Abrogation of betaglycan attenuates TGF-beta-mediated inhibition of embryonic murine lung branching morphogenesis in culture.

Although betaglycan (TGF-beta type III receptor) is known to enhance TGF-beta ligand binding to its type II receptor in murine lung epithelial cell lines, the biological significance of this phenomenon in the process of lung organogenesis is not understood. Betaglycan gene expression was detected in embryonic murine lungs undergoing branching morphogenesis in ex vivo culture. Antisense betaglycan oligodeoxynucleotides (ODN) resulted in up to 56% stimulation of lung branching morphogenesis in culture, while betaglycan mRNA and protein expression levels were suppressed by 90 and 82%, respectively. Following abrogation of betaglycan expression with antisense oligodeoxynucleotide, embryonic lungs were relatively insensitive to TGF-beta: TGF-beta2 (0.5 ng/ml) and TGF-beta1 (20 ng/ml), respectively, down-regulated lung morphogenesis by 38 and 34% in control cultures, whereas TGF-beta-induced inhibition was attenuated to 13 and 26% respectively, in the presence of betaglycan antisense oligodeoxynucleotides. TGF-beta neutralizing antibodies also prevented TGF-beta-mediated inhibition of lung branching in culture, supporting the speculation that autocrine/paracrine TGF-beta signaling is minimal in the absence of betaglycan. Betaglycan was immunolocalized mainly to the epithelial cells in developing airways, a spatial distribution which overlaps with that of TGF-beta type II receptor. Furthermore, abrogation of endogenous betaglycan gene expression prevented the characteristic down-regulation of cyclin A and surfactant protein C (SP-C) mRNAs by exogenous TGF-beta ligands. These results show that betaglycan expression is essential for optimal TGF-beta signaling during embryonic lung development. We therefore conclude that the abrogation of endogenous betaglycan attenuates endogenous autocrine and/or paracrine TGF-beta-mediated negative regulation of lung organogenesis.

Identification of a novel DNA regulatory element in the rabbit surfactant protein B (SP-B) promoter that is a target for ATF/CREB and AP-1 transcription factors.

Surfactant protein B (SP-B) is required for the maintenance of biophysical properties and physiological function of pulmonary surfactant. SP-B is expressed in a cell/tissue-specific manner by the alveolar type II and bronchiolar (Clara) epithelial cells of the lung and is developmentally and hormonally regulated. We previously identified a minimal promoter region containing -236/+39 base pairs (bp) of rabbit SP-B gene that is necessary and sufficient for high level promoter activity in NCI-H441 cells, a cell line with characteristics of Clara cells. In this study, we have characterized the functional importance of a novel DNA regulatory element, termed SP-B CRE, with the sequence TGAGGTCA in the SP-B minimal promoter. The SP-B CRE sequence shared homology to cyclic AMP responsive element (CRE) binding sequence and contained an overlapping nuclear receptor element binding half-site. Mutation of SP-B CRE into a scrambled sequence reduced promoter activity by greater than 70%, whereas mutation into a palindromic consensus CRE increased the promoter activity by 100%. Electrophoretic mobility shift assay (EMSA) and Western immunoblot analysis of affinity purified proteins interacting with SP-B CRE showed that it is a target for binding of members of the activating transcription factor (ATF)/cyclic AMP response element binding protein (CREB) family of transcription factors, such as CREB, CREM, ATF-1, ATF-2 as well as c-Jun and TTF-1. Overexpression of CREB, ATF-2 and c-Jun inhibited SP-B promoter activity in NCI-H441 cells. These data have shown that members of the ATF/CREB family of transcription factors and c-Jun play important roles in mediating the transcriptional regulation of the SP-B gene.

Hypertrophy and hyperplasia of alveolar type II cells in response to silica and other pulmonary toxicants.

