Gastric fluid cytokines are associated with chorioamnionitis and white blood cell counts in preterm infants.

AIM: The aim of this study was to determine whether the concentration of cytokines in the gastric fluid at birth was associated with chorioamnionitis or funisitis and with the white blood cell counts of very premature newborns. METHODS: We retrieved gastric fluid from 27 preterm infants with a gestational age of <29 weeks within 1 h of birth and used enzyme-linked immunosorbent assay to measure the concentrations of interleukin (IL)-1beta, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IL-8 and growth-related oncogene (Gro)-alpha. The presence of histologic chorioamnionitis or funisitis in the placentas and the highest white blood cell count of the infants during the first week of life were compared to the cytokine concentrations. RESULTS: Gastric fluid concentrations of IL-1beta, ENA-78, IL-8 and Gro-alpha were strongly associated with chorioamnionitis and funisitis. In addition, chorioamnionitis and funisitis and gastric aspirate cytokine levels were associated with the highest white blood cell counts of the infants during the first week of life. CONCLUSION: This study suggests that levels of inflammatory cytokines in the gastric fluid of premature infants at birth can be used to assess the exposure of the infants to antenatal inflammation.

Inflammatory cytokines in gastric fluid at birth and the development of bronchopulmonary dysplasia.

AIM: To assess whether the levels of inflammatory and anti-inflammatory proteins in gastric fluid of premature infants shortly after birth are associated with the development of bronchopulmonary dysplasia (BPD). METHODS: Gastric fluid retrieved within 1 h of birth of premature infants (gestational age <29 weeks) was analysed for interleukin (IL)-8, growth-related oncogene (Gro)-α, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IL-1ß and Clara cell secretory protein with ELISA. RESULTS: Of 51 enrolled infants, 86% had BPD. Of these, 54% had mild BPD, 30% had moderate BPD and 16% had severe BPD. Clinical chorioamnionitis was associated with high levels of IL-8, Gro-α, Epithelial cell-derived neutrophil-activating peptide-78 (ENA-78) and IL-1ß in gastric fluid. Gastric fluid levels of IL-8, Gro-α, ENA-78 and IL-1ß were higher in infants with moderate or severe BPD than in those with no or mild BPD. Ligation of the patent ductus arteriosus was associated with the development of moderate or severe BPD. These associations were no longer significant after adjustment for gestational age. CONCLUSION: The levels of inflammatory mediators in gastric fluid samples retrieved soon after birth from intubated or nonintubated infants can be used to assess the infants' perinatal exposure to inflammatory mediators and its association with neonatal outcome.

Intraamniotic interleukin-1 accelerates surfactant protein synthesis in fetal rabbits and improves lung stability after premature birth.

Intraamniotic infection is associated with increased IL-1 activity in amniotic fluid, increased incidence of preterm labor, and with decreased incidence of respiratory distress syndrome in infants born prematurely. We hypothesized that an elevated IL-1 in amniotic fluid promotes fetal lung maturation. On day 23 or 25 of gestation (term 31 d), either IL-1alpha (150 or 1,500 ng per fetus) or its antagonist IL-1 receptor antagonist (IL-1ra, 20 microg) was injected to the amniotic fluid sacs in one uterine horn, whereas the contralateral amniotic sacs were injected with vehicle. Within 40 h, IL-1alpha caused a dose-dependent increase in surfactant protein-A (SP-A) and SP-B mRNAs (maximally, fivefold), without affecting lung growth or increasing inflammatory cells in the lung. Both genders, and upper and lower lung lobes were similarly affected. IL-1ra did not modify SP-A, -B, or -C mRNA. IL-1 increased the intensity of staining of alveolar type II cells for SP-B, and the concentrations of SP-B, -A, and disaturated phosphatidylcholine in bronchoalveolar lavage. The dynamic lung compliance and the postventilatory expansion of lungs were increased two- to fourfold after IL-1alpha treatment. In fetal lung explants, IL-1alpha increased the expression of SP-A mRNA. IL-1 in amniotic fluid in preterm labor may promote lung maturation and thus be part of a host-defense mechanism that prepares the fetus for extrauterine life.

Interleukin-1 binding and prostaglandin E2 synthesis by amnion cells in culture: regulation by tumor necrosis factor-alpha, transforming growth factor-beta, and interleukin-1 receptor antagonist.

