which (2% by weight) chain-perdeuterated dipalmitoylphosphatidycholine (DPPG mixtures-d(62)) had been added, were studied using deuterium-NMR spectroscopy ((2)H-NMR) and differential scanning calorimetry (DSC). DSC scans of BLES showed a broad gel to liquid-crystalline phase transition between 10-35 degrees C, with a temperature of maximum heat flow (T(max)) around 27 degrees C. Incorporation of the DPPC-d(62) into BLES-reconstituted vesicles did not alter the T(max) or the transition range as observed by DSC or the hydrocarbon stretching modes of the lipids observed using infrared spectroscopy. Transition enthalpy change and (2)H-NMR order parameter profiles were not significantly altered by addition of calcium and cholesterol to BLES. (2)H-NMR spectra of the DPPC-d(62) probes in these samples were characteristic of a single average lipid environment at all temperatures. This suggested either continuous ordering of the bilayer through the transition during cooling or averaging of the DPPC-d(62) environment by rapid diffusion between small domains on a short timescale relative to that characteristic of the (2)H-NMR experiment. Addition of 10% by weight of soluble bovine serum albumin (1:0.1, BLES/albumin, dry wt/wt) broadened the transition slightly and resulted in the superposition of (2)H-NMR spectral features characteristic of coexisting fluid and ordered phases. This suggests the persistence of phase-separated domains throughout the transition regime (5-35 degrees C) of BLES with albumin. The study suggests albumin can cause segregation of protein bound-lipid domains in surfactant at NMR timescales (10(-5) s). Persistent phase separation at physiological temperature may provide for a basis for loss of surface activity of surfactant in dysfunction and disease.

Animals↗

PubMed2001

Pulmonary surfactant function studied with the pulsating bubble surfactometer (PBS) and the capillary surfactometer (CS).

Two instruments, the pulsating bubble surfactometer (PBS) and the capillary surfactometer (CS), were constructed for a study of pulmonary surfactant's physical properties. The instruments study spherical surfaces as in alveoli (PBS) and cylindrical surfaces as in terminal conducting airways (CS). Phospholipids, pulmonary surfactant's main components, are amphiphilic and, therefore, spontaneously form a film at air-liquid interfaces. When the film in the PBS is compressed to a reduced area during 'expiration', the molecules come closer together. Thereby, a high surface pressure develops, causing surface tension to be reduced more than bubble radius. If these conditions, observed with the PBS are analogous in lungs, alveolar stability would be promoted. The CS was developed for a study of how surfactant has ability to maintain patency of narrow conducting airways. Provided adsorption is extremely fast, a surfactant film will line the terminal conducting airway as soon as liquid blocking the airway has been extruded. During expiration that film will develop high surface pressure (=low surface tension). This will counteract the tendency for liquid to accumulate in the airway's most narrow section. If surfactant is dysfunctioning, liquid is likely to accumulate and block terminal airways. Airway resistance would then increase, causing FEV(1) to be reduced.

Animals↗

PubMed2003

High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis.

Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mice results in pulmonary alveolar proteinosis (PAP) from impaired surfactant catabolism by alveolar macrophages (AMs). Recently, we have shown that neutralizing anti-GM-CSF autoantibodies develop specifically in patients with idiopathic pulmonary alveolar proteinosis (iPAP). Analogous to murine PAP models, it is plausible that the autoantibodies reduce GM-CSF activity, resulting in AM dysfunction and surfactant accumulation. To examine this hypothesis, we estimated the neutralizing activity of the autoantibodies in the lungs of patients and characterized their biologic properties. GM-CSF bioactivity was completely abrogated in the bronchoalveolar lavage fluid (BALF) of patients with iPAP but not in healthy subjects. Autoantibodies were present in the alveoli in high concentrations and colocalized with GM-CSF. They recognized human GM-CSF with high avidity (K(AV) = 20.0 +/- 7.5 pM) and high specificity, reacting with its superstructure and neutralizing GM-CSF activity to a level 4000 to 58 000 times the levels of GM-CSF normally present in the lung. Although target epitopes varied among patients, GM-CSF amino acids 78 to 94 were consistently recognized. Thus, autoantibodies bind GM-CSF with high specificity and high affinity, exist abundantly in the lung, and effectively block GM-CSF binding to its receptor, inhibiting AM differentiation and function. Our data strengthen the evidence associating anti-GM-CSF autoantibodies with the pathogenesis of this disease.