Alveolar Type II cells serve two major functions in the lung, both of which are essential for the preservation of normal lung function. First, Type II cells synthesize and secrete pulmonary surfactant, and second, they function as progenitor cells for maintaining the alveolar epithelium. The Type II cell population of the lung is quite sensitive to the deposition of toxicants in the distal lung, responding in two principal ways. Damage to the Type I epithelium stimulates Type II cells to proliferate and subsequently differentiate to replace the injured Type I cells. Second, a portion of the Type II cell population may become hypertrophic. Both of these events are frequent findings in the diseased or damaged lung. The Type II cell changes are often associated with increases in surfactant pools. In those cases where ultrastructural characteristics of hypertrophic Type II cells were examined, the appearance of these cells was consistent with that of an activated cell type. Alterations in the lamellar body compartment are a common finding in hypertrophic Type II cells, with increases in both lamellar body size and number. It is likely that the hypertrophic, or activated, Type II cells account for the increased levels of surfactant found in the lungs after exposure to a variety of toxic agents. We examined, in detail, Type II cell hyperplasia and hypertrophy induced by silica deposition. Both Type II cell hyperplasia and hypertrophy were prominent responses. The proliferative response led to an approximate doubling of the number of Type II cells in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary surfactant function following endotoxin: effects of exogenous surfactant treatment.

In a porcine model of endotoxin-induced adult respiratory distress syndrome (ARDS) we tested the hypothesis that the severity of lung injury would vary with the concentration of endotoxin and that reestablishment of normal surfactant function with exogenous surfactant would vary with the severity of lung injury. The therapeutic effects of exogenous surfactant treatment on pulmonary surfactant function have varied greatly in animal models of ARDS. This has created discrepancies in the literature that may be due in part to a difference in the severity of the pulmonary lesion. Yorkshire pigs were anesthetized, placed on a ventilator, and surgically prepared for hemodynamic and lung function measurements. Pigs received either 25 (25LPS) or 50 (50LPS) micrograms/kg of Escherichia coli lipopolysaccharide (LPS) followed by exogenous surfactant (SURF, 100 mg/kg) instillation, and were randomized into five groups: Control = sham LPS (n = 4); 25LPS (n = 6); 50LPS (n = 6); 25LPS + SURF (n = 5); and 50LPS + SURF (n = 6). Treatments were followed by histological and surfactant function evaluation. Histological evaluation showed the hallmarks of ARDS. Pulmonary surfactant function assessed by surfaced tension minimum (Ymin) was significantly (P < .05) elevated in both the 25LPS (20.2 +/- 2, dyne/cm) and 50LPS (19 +/- 3, dyne/cm) groups as compared with the Control group (10 +/- 1, dyne/cm). Exogenous surfactant reduced Ymin in the 25LPS + SURF group (9 +/- 2 dyne/cm, p < .05 vs. 25LPS) but not in the 50LPS + SURF group (20 +/- 1 dyne/cm, p < .05 vs. Control and 25LPS + SURF). Surfactant treatment was more effective in reestablishing normal surfactant function in animals subjected to a low dose of endotoxin, compared with animals receiving a higher dose.

Effects of eicosapentaenoic and gamma-linolenic acids (dietary lipids) on pulmonary surfactant composition and function during porcine endotoxemia.

STUDY OBJECTIVES: To investigate whether a diet enriched with fish and borage oils, with their high polyunsaturated fatty acid (PUFA) content, alters surfactant composition and function during endotoxemia. DESIGN: Prospective, randomized, blinded, controlled animal study. SETTING: Research laboratory at a medical center. PARTICIPANTS: Thirty-six 15- to 25-kg, disease-free, castrated male pigs. DIETS AND MEASUREMENTS: Three groups of pigs (n = 12 per group) were fed for 8 days diets containing either omega-6 fatty acids (FAs) (corn oil; diet A), or omega-3 FAs (fish oil; diet B), or a combination of omega-6 and omega-3 FAs (borage and fish oils; diet C). Eight of 12 pigs in each group received a 0.1-mg/kg bolus of Escherichia coli endotoxin followed by a continuous infusion (0. 075 mg/kg/h). One lung was subsequently isolated ex vivo, and pressure-volume curves were measured. The contralateral lung was lavaged, and surfactant was analyzed for total and individual phospholipids and FA composition. Minimum and maximum surface tension was measured by bubble surfactometry. RESULTS: Pigs fed either diet B or C had increased oleic acid (C(18:1) omega-9), eicosapentaenoic acid (EPA; C(20:5) omega-3), docosahexaenoic acid (C(22:6) omega-3), and total omega-3 and monounsaturated FAs in their surfactant PUFA pools. The relative percentage of linoleic acid (C(18:2) omega-6) and total omega-6 FAs were significantly lower from pigs fed diets B and C compared with diet A. Palmitic acid (C(16:0)) concentrations, the primary FA in surfactant, had a tendency to be lower in pigs fed diets B and C. There were no demonstrable effects on surfactant function or pulmonary compliance. CONCLUSIONS: Diets containing EPA or EPA and gamma-linolenic acid altered the PUFA composition of pulmonary surfactant, but without demonstrable effects on surfactant function during porcine endotoxemia.