Proinflammatory cytokines may promote preterm labor in the setting of intrauterine infection. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) synergistically stimulate the production of prostaglandin E2 (PGE2) by amnion cells. Transforming growth factor-beta (TGF-beta) inhibits the cytokine-stimulated PGE2 production. In the present study, we investigated the binding of IL-1 beta on human amnion cells in culture. Untreated amnion cells possessed 540 +/- 60 IL-1 receptors per cell, with a dissociation constant of 1.4 +/- 0.4 nM. Cells treated with TGF-beta 1 (10 ng/ml) had 570 +/- 110 receptors per cell. TNF-alpha (50 ng/ml) increased the number of IL-1 receptors to 2930 +/- 590. TGF-beta 1 inhibited the receptor upregulation by TNF-alpha. Cells treated with TGF-beta 1 and TNF-alpha expressed 1140 +/- 590 receptors per cell. The binding affinity was not changed by the cytokines. IL-1 receptor antagonist (IL-1ra) inhibited the stimulation of amnion cell PGE2 production by IL-1 beta, but not by TNF-alpha. Amnion cells secreted large amounts of IL-1ra (1.1 +/- 0.3 ng/10(5) cells). Treatment of the cells with TGF-beta 1 or TNF-alpha did not affect the release of IL-1ra. We conclude that IL-1 receptor expression is an important step in the regulation of the effects of cytokines on amnion cell PGE2 production.

Monoacylglycerol hydrolase in human platelets.

In the present paper we show for the first time monoacylglycerol hydrolase in human platelets. No monoacylglycerol hydrolase activity could be demonstrated in the other blood cells. The monoacylglycerol hydrolase of platelets could not be released from the cells by heparin, thus the enzyme is distinct from the postheparin plasma lipases. The enzyme could be solubilized by a non-ionic detergent, Triton X-100. The solubilized monoacylglycerol hydrolase from platelets was optimally active at pH between 7 and 8 and at ionic strength corresponding to [NaCl] between 0.1 and 0.3 M. The optimal assay temperature was 37 degrees C. The enzyme activity was sensitive to HgCl2 but not to NaF. Accordingly, it was stabilized by 2-mercaptoethanol.

Association between neonatal care practices and efficacy of exogenous human surfactant: results of a bicenter randomized trial.

The purpose of this study was to analyze the impact of neonatal care practices on the efficacy of exogenous human surfactant. Two hundred newborns (gestational age 24.0 to 29.9 weeks, lecithin-sphingomyelin ratio less than 2 or absent phosphatidylglycerol, and requirement of mechanical ventilation at birth) participated in a randomized bicenter trial of human surfactant substitution. In only one of the two sites (site 2) surfactant substitution decreased the severity of respiratory failure and increased neonatal survival without bronchopulmonary dysplasia. For analysis of three-way association, continuous variables describing patient characteristics and treatment were dichotomized at the median. The following variables were significantly associated with good outcome in site 1 and 2 and with surfactant substitution in site 2: low oxygen requirement during first three neonatal days, low mean airway pressure during second and third day, low PaCO2 during first two neonatal days, and no ligation of ductus arteriosus. Low fluid intake during the first three days and low colloid intake during the first two days of life were associated with good outcome in both sites. The ratio between mean airway pressure and the oxygen requirement was higher in site 2 than in site 1 during the first day of life. Fluid intake and ventilatory management may influence the efficacy of exogenous surfactant.

The fate of exogenous surfactant in neonates with respiratory distress syndrome.