Adult↗

PubMed2002

Increase of inactive intra-alveolar surfactant subtypes in lungs of asthmatic Brown Norway rats.

We tested the hypothesis whether allergic airway inflammation in ovalbumin sensitized and challenged Brown Norway rats is associated with intrinsic surfactant alteration and dysfunction. The determination of intra-alveolar surfactant subtypes and alveolar edema within their original microenvironment is only possible using an ultrastructural stereological approach. Therefore both lungs of control and asthmatic rats were fixed by vascular perfusion. The volume fractions of surfactant subtypes and the epithelial surface fraction covered with alveolar edema were determined by point and intersection counting. Furthermore, lung resistance was measured by means of whole-body plethysmography. The surface activity of surfactant from bronchoalveolar lavage was determined as minimum surface tension at minimal bubble size with a pulsating bubble surfactometer. Compared with controls, in asthmatics (1) the fraction of inactive unilamellar forms was significantly increased from 56% to 66%, (2) the fraction of alveolar epithelium covered with alveolar edema visible by light microscopy was significantly increased from 0.7% to 5.0%, (3) the fraction of alveolar epithelium covered with fluid seen by electron microscopy expanded significantly from 5% to 21%, (4) lung resistance was significantly elevated from 14% to 86% and (5) surface tension was enhanced from 6 mN/m to 12 mN/m. Thus, the inflammatory process after allergen challenge of sensitized Brown Norway rats causes intra-alveolar surfactant alterations. These surfactant alterations might contribute to small airway dysfunction.

Administration, Inhalation↗

PubMed1982

Effect of hyperventilation and starvation on rat lung mechanics and surfactant.

We studied the effects of hyperventilation and starvation on rat lung mechanics and surfactant. We hyperventilated lungs by excising and ventilating them at 3 times the normal tidal volume. Three days starvation reduced the alveolar pool of disaturated phosphatidyl choline by about 20% but did not significantly reduce the functional residual capacity. Air and saline deflation pressure-volume curves were performed in 4 groups: control lungs, lungs from starved rats, hyperventilated lungs, and hyperventilated lungs from starved rats. The area under each curve was calculated; this indicated the relative position of the curve in the pressure-volume diagram. We found that starvation did not change recoil, that hyperventilation increased surface recoil, and that combined starvation and hyperventilation increased it even more. We conclude that hyperventilation-induced dysfunction of surfactant is greater when the alveolar pool of surfactant is reduced by starvation. This effect might also occur clinically in the intensive care setting.

Air Pressure↗

PubMed2001

[Surfactant--treatment of complete lobar atelectasis after exacerbation of bronchial asthma by infection].

Dysfunction of airway surfactant is suggested as an important factor contributing to the pathogenesis of bronchoconstriction of patients with asthma. We report the case of a 59-year-old female who had an infect-exacerbation of her asthma complicated by a complete collapse of the left lower lung lobe. Only the local application of 150 mg of bovine surfactant resulted in a complete reexpansion of the lobe. Local therapy with replacement of surfactant may be a promising therapeutic approach in treatment of forms of atelectasis, which depend on a dysfunction or disturbed homeostasis of surfactant.

Animals↗

PubMed2000

Significance of vagal innervation in perinatal breathing and gas exchange.

The mechanisms responsible for the establishment of continuous breathing at birth remain unknown. Several studies have shown that postnatal vagal denervation produces deleterious effects on ventilation as well as breathing patterns during the newborn period. However, the validity of these studies was compromised by anesthesia, tracheostomy or possible secondary laryngeal obstruction. We have recently developed an unanesthetized lamb model in which vagal denervation was performed antenatally and below the recurrent laryngeal nerves thereby avoiding anesthesia, tracheostomy and laryngeal paralysis. The denervated animals developed life-threatening respiratory failure shortly after birth, implying that vagal innervation of the lungs plays an essential role in establishing adequate gas exchange in the first hours after birth. We have subsequently investigated various mechanisms of respiratory failure in denervated animals. Our results show that the surfactant system dysfunction and loss of vagally mediated volume feedback likely contributed to the respiratory failure observed in the intrathoracically denervated animal model.