Effect of N-nitroso-N-methylurethane on gas exchange, lung compliance, and surfactant function of rabbits.

OBJECTIVES: To define the effect of N-nitroso-N-methyl-urethane (NNNMU) on pulmonary gas exchange, compliance and the biochemical and functional properties of the lung surfactant system. DESIGN: Four days after inducing lung injury, gas exchange and pulmonary compliance were studied and a bronchoalveolar lavage was taken. SETTING: Experimental laboratory of a university department of medicine, division of pulmonary and critical care medicine. ANIMALS: Ten rabbits after they had received an injection of NNNMU and five control animals. INTERVENTIONS: Controlled mechanical ventilation and bronchoalveolar lavage. MEASUREMENTS AND RESULTS: Measurements of gas exchange (using the multiple inert gas elimination technique), hemodynamics and pulmonary compliance were performed during ventilatory and hemodynamic steady state. A bronchoalveolar lavage (BAL) was taken after sacrificing the animal. BAL samples were processed for cell count and biochemical and functional surfactant analysis. Animals injected with NNNMU developed mild, but significant reduction in PaO2, while maintaining eucapnia during spontaneous air breathing. V/Q distributions and arterial blood gases were similar in all animals when ventilated mechanically with a fixed tidal volume. Compliance of the lung and phospholipid levels in lavage of NNNMU animals was significantly lower than in control animals (CON). Function of surfactant recovered from animals receiving NNNMU was decreased significantly where compared to CON. Thus, NNNMU resulted in a lowered lavage surfactant phospholipid content, impaired surfactant function, decreased compliance and hypoxemia during spontaneous ventilation. However, gas exchange was similar to that of control animals during mechanical ventilation. CONCLUSION: We conclude that NNNMU-induced gas exchange abnormalities present after 4 days are mild and are reversed by fixed volume mechanical ventilation despite marked alteration in surfactant function and lung compliance. These observations further define properties of a lung injury model that is of value in the study of surfactant replacement.

Inhibition of surfactant function by copper-zinc superoxide dismutase (CuZn-SOD).

The efficacy of antioxidant enzymes to limit oxidant lung injury by instillation with surfactant mixtures in preterm infants with hyaline membrane disease is under investigation. However, there is concern that instillation of proteins in the alveolar space may inactivate pulmonary surfactant. We studied the effects of bovine copper-zinc superoxide dismutase (CuZn-SOD) on the biophysical properties of two distinct surfactant preparations. Incubation of calf lung surfactant extract (CLSE, 1 mg phospholipid/ml) and Exosurf (0.1 mg phospholipid/ml) with CuZn-SOD (1-10 mg/ml) prevented the fall of surface tension at minimal bubble radius (Tmin) to low values with dynamic compression in a pulsating bubble surfactometer. CuZn-SOD also enhanced the sensitivity to inactivation by albumin, normal human serum, and after treatment with peroxynitrite. The inhibitory effects of CuZn-SOD on CLSE, but not Exosurf, were abolished at high lipid concentrations (3 mg/ml) and after the addition of human surfactant protein A (by weight). We conclude that CuZn-SOD may interfere with the surface activity of surfactant mixtures, leading to decreased effectiveness of surfactant replacement therapy.

Effect of budesonide and salbutamol on surfactant properties.

