Surfactant replacement increases compliance in premature lamb lungs during partial liquid ventilation in situ

Treatmentsavailable to improve compliance in surfactant-deficient states includeexogenous surfactant (ES) and either partial (PLV) or total liquidventilation (TLV) with perfluorochemical (PFC). Because of theadditional air-lung and air-PFC interfaces introduced during PLVcompared with TLV, we hypothesized that compliance would be worseduring PLV than during TLV. Because surfactant is able to reduceinterfacial tension between air and lung as well as between PFC andlung, we further hypothesized that compliance would improve withsurfactant treatment before PLV. In excised preterm lamb lungs, we usedSurvanta for surfactant replacement and perflubron as the PFC.Compliance during PLV was intermediate between TLV and gas inflation,both with and without surfactant. Surfactant improved compliance duringPLV, compared with PLV alone. Because of the force-balance equationgoverning the behavior of immiscible droplets on liquid surfaces, wepredict that PFC droplets spread during PLV to cover the alveolarsurface in surfactant-deficient lungs during most of lung inflation and deflation but that the PFC would retract into droplets insurfactant-sufficient lungs, except at end inspiration.

     

Cigarette smoke ventilation decreases prostaglandin inactivation in rat and hamster lungs

The effects of cigarette smoke on the metabolism of exogenous PGE₂ and PGF_2α were investigated in isolated rat and hamster lungs. When isolated lungs from animals were ventilated with cigarette smoke during pulmonary infusion of 100 nmol of PGE₂ or PGF_2α, the amounts of the 15-keto-metabolites in the perfusion effluent were decreased. Pre-exposure of animals to cigarette smoke daily for 3 weeks did not change the metabolism of PGE₂ when the lungs were ventilated with air. Cigarette smoke ventilation of lungs from pre-exposed animals caused, however, a similar decrease in the metabolism of PGE₂ as in animals not previously exposed to smoke. After pulmonary injection of 10 nmol of ¹⁴C-PGE₂ the radioactivity appeared more rapidly in the effluent during cigarette smoke ventilation suggesting inhibition of the PGE₂ uptake mechanism. In rat lungs pulmonary vascular pressor responses to PGE₂ and PGF_2α were inhibited by smoke ventilation.     

Lung function and ventilation inhomogeneity in rat lungs after allergen challenge.

We studied the early response to ovalbumin challenge in sensitized Brown-Norway rats through its effect on N(2), He, and SF(6) phase III slopes of the single-breath washout and on indexes of lung function. Sensitized rats showed varying degrees of response in terms of pulmonary pressure (PL), with increases ranging between 125 and 225% of baseline. The sensitized rats presented decreased quasistatic compliance, forced vital capacity, and end-expiratory flow, with all three lung function indexes showing a significant negative correlation with corresponding PL values. They also showed significant positive correlations of PL with the N(2), He, and SF(6) phase III slopes, reflecting diffusion-convection-dependent inhomogeneities generated by conformation changes throughout the entire rat lung. In addition, the rats showing the most marked PL increases (>150% baseline PL) also revealed a reversal of the SF(6)-He slope difference because of a more marked SF(6) than He slope increase. This latter finding suggests that the degree of structural heterogeneity during early response is even more marked in the most peripheral rat lung generations.     

Mechanical ventilation of isolated septic rat lungs: effects on surfactant and inflammatory cytokines.

The effects of mechanical ventilation (MV) on the surfactant system and cytokine secretion were studied in isolated septic rat lungs. At 23 h after sham surgery or induction of sepsis by cecal ligation and perforation (CLP), lungs were excised and randomized to one of three groups: 1) a nonventilated group, 2) a group subjected to 1 h of noninjurious MV (tidal volume = 10 ml/kg, positive end-expiratory pressure = 3 cmH(2)O), or 3) a group subjected to 1 h of injurious MV (tidal volume = 20 ml/kg, positive end-expiratory pressure = 0 cmH(2)O). Nonventilated sham and CLP lungs had similar compliance, normal lung morphology, surfactant, and cytokine concentrations. Injurious ventilation decreased compliance, altered surfactant, increased cytokines, and induced morphological changes compared with nonventilation in sham and CLP lungs. In these lungs, the surfactant system was similar in sham and CLP lungs; however, tumor necrosis factor-alpha and interleukin-6 levels were significantly higher in CLP lungs. We conclude that injurious ventilation altered surfactant independent of sepsis and that the CLP lungs were predisposed to the secretion of larger amounts of cytokines because of ventilation.     