Respiratory distress syndrome (RDS) in newborn neonates is characterised by deficient secretion of surfactant from type III alveolar cells. Administration of surfactant to airways acutely decreases the degree of respiratory failure and increases the survival rate in neonates with RDS. Clinically available surfactants are lipid extracts derived from animal lung lavage or from whole lung. Synthetic surfactants contain phospholipids or additional spreading agents. An optimal exogenous surfactant would be efficacious, nontoxic and nonimmunogenic, resistant to oxidants and proteolytic agents, widely available at reasonable cost and manufactured with little batch-to-batch variability. Surfactant has been instilled into the airways as a bolus infusion through the endotracheal tube. In addition, surfactant may be given by aerosolisation or continuous infusion into the airways. Suggested dosages range from 50 to 200 mg/kg. Exogenous surfactant is cleared from the epithelial lining fluid (ELF) mainly by alveolar epithelial cells, although alveolar macrophages and the central airways may also contribute to clearance of the drug. Only small quantities of surfactant actually enter the blood stream. A significant fraction of surfactant is taken up, processed, and secreted back into the alveolar space by type II alveolar cells. This process is termed recycling. Phosphatidylglycerol, given to small premature neonates as a component of exogenous human surfactant, has an apparent pulmonary half-life of 31 +/- 3 hours (n = 11). The apparent pulmonary half-life of the main surfactant component dipalmitoyl phosphatidylcholine is 45 hours (n = 3) and that of surfactant protein A is about 9 hours (n = 4). A relationship between the dose of exogenous surfactant and its concentration in the ELF has been demonstrated. Some neonates with RDS respond poorly to surfactant therapy. The reasons for this include insufficient levels of surfactant in the ELF, uneven distribution of exogenous surfactant, inability of exogenous surfactant to enter the metabolic pathways, inhibition of surface activity by plasma-derived proteins, or inactivation of surfactant as a result of proteases, phospholipases, or oxygen free radicals. In addition, surfactant therapy may be ineffective in neonates with respiratory failure caused by factors other than surfactant deficiency. The efficacy of exogenous surfactant can be improved by increasing the dosage of surfactant and by administration of surfactant very early in respiratory failure.

Interaction of transferrin saturated with iron with lung surfactant in respiratory failure.

Proteins that decrease the surface activity of surfactant accumulate in epithelial lining fluid in respiratory failure. The aim of this study was to isolate a surfactant inhibitor from the airways of rabbits in acute respiratory failure induced by bronchoalveolar lavage (BAL). This inhibitor was identified as being transferrin (TF). Unlike serum TF, TF recovered in respiratory failure was saturated with iron (Fe(3+)-TF). Fe(3+)-TF decreased the surface activity of normal surfactant in vitro, whereas iron-free TF had no effect. In the presence of H2O2 and a reducing agent, Fe(+3)-TF inactivated the surfactant complex: the surface absorption rate was decreased, immunoreactive surfactant protein A was decreased, and malondialdehyde was formed. The acute effects of Fe(3+)-TF and iron-free TF applied to the airways were studied in animal models. In respiratory failure induced by BAL, Fe(3+)-TF deteriorated respiratory failure, whereas iron-free TF had no effect. In respiratory failure induced by hyperoxia for 48 h, administration of iron-free TF ameliorated the respiratory failure and improved the surface activity in BAL. We propose that Fe(3+)-TF accumulating in epithelial lining fluid during lung damage contributes to surfactant inhibition and promotes the formation of free radicals that inactivate the surfactant system.

A mechanism of nitric oxide-induced surfactant dysfunction.

Inhaled nitric oxide (NO) may modify surfactant either by interacting with the surfactant complex or by changing the capacity of the proteins of the epithelial lining fluid to inhibit the surface activity. Natural surfactant was exposed to NO (80 parts/million) in air in vitro while the gas-liquid surface was cycled. In the presence or absence of oxidants (Fe2+, xanthine, xanthine oxidase), surfactant exposed to NO retained the high surface activity significantly better than control surfactants exposed to air. Two surfactant inhibitors, hemoglobin (Hb) and albumin, were separately exposed to NO. In contrast to albumin, NO-exposed Hb and methemoglobin (MetHb; 16-125 micrograms/ml) decreased the surface activity at low surfactant concentrations, whereas native Hb had no effect. Surfactant recovered by sedimentation after exposure to MetHb had decreased surface activity and contained MetHb, whereas Hb did not bind to surfactant. Acidic phospholipid phosphatidylglycerol increased the binding of MetHb to surfactant. The MetHb-induced decrease in surface activity was elicited in the presence of surfactant proteins, including a peptide mimicking surfactant protein B. MetHb (but not Hb) added to a low dose of exogenous surfactant decreased the efficacy of surfactant to improve the lung compliance of premature rabbits. We propose that inhaled NO promotes the surface activity of surfactant during tidal ventilation and that, in high-permeability lung edema and surfactant deficiency, inhaled NO increases the inhibition of surface activity by converting Hb to MetHb in the alveolar space.

Surfactant dysfunction after inhalation of nitric oxide.