The objective of this study was to evaluate the in vitro effect of budesonide and salbutamol on the surfactant biophysical properties. The surface-tension properties of two bovine lipid extracts [bovine lipid extract surfactant (BLES) and Survanta] and a rat lung lavage natural surfactant were evaluated in vitro by the captive bubble surfactometer. Measurements were obtained before and after the addition of a low and high concentration of budesonide and salbutamol. Whereas salbutamol had no significant effect, budesonide markedly reduced the surface-tension-lowering properties of all surfactant preparations. Surfactant adsorption (decrease in surface tension vs. time) was significantly reduced (P < 0.01) at a high budesonide concentration with BLES, both concentrations with Survanta, and a low concentration with natural surfactant. At both concentrations, budesonide reduced (P < 0.01) Survanta film stability (minimal surface vs. time at minimum bubble volume), whereas no changes were seen with BLES. The minimal surface tension obtained for all surfactant preparations was significantly higher (P < 0.01), and the percentage of film area compression required to reach minimum surface tension was significantly lower after the addition of budesonide. In conclusion, budesonide, at concentrations used therapeutically, adversely affects the surface-tension-lowering properties of surfactant. We speculate that it may have the same adverse effect on the human surfactant.

Amiodarone--induced changes in surfactant phospholipids of rat lung.

Amiodarone HCl (AD) is a very effective antiarrhythmic drug, but its use is often associated with serious pulmonary complications. It is shown to induce lung phospholipidosis. Nevertheless, the effects of this drug on pulmonary surfactant which is composed of about 75% phospholipids and which prevents alveolar collapse is not known. Therefore, we have examined the effect of AD on the intra- and extracellular surfactant pools and on the levels of phosphatidylcholine (PC), the primary constituent of pulmonary surfactant. Male Wistar rats were fed AD (175 mg/kg) by oral gavage for three weeks. At the end of the experimental period, the rats were killed, the lungs removed and perfused, and surfactant isolated. Some lungs were prepared for ultrastructural examination. Phospholipid was assayed in the intra- and extracellular surfactant. Amiodarone produced a significant increase in both the intra- and extracellular surfactant phospholipid along with an appreciable change in the phospholipid profile. Also, the drug seemed to increase the number of lamellar inclusions in the surfactant producing type II alveolar cells. These data suggest that administration of AD leads to an increase in the lung surfactant phospholipid levels and lamellar bodies in alveolar type II cells.

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.

Pulmonary microsomal alterations following short-term low level inhalation of p-xylene in rats.

Rats exposed to 300 ppm para-xylene vapor for 1, 3 or 5 days, 6 h/day, exhibited alterations in pulmonary microsomal membrane structural and metabolic parameters. Following 1 day of exposure, conjugated diene levels were elevated while total phospholipid levels, P-450 content, benzyloxyresorufin O-dealkylase activity and 2-aminofluorene N-hydroxylase activity were decreased. Core and leaflet membrane fluidity, ethoxyresorufin O-deethylase activity and aryl hydrocarbon hydroxylase (AHH) activity were unchanged at this time. Altered parameters began to return to control values by day 3 of exposure except for 2-aminofluorene N-hydroxylase activity, which remained decreased throughout the time course, and core membrane fluidity which was increased following 3 days of exposure. After 5 days of exposure, all parameters returned to control levels with the exception of AHH activity which was increased 41% at this time. Extracellular surfactant levels were also decreased by 1 and 3 days of exposure but returned to control values after 5 days. Initial pulmonary alterations produced by low level p-xylene exposure may be mediated by a peroxidative process. The initial damage triggers an adaptive response in lung tissue which possibly involves enzyme induction and/or cell proliferation. The increase in AHH activity after 5 days of exposure could have important consequences on the metabolism of co-administered xenobiotics.

Pre- and postnatal stimulation of pulmonary surfactant protein D by in vivo dexamethasone treatment of rats.

Fetal (days 18 and 20 of gestation), neonatal (days 0, 2 and 4 of neonate) and adult rats were injected with dexamethasone (1 mg/kg) in vivo and 24 hours later the effect on the contents of surfactant protein D (SP-D) in the rat lungs were examined in comparison with surfactant protein A, disaturated phosphatidylcholine and phosphatidylglycerol. In vivo dexamethasone treatment resulted in significant increases of SP-D content as the other 3 components of surfactant in both fetuses and neonates, but not in adults. Responsiveness to glucocorticoid treatment on SP-D content was maximum on day 1 of neonate (2.7 times control value). The contents of surfactant components examined tend to respond better to steroid in postnatal rats. These data demonstrated that glucocorticoid treatment in vivo for short durations exhibits the stimulatory effect on the contents of SP-D in the fetal and neonatal rat lungs.