Surfactant metabolism and anti-oxidative capacity in hyperoxic neonatal rat lungs: effects of keratinocyte growth factor on gene expression in vivo

Development of preterm infant lungs is frequently impaired resulting in bronchopulmoary dysplasia (BPD). BPD results from interruption of physiologic anabolic intrauterine conditions, the inflammatory basis and therapeutic consequences of premature delivery, including increased oxygen supply for air breathing. The latter requires surfactant, produced by alveolar type II (AT II) cells to lower surface tension at the pulmonary air:liquid interface. Its main components are specific phosphatidylcholine (PC) species including dipalmitoyl-PC, anionic phospholipids and surfactant proteins. Local antioxidative enzymes are essential to cope with the pro-inflammatory side effects of normal alveolar oxygen pressures. However, respiratory insufficiency frequently requires increased oxygen supply. To cope with the injurious effects of hyperoxia to epithelia, recombinant human keratinocyte growth factor (rhKGF) was proposed as a surfactant stimulating, non-catabolic and epithelial-protective therapeutic. The aim of the present study was to examine the qualification of rhKGF to improve expression parameters of lung maturity in newborn rats under hyperoxic conditions (85 % O₂ for 7 days). In response to rhKGF proliferating cell nuclear antigen mRNA, as a feature of stimulated proliferation, was elevated. Similarly, the expressions of ATP-binding cassette protein A3 gene, a differentiation marker of AT II cells and of peroxiredoxin 6, thioredoxin and thioredoxin reductase, three genes involved in oxygen radical protection were increased. Furthermore, mRNA levels of acyl-coA:lysophosphatidylcholine acyltransferase 1, catalyzing dipalmitoyl-PC synthesis by acyl remodeling, and adipose triglyceride lipase, considered as responsible for fatty acid supply for surfactant PC synthesis, were elevated. These results, together with a considerable body of other confirmative evidence, suggest that rhKGF should be developed into a therapeutic option to treat preterm infants at risk for impaired lung development.     

Mechanical ventilation of isolated rat lungs changes the structure and biophysical properties of surfactant.

Mechanical ventilation is an essential but potentially harmful therapeutic intervention for patients with acute lung injury. The objective of this study was to investigate the effects of mechanical ventilation on large-aggregate surfactant (LA) structure and function. Isolated rat lungs were randomized to either a nonventilated control group, a relatively noninjuriously ventilated group [1 h, 10 ml/kg tidal volume, 3 cmH(2)O positive end-expiratory pressure (PEEP)], or an injuriously ventilated group (1 h, 20 ml/kg tidal volume, 0 cmH(2)O PEEP). Injurious ventilation resulted in significantly decreased lung compliance compared with the other two groups. LA structure, as determined by electron microscopy, revealed that LA from the injurious group had significantly lower amounts of organized lipid-protein structures compared with LA obtained from the other groups. Analysis of the biophysical properties by using a captive bubble surfactometer demonstrated that adsorption and surface tension reduction were significantly impaired with LA from the injuriously ventilated lungs. We conclude that the injurious mechanical ventilation impairs LA function and that this impairment is associated with significant morphological alterations.     

Surfactant treatments alter endogenous surfactant metabolism in rabbit lungs

The effect of exogenous surfactant on endogenous surfactant metabolism was evaluated using a single-lobe treatment strategy to compare effects of treated with untreated lung within the same rabbit. Natural rabbit surfactant, Survanta, or 0.45% NaCl was injected into the left main stem bronchus by use of a Swan-Ganz catheter. Radio-labeled palmitic acid was then given by intravascular injection at two times after surfactant treatment, and the ratios of label incorporation and secretion in the left lower lobe to label incorporation and secretion in the right lung were compared. The treatment procedure resulted in a reasonably uniform surfactant distribution and did not disrupt lobar pulmonary blood flow. Natural rabbit surfactant increased incorporation of palmitate into saturated phosphatidylcholine (Sat PC) approximately 2-fold (P less than 0.01), and secretion of labeled Sat PC increased approximately 2.5-fold in the surfactant-treated left lower lobe relative to the right lung (P less than 0.01). Although Survanta did not alter incorporation, it did increase secretion but not to the same extent as rabbit surfactant (P less than 0.01). Alteration of endogenous surfactant Sat PC metabolism in vivo by surfactant treatments was different from that which would have been predicted by previous in vitro studies.     

Segmentary topography and ventilation gradients in human lungs]

Segmentary topography of the air volume was studied by regional electroplethysmography of the lungs. A distinct apical-basal gradient was shown to be present in men tested in supine position, along with the dorsal-ventral gradient; the origin of the apical-basal gradient could not be explained from the point of view of the gravitational mechanism. A possibility of recalculation of the electroplethysmographic index of the percentage of the air content in the lobe of the lung to the regional air volume index in the lungs, and the principal possibility of calculation of the regional total lung capacity index with the help of electroplethysmography was shown.     