Animals↗

PubMed2003

[Current views of tuberculosis inflammation].

The value of histological and histochemical studies in the diagnosis of a phase of tuberculosis progression or healing is shown. Electron microscopic study of tuberculous inflammation in different phases of its evolution evaluated the functional status of cellular elements of the lung and granuloma. The body's antituberculous resistance due to molecular genetic mechanisms is realized through intercellular interactions and macrophageal functions. Immune macrophages are characterized by a higher metabolic activity, they suppress the intracellular multiplication of Mycobacterium tuberculosis (MBT) and are more protected from their toxic action. The pathogenetic mechanisms responsible for caseous pneumonia were studied. Three stages of evolution of the process: Stage 1 is the breakdown of defense and adaptive mechanisms: disorganization of connective tissue and alveolar parenchyma; enhanced permeability of blood and lymphatic microvascular walls with developed interstitial and intraalveolar edema, plasma and fibrin exudation, fibrinoid swelling of collagenous fibers, and their lysis; occurrence of lung parenchymal microinfarcts and infarction-pneumonia; type 2 alveolocytic dysfunction with surfactant destruction; Stage 2 is the breakdown of local immunity; exudative and alterative tuberculous inflammation with involvement of immunocompetent organs; suppressed T-cellular immunity, a shift of a T helper/T suppressor ratio to the latter, lymphopenia; impaired intercellular interactions, cellular apoptosis in blood and inflammation areas, and suppressed granulomatous reaction; inhibited L transformation of Mycobacteria tuberculosis, intensive MBT multiplication in the foci of tuberculous inflammation, particularly those which are resistant to many antibiotic drugs, a larger number of associations of the nonspecific microflora and fungi. Stage 3 is caseous pneumonia and generalization of a tuberculous process: a predominance of an alterative reaction of inflammation; the presence of allergic and caseous and necrotic vasculitis, bronchiolitis, and endo-panbronchitis; depressed granulomatous reaction; the development of acute alterative sequestrating pneumoniogenic caverns. Histological, histochemical, and electron microscopic studies of tuberculous inflammation may specify the mechanisms of the pathogenesis of tuberculosis and may serve as the basis for early diagnosis of the disease and for timely correction of performed treatment in order to enhance its efficiency.

Giant Cells↗

PubMed1996

Eustachian tube dysfunction.

There are several types of eustachian tube dysfunction, including obstruction and abnormal patency. This article presents an update on several selected areas of eustachian tube function and dysfunction, including surfactants, cleft palate, tympanic membrane atelectasis, abnormal eustachian tube patency, and long-term middle ear ventilation.

Cholesteatoma, Middle Ear↗

PubMed1998

[Prenatal diagnosis and therapy of congenital diaphragmatic hernia].

The diagnosis and treatment of congenital diaphragmatic hernia, CDH, is an interdisciplinary problem. The patient concentration with prenatally diagnosed CDH for comprehensive examination with subsequent decision on the type of delivery improves the prognosis of patients with CDH. Introduction of corticoid therapy in prenatally assessed CDH reduces dysfunction and surfactant deficiency and can reduce the degree of respiratory failure during delivery. In very early prenatally assessed CDH it is possible to consider the possibility of combined corticoid and TRH (thyroxin releasing hormone) treatment of CDH. The authors submit also contemporary possibilities of prenatal intervention treatment of CDH (indication criteria for reconstruction operations of foetal surgery, intrauterine closure of the trachea and artificial laparoschisis). The concentration of patients with postnatally diagnosed CDH and a severe grade of acute respiratory insufficiency in a department with conventional and non-conventional artificial pulmonary ventilation incl. inhalation of NO oe extracorporeal membrane oxygenation, ECMO, is a further step towards optimation of treatment. Continuous evaluation of parameters of pulmonary functions during the pre- and postoperative period may prove that a therapeutic protocol with delayed surgery is useful.