Methylmercury-induced alterations in lung and pulmonary surfactant properties of adult mice.

Exposure to methylmercuric chloride (MMC) has been shown to significantly affect development of the lung and pulmonary surfactant system of the fetus. Preliminary results suggest it may also affect adult lung and associated bronchoalveolar lavage (BAL), which represents the extracellular surfactant pool. To determine if mercury exposure has the potential to alter surfactant function, adult mice were treated with MMC, 15 mg/kg by intragastric intubation on 4 successive days. BAL was collected by repeated intratracheal lavage 24 h after the last treatment. Nucleated cell numbers in lavage were determined. Tissue was prepared for scanning electron microscopy (SEM). Lavage fluid was extracted into chloroform:methanol and phospholipid concentration determined. A sample of the extract was used at a constant phospholipid concentration to measure surface activity on a bubble surfactometer. Lung weight to body weight ratio increased whereas total numbers of nucleated cells in BAL were not altered by MMC. SEM of samples from lungs of animals exposed to MMC showed normal architecture. Surface tension measurements suggest that the mean time to minimum surface tension and the minimum surface tension were greater in BAL from mice exposed to MMC for 4 days. In addition samples of BAL were prepared for Fourier-transform infrared spectrophotometry (FT-IR). Spectra showed changes in both lipid and protein components of BAL. Morphometric analyses of micrographs showed that mean alveolar diameter was reduced and wall thickness increased after mercury exposure. These results suggest that methylmercury exposure may significantly affect surface tension characteristics and composition of BAL, possibly through leakage of edematous interstitial tissue.

Tracheal aspirate surface tension in babies with hyaline membrane disease: effects of synthetic surfactant replacement.

Our objective was to determine changes in surface tension of tracheal aspirate over the first 4-5 days of life in babies with hyaline membrane disease, with and without synthetic surfactant replacement. Tracheal aspirates were collected prior to and for 96-108 hr after initiation of a randomized double-blind trial of synthetic surfactant (EXOSURF Neonatal) or air-treated control patients. Using the captive bubble technique, we measured minimum surface tension (initial adsorption, first quasi-static compression, dynamic cycling at 30 cpm, second quasi-static compression and 5 min after quasi-static compressions) in 39 surfactant-treated and 44 control babies. We also compared minimum surface tension with the respiratory support provided. Twelve hours after one dose of synthetic surfactant, minimum surface tension on first quasistatic compression decreased significantly from 20.9+/-1.4 to 17.6+/-1.3 mN/m compared to air-treated babies, who did not show any change. Reduction in minimum tracheal aspirate surface tension on first quasi-static compression and during dynamic cycling over 48-60 hr occurred more rapidly in surfactant-treated babies. Ventilator support did not correlate with minimum tracheal aspirate surface tension. We conclude that treatment of babies with synthetic surfactant improved tracheal aspirate minimum surface tension within 12 hr of the first dose and for the next 48-60 hr.

Ultrastructural alterations of pulmonary surfactant in rat lungs after inhibition of protein synthesis by puromycin.

The effects of systematically administered puromycin on the fine structure of the lung were studied. The effects varied depending on the duration of exposure and the time interval between the last injection and sacrifice. After short term exposure most surfactant had separated from the epithelial surface and profound alterations in the tubular myelin structure were seen. After moderate duration of exposure a previously undescribed multilamellar lining layer was observed which was often detached from the alveolar epithelium. Six hours after the last injection the regular tubular myelin pattern reappeared. Puromycin treatment results in inhibition of various proteins synthesized by type II epithelial cells. Inhibition of synthesis of some proteins, most probably that of glycoprotein A, causes a primary effect on the structure of surfactant. The loss of at least some of the cytoskeletal proteins in Type II epithelial cells apparently results in interference with exocytosis of lamellar body contents.

Effect of bronchodilators on surfactant system of lung.