To study whether nitric oxide (NO) affects surfactant function, 36 young rats inhaled one of the following humidified environments for 24 h: 1) air; 2) 95% O2; 3) air and 100 parts/million (ppm) NO; and 4) 95% O2 and 100 ppm NO. The treatments did not change the recovery of phospholipid from bronchoalveolar lavage (BAL). Exposure to NO of animals that breathed either air or 95% O2 increased the minimum surface tension of surfactant from BAL at low (1.5 mumol/ml), but not at high (4 mumol/ml), phosphatidylcholine concentration. After inhaled NO, the nonsedimentable protein of BAL decreased the surface activity of surfactant (1 mumol phosphatidylcholine/ml) more than the protein from the controls. NO treatment of animals that breathed either air or 95% O2 affected neither the quantity nor the molecular weight distribution of nonsedimentable protein. Hyperoxia increased the amount of the nonsedimentable protein, whereas NO increased the iron saturation of transferrin. The surfactant fraction and the nonsedimentable protein from BAL were separately exposed to 80 ppm NO in vitro. NO exposure had no effect on the surface activity of surfactant fraction. NO exposure of nonsedimentable protein from the control animals (no NO) increased the inhibition of the surface activity and changed the adsorption spectrum of the protein, suggesting conversion of hemoglobin to methemoglobin. Nonsedimentable protein from NO-exposed animals contained methemoglobin. We propose that surfactant dysfunction caused by inhaled NO is in part due to alteration of protein(s) in epithelial lining fluid that in turn inactivates surfactant.

Epidermal growth factor and transforming growth factor-alpha enhance the interleukin-1- and tumor necrosis factor-stimulated prostaglandin E2 production and the interleukin-1 specific binding on amnion cells.

Interleukin-1 (IL-1), tumor necrosis factor (TNF), epidermal growth factor (EGF), and transforming growth factor-alpha (TGF-alpha) stimulate prostaglandin E2 (PGE2) production by amnion cells whereas TGF-beta inhibits the PGE2 production. During labor occurring in the setting of infection, several of these cytokines may be simultaneously present in amniotic fluid. The aim of the present study was to examine whether these cytokines modify each others' effects on amnion cell PGE2 production. Amnion cells in monolayer culture were treated with IL-1, TNF, EGF, TGF-alpha, TGF-beta 1, their combination, or vehicle. The PGE2 production and the specific binding of radiolabeled IL-1 beta on the cells were measured. IL-1 or TNF in combination with EGF or TGF-alpha stimulated synergistically the production of PGE2 by amnion cells. TGF-beta 1 did not modify the PGE2-stimulatory effect of EGF/TGF-alpha. Untreated amnion cells expressed 1030 +/- 100 IL-1 beta receptors per cell with a binding affinity of 1.40 +/- 0.26 nM. Treatment with TGF-alpha increased the number of receptors to 3940 +/- 260 per cell with no change in binding affinity. The potentiation of the PGE2-stimulatory effect of IL-1 by TGF-alpha may be related to its ability to induce IL-1 receptors on amnion cells. The synergistic effects of cytokines on amnion cell PGE2 production may promote labor.

Synergistic stimulation of amnion cell prostaglandin E2 synthesis by interleukin-1, tumor necrosis factor and products from activated human granulocytes.

We examined the interactions between supernatant from FMLP-activated human granulocytes, recombinant interleukin-1 (IL-1) and recombinant tumor necrosis factor (TNF) in the stimulation of prostaglandin E2 (PGE2) production by human amnion cells. Amnion cells from elective term cesarian sections were cultured in monolayer culture. Human granulocytes were activated with FMLP and centrifuged to obtained cell-free supernatant. Amnion cells were treated with granulocyte supernatant, IL-1 alpha, IL-1 beta, TNF-alpha, TNF-beta, or different combinations of these. Each of the stimulators alone enhanced the PGE2 production 5- to 27-fold. Granulocyte supernatant was synergistic with each of the cytokines. The combinations of IL-1 alpha or IL-1 beta with either TNF-alpha or TNF-beta caused a synergistic stimulation of amnion cell PGE2 production as well, whereas the combinations of IL-1 alpha with IL-1 beta or of TNF-alpha with TNF-beta were not synergistic. Furthermore, granulocyte supernatant was synergistic with the combination of IL-1 and TNF, resulting in a more than 150-fold stimulation of PGE2 production. Indomethacin completely suppressed these effects. We propose that granulocyte products acting together with IL-1 and TNF enhance PGE2 synthesis during inflammation, and serve as signals for the initiation of preterm labor in the setting of intra-amniotic infection.

A product of activated human granulocytes stimulates prostaglandin E2 synthesis in human amnion cells.