Female↗

PubMed1994

Role of alveolar type II cells and of surfactant-associated protein C mRNA levels in the pathogenesis of respiratory distress in mink kits infected with Aleutian mink disease parvovirus.

Neonatal mink kits infected with Aleutian mink disease parvovirus (ADV) develop an acute interstitial pneumonia with clinical symptoms and pathological lesions that resemble those seen in preterm human infants with respiratory distress syndrome and in human adults with adult respiratory distress syndrome. We have previously suggested that ADV replicates in the alveolar type II epithelial cells of the lung. By using double in situ hybridization, with the simultaneous use of a probe to detect ADV replication and a probe to demonstrate alveolar type II cells, we now confirm this hypothesis. Furthermore, Northern (RNA) blot hybridization showed that the infection caused a significant decrease of surfactant-associated protein C mRNA produced by the alveolar type II cells. We therefore suggest that the severe clinical symptoms and pathological changes characterized by hyaline membrane formation observed in ADV-infected mink kits are caused by a dysfunction of alveolar surfactant similar to that observed in respiratory distress syndrome in preterm infants. However, in the infected mink kits the dysfunction is due to the replication of ADV in the lungs, whereas the dysfunction of surfactant in preterm infants is due to lung immaturity.

Aleutian Mink Disease↗

PubMed2004

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.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2005

Bronchoscopic surfactant administration in pediatric patients with persistent lobar atelectasis.

Persistent lobar atelectasis in pediatric patients on mechanical ventilation results in impaired gas exchange and lung mechanics and contributes to a further need for mechanical ventilation. The most common types of atelectasis in children are resorption atelectasis following airway obstruction, and atelectasis due to surfactant deficiency or dysfunction. We aimed to determine whether bronchoscopic suctioning and surfactant application to atelectatic lung segments would result in improved oxygenation, ventilation, chest X-ray scoring, and early extubation. Five children with heterogeneous lung diseases (aged between 7 months and 15 years) were treated with a diluted surfactant preparation (Curosurf) in a concentration of 5-10 mg/ml (total dose 120-240 mg) which was instilled into the affected segments. Outcome parameters were gas exchange, radiographic resolution of atelectasis and extubation. All mechanically ventilated patients could be extubated within 24 h following the intervention. Bronchoscopic surfactant application could be carried out without adverse effects and brought improvements in oxygenation, respiratory rate, and partial or complete resolution of atelectases without recurrence.

Adolescent↗

PubMed1996

Surface tension measurements on pharyngeal and tracheal aspirate samples from newborns without and with respiratory distress syndrome.

A rapid test determining surfactant deficiency or dysfunction might help in controlling therapy of respiratory distress syndrome (RDS). Forty tracheal aspirate samples (TA) from 40 newborns with RDS (group 1) and 46 pharyngeal from 46 newborns without RDS (reference group) were analyzed by surface tension measurement with the pulsating bubble surfactometer. Five surface tension parameters were compared. Marked differences between both groups could be noted for the parameters: minimum surface tension (gamma min) and stability index (S), while maximum surface tension (gamma max), surface tension after a 10-second adsorption period and hysteresis area did not have striking differences. The parameters gamma min and S have the highest diagnostic value for determining surfactant deficiency or dysfunction. For a rapid test it is sufficient to compare gamma min with reference values, because S is calculated from gamma min and gamma max.

Body Fluids↗

PubMed2001

Effects of Stachybotrys chartarum on surfactant convertase activity in juvenile mice.