Pulmonary surfactant activity of healthy male albino rats was estimated in terms of the maximum and minimum surface tension values of alveolar washings and the phospholipid content of the extract. The results obtained in these (control) animals were compared with those in three groups of animals treated with therapeutic doses of terbutaline, adrenaline and aminophylline. A significant decrease in the surface tension values without a significant increase in the phospholipid content was observed with aminophylline, whereas a significant increase in phospholipid concentration without a significant decrease in surface tension values was observed in case of terbutaline and adrenaline. These findings suggest that aminophylline, in addition to a bronchodilator action, lowers the elastic resistance of lung. The study also indicates caution in interpreting phospholipid concentration as surfactant activity.

Effects of cationic liposome-DNA complexes on pulmonary surfactant function in vitro and in vivo.

Cationic liposome-DNA complexes are being evaluated as potential gene therapy agents for the lung. Cations have strong effects on the biophysical functions of lung surfactant. Therefore, we assessed whether cationic liposomes [composed of N-(1-(2,3-dioleyloxy) propyl)-N,N,N-trimethyl-ammonium chloride and dioleylphosphatidylethanolamine] with or without DNA affect behavior of four types of surfactant in vitro. Experiments were carried out using a modified Wilhelmy surface balance. The ability of surfactants that contain protein and anionic lipids to lower surface tension was inhibited in the presence of cationic liposomes. Inactivation was less when DNA was preincubated with cationic liposomes. Surfactant that contained neither protein nor anionic lipids was not inactivated. Mechanical properties of the lung were studied to assess in vivo surfactant function after intratracheal instillation of a cationic liposome-DNA complex into adult rats. Pressure-volume deflation curves were shifted by 18% compared with those from normal (untreated) animals, but this effect was transient and not different from that observed in animals who received a similar volume of saline. These findings indicate that cationic liposomes alone may have deleterious effects on behavior of some surfactants possibly by disrupting charge interactions between negatively charged phospholipids and surfactant proteins. When DNA is added to liposomes before exposure to surfactants, the adverse charge interactions may be obviated by charge neutralization of liposomes by DNA.

The effects of volatile anesthetic agents on pulmonary surfactant function.

The purpose of this article is to review the findings from research directed at understanding the effects of volatile anesthetics on the respiratory surface known as pulmonary surfactant. Anesthetics have long been known to have a disruptive effect on biological membranes. This review will highlight the interactions of volatile anesthetics with pulmonary surfactant. This paper has emphasized the interaction of volatile anesthetics with the pulmonary surfactant monolayer versus the lipid bilayer. The goal of this review is to uncover to what extent this understanding has progressed in forty years. Although the goal is quite broad, the information gathered and the advice given is specific. Theories of anesthesia and surfactant structure and function are summarized and discussed in light of early physico-chemical approaches and extend to an era where powerful new three-dimensional structural techniques can be used to answer this question.

Is liquid ventilation a reasonable alternative?

Liquid breathing has been in medical literature for nearly 80 years and has been proposed as a means of improving gas exchange in critically ill infants since the 1970s. Extensive laboratory experience with perfluorochemical liquid ventilation has lead to clinical trials in infants, children, and adults. This article discusses the process and physiologic response to liquid breathing in neonates, and reviews some of the factors that need clarification prior to approval as a routine clinical therapy.

Paraquat poisoning: an experimental model of dose-dependent acute lung injury due to surfactant dysfunction.

Since the most characteristic feature of paraquat poisoning is lung damage, a prospective controlled study was performed on excised rat lungs in order to estimate the intensity of lesion after different doses. Twenty-five male, 2-3-month-old non-SPF Wistar rats, divided into 5 groups, received paraquat dichloride in a single intraperitoneal injection (0, 1, 5, 25, or 50 mg/kg body weight) 24 h before the experiment. Static pressure-volume (PV) curves were performed in air- and saline-filled lungs; an estimator of surface tension and tissue works was computed by integrating the area of both curves and reported as work/ml of volume displacement. Paraquat induced a dose-dependent increase of inspiratory surface tension work that reached a significant two-fold order of magnitude for 25 and 50 mg/kg body weight (P < 0.05, ANOVA), sparing lung tissue. This kind of lesion was probably due to functional abnormalities of the surfactant system, as was shown by the increase in the hysteresis of the paraquat groups at the highest doses. Hence, paraquat poisoning provides a suitable model of acute lung injury with alveolar instability that can be easily used in experimental protocols of mechanical ventilation.