Cell-free supernatant from formylmethionyl-leucyl-phenylalanine (fMLP)-activated granulocytes causes a time- and concentration-dependent stimulation of prostaglandin E2 (PGE2) production in amnion cells. PGE2 concentration in the culture medium after 36 h treatment with granulocyte supernatant (from 40 x 10(6) granulocytes/ml of amnion cell medium), 1.49 +/- 0.71 pg/ng DNA (n = 13), was significantly higher (p = 0.0015) than in control cells (0.33 +/- 0.23 pg/ng DNA, n = 13). Indomethacin abolished this stimulation. Granulocyte supernatant and human epidermal growth factor (hEGF) had an additive effect on amnion cell PGE2 production. Catalase, superoxide dismutase (SOD), protease inhibitors or the platelet-activating factor (PAF) antagonist L-659,989 had no effect. Actinomycin D, cycloheximide and mepacrine reduced the PGE2 production. The phospholipase A2 activity present in granulocyte supernatants was resistant to heating, whereas heating decreased their PGE2-stimulating activity by 92%. Exogenous phospholipase A2 had no effect on PGE2 synthesis. The granulocyte product could be precipitated with ammonium sulphate. On gel filtration of supernatant, two peaks of PGE2-synthesis stimulating activity were obtained (molecular weights 12,000 and 60,000). This data serve to explain the association of chorioamnionitis with preterm labor: activated granulocytes release a protein(s) that induces prostaglandin production in amnion cells, and thus promote labor.

Nitric oxide and lung surfactant.

Inhalation of nitric oxide (NO) is an experimental treatment for severe pulmonary hypertension. Being rapidly metabolized by hemoglobin, inhaled NO causes selective vasodilation in the pulmonary vascular bed. In addition to the vascular smooth muscle, other pulmonary structures are exposed to inhaled NO, resulting in suppression of NO synthesis in a variety of pulmonary cells and in potential toxicity. NO is a free radical that interacts with a number of proteins, particularly metalloproteins. Together with superoxide radical, it rapidly forms highly toxic peroxynitrite. Peroxynitrite is involved in the killing of microbes by activated phagocytosing macrophages. In severe inflammation, peroxynitrite may be responsible for damaging proteins, lipids, and DNA. Peroxynitrite added to surfactant in vitro is capable of decreasing the surface activity, inducing lipid peroxidation, decreasing the function of surfactant proteins, SP-A and SP-B, and inducing protein-associated nitro-tyrosine. Exposure of animals for prolonged periods (48 to 72 hours) to inhaled NO (80 to 120 ppm) has been associated with a decrease in surface activity. This is caused by binding of surfactant to iron-proteins that are modified by NO (particularly methemoglobin), or by peroxynitrite induced damage of surfactant. In contrast, exposure of isolated surfactant complex to NO during surface cycling strikingly decreases the inactivation of surfactant, preventing the conversion of surfactant to small vesicles that are no longer surface-active, and preventing lipid peroxidation. This finding is consistent with the function of NO as a lipid-soluble chain-braking antioxidant. It is possible that this lipophilic gas has as yet undefined roles in regulation of surfactant metabolism and maintenance of surface activity. Deficiency in pulmonary NO may be present during the early neonatal period in respiratory distress syndrome and in persistent fetal circulation. The premature lung is likely to be sensitive to NO toxicity that may include lung damage, abnormal alveolarization, and mutagenicity. Defining of the indications, the dosage, and the toxicity of inhaled NO therapy remains the challenge for experimental and clinical research.

Cytokines and production of surfactant components.

The production of pulmonary surfactant, a complex of lipids and proteins that reduces surface tension at the alveolar air-liquid interface, is developmentally regulated. Several hormones, most notably glucocorticoids, are known to accelerate maturation of the surfactant system. Cytokines are polypeptides that act mostly in a paracrine fashion and possess a wide spectrum of activities on multiple types of cells. Many cytokines are produced by different lung cells a various stages of fetal development or under pathological conditions affecting the fetus. In addition, cytokines present in amniotic fluid or in the blood stream may reach the fetal lungs. Some cytokines, including epidermal growth factor, transforming growth factor-alpha, and interferon-gamma have been shown to stimulate the production of surfactant components. On the other hand, tumor necrosis factor and transforming growth factor-beta downregulate the production of surfactant lipids and proteins. We have recently shown that the proinflammatory cytokine interleukin-1 (IL-I) enhances the expression of surfactant protein A (SP-A) in fetal rabbit lung explants. In addition, injection of IL-I into the amniotic fluid of fetal rabbits enhances the expression of surfactant proteins and improves the lung compliance of preterm animals. Preterm delivery is often associated with subclinical intraamniotic infection. In these cases, amniotic fluid concentrations of IL-I are often elevated. We propose that this cytokine accelerates maturation of the surfactant system in fetal lungs and thus prepares the fetus for extrauterine life.