Histochemical studies of rat lungs after the short-term influence of soil dust

There was examined the biological activity of soil dusts using histochemical methods. Intratracheal administration of dusts used in this study is a common method for testing activity of industrial dusts. The used soil dusts were characterized by high content of free silicon dioxide, 3 times higher than its content in dusts from power stations released in the process of burning coal and approximately to the amount in graphite dust. Both coal dusts and graphite dusts absorbed by the lungs cause silicoanthracosis. The investigations have been shown that soil dusts caused stimulation of the mitochondrial metabolism giving an increase of the activity of succinic dehydrogenase, lactic dehydrogenase, and ATPase induced by Mg++ ions. This was additionally confirmed by an increase of NADP activity which is an enzyme binding a chain or reactions regulating the hydrocarbonic metabolism. There was also observed an increased activity of the hydrolytic enzyme acid phosphatase. High activity occurred in the epithelium of bronchi and bronchioli and focally in pulmonary parenchyma.     

The metabolism of arachidonic acid in isolated rat lungs is not changed during cigarette smoke ventilation

Cigarette smoke ventilation of isolated perfused rat lungs partially inhibited the pulmonary vascular pressor response to arachidonic acid. The amounts of metabolites of exogenous arachidonic acid in the perfusion effluent remained unchanged during smoke ventilation. The antiaggregatory effect of the effluent during pulmonary infusion of AA was not decreased by smoke ventilation. The cause of the previously reported increased platelet aggregation after smoking remains unclear.     

Surfactant protein-A suppresses eosinophil-mediated killing of Mycoplasma pneumoniae in allergic lungs

Surfactant protein-A (SP-A) has well-established functions in reducing bacterial and viral infections but its role in chronic lung diseases such as asthma is unclear. Mycoplasma pneumoniae (Mp) frequently colonizes the airways of chronic asthmatics and is thought to contribute to exacerbations of asthma. Our lab has previously reported that during Mp infection of non-allergic airways, SP-A aides in maintaining airway homeostasis by inhibiting an overzealous TNF-alpha mediated response and, in allergic mice, SP-A regulates eosinophilic infiltration and inflammation of the airway. In the current study, we used an in vivo model with wild type (WT) and SP-A(-/-) allergic mice challenged with the model antigen ovalbumin (Ova) that were concurrently infected with Mp (Ova+Mp) to test the hypothesis that SP-A ameliorates Mp-induced stimulation of eosinophils. Thus, SP-A could protect allergic airways from injury due to release of eosinophil inflammatory products. SP-A deficient mice exhibit significant increases in inflammatory cells, mucus production and lung damage during concurrent allergic airway disease and infection (Ova+Mp) as compared to the WT mice of the same treatment group. In contrast, SP-A deficient mice have significantly decreased Mp burden compared to WT mice. The eosinophil specific factor, eosinophil peroxidase (EPO), which has been implicated in pathogen killing and also in epithelial dysfunction due to oxidative damage of resident lung proteins, is enhanced in samples from allergic/infected SP-A(-/-) mice as compared to WT mice. In vitro experiments using purified eosinophils and human SP-A suggest that SP-A limits the release of EPO from Mp-stimulated eosinophils thereby reducing their killing capacity. These findings are the first to demonstrate that although SP-A interferes with eosinophil-mediated biologic clearance of Mp by mediating the interaction of Mp with eosinophils, SP-A simultaneously benefits the airway by limiting inflammation and damage.     

On the significance of Surfactant Protein-A within the human lungs

Background

As there is no optimal treatment of non small cell lung cancer due to its resistance to common chemotherapeutics, we investigated the effect of human placenta-conditioned medium on tumor tissue. The human placenta constitutes a mixture of maternal and fetal origin and displays a variety of immunomodulatory aspects.

Methods

Freshly resected non small cell lung cancer tissues were incubated with placenta-conditioned medium in a short-term tissue culture model and A549 cells were challenged, respectively. Term placenta was used for producing conditioned medium and HOPE-fixed stimulated tumor tissue was analyzed for expression of caspase-3 and Ki67 via immunohistochemistry. The effects of conditioned medium on squamous cell carcinoma were further compared to physiological concentrations of Carboplat/Gemzar.

Results

Conditioned medium caused in 2 of 3 cases elevated expression of caspase-3 and reduced expression of Ki67 in 3 out of 3 cases, while the chemotherapeutic agents caused no comparable expression of caspase-3 or reduction of Ki67. In cell culture up to 50% of karyopyknosis was investigated and even sterile-filtrated medium caused widespread reduction of Ki67 on protein level.

Conclusion

Human placenta releases substances that mediate apoptosis and reduce proliferation in tumor tissue and cell culture. As even sterile-filtrated medium caused the mentioned effects we hypothesize one or more soluble mediators. The detailed way of promoting apoptosis and nature of these mediators need to be elucidated in further studies.     

Surfactant surface activity and ultrastructural changes in the type-II alveolocytes of fetal and neonatal lungs in experimental inflammation of the maternal lungs

The lungs of 19 guinea pigs, born from 8 females in which acute and chronic pneumonia had been modelled by transtracheal introduction of sterile fishing-line were investigated. It was established, that in guinea pigs, born in females with acute and chronic pneumonia, the functional immaturity of pneumocytes of the 2-nd type took place. The functional immaturity of pneumocytes of the 2-nd type results in suppression of the surface active characteristics of surfactant.