We have shown recently that alveolar type II cells are sensitive to exposure to Stachybotrys chartarum spores, both in vitro and in an in vivo juvenile mouse model. In mice, this sensitivity is manifest in part as a significant increase in the newly secreted, biologically active, heavy aggregate form of alveolar surfactant (H) and the accumulation of the lighter, "metabolically used", biologically inactive alveolar surfactant forms (L(vivo)) in the interalveolar space. Conversion of the heavy, surface-active alveolar surfactant to the light metabolically used, nonsurface active forms is believed to involve the activity of an enzyme, namely convertase, which is thought to be derived from lamellar bodies (LB) in alveolar type II cells. The purpose of this study was to evaluate the effects of S. chartarum spores on mouse H and LB convertase activity by measuring their rates of conversion to L(vivo) using the in vitro surface area cycling technique. It was determined whether there were concurrent changes in the protein and phospholipid concentrations of the raw bronchoalveolar lavage fluid (RL) and LB fractions that could be correlated with changes in convertase activity. Conversions of H to L(vivo) in untreated control mice and saline-, isosatratoxin F-, and Cladosporium cladosporioides-exposed mice were not significantly different (p > 0.05). However, conversion from H to L(vivo) in the mice exposed to S. chartarum spores was significantly higher than all other treatment groups (p < 0.001). LB to L(vivo) conversions in untreated and saline-exposed mice were not significantly different, although they were significantly higher than the H to L(vivo) conversions in these two animal treatment groups (p < 0.005), which supports the position that LB is a source of convertase activity in animals. LB to L(vivo) conversion from C. cladosporioides-, isosatrotoxin F-, and S. chartarum-exposed mice were all significantly depressed (p < 0.003) compared to the LB to L(vivo) conversion values obtained from untreated and saline-exposed mice. Protein concentrations in RL, H, L(vivo), and LB from mice exposed to S. chartarum spores were significantly elevated compared to those from the other treatment groups (p < 0.001). Protein concentration in H isolated from C. cladosporioides-exposed mice was also significantly elevated above untreated and saline control animal levels. Phospholipid concentrations in H isolated from S. chartarum-exposed mice were significantly elevated compared to those from other treatment groups, while LB phospholipid concentrations were significantly increased compared to saline and untreated control animal groups. These results show that S. chartarum spores significantly alter convertase activity in both the H and LB surfactant fractions in juvenile mice and that these changes can be related to changes in protein and phospholipid concentrations in alveolar lavage fractions. As surfactant promotes lung stability by reducing the surface tension of the air-alveolar interface, these results further support our position that inhalation exposure to S. chartarum spores in exposed individuals may lead to altered surfactant metabolism, and possibly to lung dysfunction through diminished alveolar surfactant surface tension attributes, and lung stability.

Animals↗

PubMed2000

Synthetic surfactants to treat neonatal lung disease.

Pulmonary surfactant is a complex of surface-active lipids mixed with specific proteins. Two of these, SP-B and SP-C, are essential for adsorption of surfactant lipids to the air-liquid interfaces of the lungs and, hence, are also essential for alveolar stability and effective gas exchange. Surfactant substitutes must contain at least one of these proteins (or analogues of them) to be optimally effective when administered into the airways of babies with surfactant deficiency or dysfunction. This review describes how an increased understanding of the properties of surfactant proteins has led to the development of improved synthetic surfactants with the potential to treat a wide range of respiratory disorders.

Amino Acid Sequence↗

PubMed2004

Pulmonary surfactant protein A isolation as a by-product of porcine pulmonary surfactant production.

A pulmonary surfactant reduces surface tension at the air/liquid interface of the alveoli and stabilizes alveoli at low lung volumes. Surfactant deficiency and dysfunction were shown to be present in a number of pulmonary diseases, and surfactant replacement therapy is the common clinical conduct. The hydrophilic SP-A (surfactant protein A) is absent when solvent extraction was used during exogenous surfactant production. Addition of SP-A to the surfactant preparation increases the surface activity and completely counteracts inhibition by blood proteins. SP-A recognizes and binds to carbohydrate structures on the surfaces of pathogenic micro-organisms, and acts as opsonins or cross-linking molecules by binding to a variety of cells that participate in the pulmonary immune response. The purification procedure yielded 206 mg of high-purity SP-A/kg of porcine lung, as judged by gel filtration, SDS/PAGE and Western blotting. The electrophoretic profiles obtained showed that pure SP-A consists of proteins of wide molecular mass in the range 26-36 kDa and a dimer in the range 56-60 kDa. The Western-blot results displayed the same band pattern profile after incubating the membrane using a commercially available polyclonal anti-SP-A antibody produced in goat. Gel-filtration experiments confirmed the molecular mass of SP-A in 10 mM NaCl solution. The isolated SP-A showed mannose-binding ability, representative of its functionality.

Animals↗