Protective effect of exogenous transferrin against hyperoxia: a study on premature rabbits.

We hypothesized that an increase in plasma iron binding capacity would decrease the generation of oxygen radicals and of lipid peroxides. To test this hypothesis, we studied whether supplementation of transferrin (TF) in premature rabbits would modify the degree of hyperoxic lung injury. Animals, delivered prematurely at 29 days of gestation (term 31 days), were randomized and given either 0.5 g/kg of albumin (Alb) (n = 116) or 0.5 g/kg of iron-free TF (n = 132) intravenously within 2 hours after birth. Another group was randomized to receive saline (n = 15), or either 0.35 g/kg (n = 12) or 0.70 g/kg of iron-free TF (n = 8). After exposure to a 100% oxygen environment for 2 or 4 days, the animals were killed, and plasma and bronchoalveolar lavage (BAL) fluid was recovered. Infusion of TF caused a dose-dependent increase in the concentration of TF and an increase in the unsaturated iron-binding capacity. Administration of TF at birth increased the gradient of TF between serum and alveolar epithelial lining fluid on day 4, suggesting decreased alveolar-capillary permeability. BAL fluid and plasma from TF-supplemented animals contained less lipid peroxidation products and more inhibitor of lipid peroxidation than BAL fluid or plasma from Alb-treated animals. In TF-treated animals, the recovery of protein in BAL fluid (TF group, 1.26 +/- 0.07 mg; Alb group, 1.78 +/- 0.10 mg; P = 0.02) and the water content of the extravascular lung tissue (TF group, 78.5 +/- 1.4%; Alb group, 83.2 +/- 1.3%; P = 0.05) were lower than in Alb-treated animals. We propose that supplementation of iron-free TF decreases iron-catalyzed redox reactions and may decrease hyperoxic lung injury in the premature.

Transferrin modifies surfactant responsiveness in acute respiratory failure: role of iron-free transferrin as an antioxidant.

In respiratory failure, transferrin (TF) with variable iron saturation accumulates in the alveolar space. Binding free iron to TF may inhibit metal-catalyzed formation of free radicals. The aim of this study was to evaluate whether the degree of the iron-saturation of TF influences the severity of respiratory failure and surfactant responsiveness. Surfactant deficiency and lung edema was induced in 42 paralyzed and ventilated young rabbits by bronchoalveolar lavage (BAL); 19 of these animals were preexposed to 100% O2 for 40 hours. The animals received (1) exogenous surfactant intratracheally (100 mg/kg in 4 ml/kg saline); (2) surfactant and Fe(3+)-TF (50 or 25 mg/kg); or (3) surfactant and iron-free TF (50 mg/kg). One hour after administration of TF, 13-25% of exogenous TF was recovered by BAL. Administration of Iron-free TF significantly decreased the iron saturation of TF in BAL. In acute respiratory failure induced by BAL, Fe(3+)-TF decreased the efficacy of exogenous surfactant in improving the gas exchange, and increased surfactant inhibition, while iron-free TF had no effect. By contrast, in respiratory failure induced by hyperoxia and BAL, iron-free TF improved the efficacy of exogenous surfactant, but Fe(2+)-TF had no effect. After administration of iron-free TF, surfactant isolated from BAL was more surface-active than surfactant from BAL of the other hyperoxia-treated animals. In animals exposed to hyperoxia, treatment with iron-free TF decreased malondialdehyde content of BAL. We propose that low iron saturation of TF decreases oxidant stress and favors the recovery from respiratory failure.

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.

Prostaglandins, inflammation, and preterm labor.

According to the current view, the fetal membranes and the amniotic fluid are central in transmission of signals resulting in labor and delivery. It has also become increasingly evident that although preterm and term labor share common pathways in activation of uterine contractions, the regulatory aspects are fundamentally different. The present article is a brief overview focusing on the participation of prostaglandins in human term and preterm labor. The involvement of bacteria in preterm labor is presented. In addition, it is proposed that inflammatory polymorphonuclear leukocytes promote preterm labor by activating prostaglandin production from human fetal membranes.