The effect of maternal protein restriction during perinatal life on the inflammatory response in pediatric rats.

Fetal growth restriction can affect health outcomes in postnatal life. This study tested the hypothesis that the response to an inflammatory pulmonary insult is altered in pediatric fetal growth restricted rats. Using a low-protein diet during gestation and postnatal life, growth-restricted male and female rats and healthy control rats were exposed to an inflammatory insult via the intratracheal instillation of heat-killed bacteria. After 6 h, animal lungs were examined for lung inflammation and status of the surfactant system. The results showed that in response to an inflammatory insult, neutrophil infiltration was decreased in both male and female rats in the growth-restricted animals compared with the control rats. The amount of surfactant was increased in the growth-restricted animals compared with the control rats, regardless of the inflammatory insult. It is concluded that fetal growth restriction results in increased surfactant and altered neutrophil responses following pulmonary insult.

Exogenous Surfactant as a Pulmonary Delivery Vehicle for Budesonide In Vivo.

BACKGROUND: Lung inflammation is associated with many respiratory conditions. Consequently, anti-inflammatory medications, like glucocorticoids, have become mainstay intrapulmonary therapeutics. However, their effectiveness for treating inflammation occurring in the alveolar regions of the lung is limited by suboptimal delivery. To improve the pulmonary distribution of glucocorticoids, such as budesonide to distal regions of the lung, exogenous surfactant has been proposed as an ideal delivery vehicle for such therapies. It was therefore hypothesized that fortifying an exogenous surfactant (BLES) with budesonide would enhance efficacy for treating pulmonary inflammation in vivo. METHODS: An intratracheal instillation of heat-killed bacteria was used to elicit an inflammatory response in the lungs of male and female rats. Thirty minutes after this initial instillation, either budesonide or BLES combined with budesonide was administered intratracheally. To evaluate the efficacy of surfactant delivery, various markers of inflammation were measured in the bronchoalveolar lavage and lung tissue. RESULTS: Although budesonide exhibited anti-inflammatory effects when administered alone, delivery with BLES enhanced those effects by lowering the lavage neutrophil counts and myeloperoxidase activity in lung tissue. Combining budesonide with BLES was also shown to reduce several other pro-inflammatory mediators. These results were shown across both sexes, with no observed sex differences. CONCLUSION: Based on these findings, it was concluded that exogenous surfactant can enhance the delivery and efficacy of budesonide in vivo.

The effects of aging and exercise on lung mechanics, surfactant and alveolar macrophages.

Purpose: Advancing age leads to changes to the respiratory system associated with increased susceptibility to lung diseases, and exercise may counteract this effect. To explore the underlying processes, we investigated the effects of aging and exercise on lung mechanics, alveolar macrophage function, and surfactant pools and activity, in mice. It was hypothesized that aging would impact lung mechanics, macrophage polarization, and the status of the surfactant system, and that these changes would be mitigated by exercise. Methods: Male C57BL/6 mice were housed from 2-3 to 22 months, for the aged group, or until 4 months of age for young mice. Mice in both groups were randomized to voluntarily running exercise or to non-exercise, for a 2-month period. Mice were euthanized and lung mechanics were analyzed using a flexiVent ventilator. Subsequently, the lungs were lavaged to obtain pulmonary surfactant and alveolar macrophages. Pulmonary surfactant was analyzed for pool sizes and activity whereas alveolar macrophages were examined for response to pro and anti-inflammatory stimuli. Results: Changes in lung mechanics, such as increased compliance and decreased airway resistance, were associated with aging but were not affected by exercise. The quantity as well as the biophysical activity of the pulmonary surfactant system was unaffected by either aging or exercise. More alveolar macrophages were recovered from exercising aged mice compared to both the young and non-exercising groups. Macrophages in this aged exercise group were more responsive to an anti-inflammatory stimulus. Conclusions: Our data supports previous literature that suggest the development of emphysema-like alterations to lung mechanics with aging. This effect was independent of exercise. Our data also indicates that surfactant is unaffected by aging and exercise. Alveolar macrophage properties and numbers were affected by exercise in the aging lung and may represent the main, potentially beneficial, effect of exercise on the pulmonary system.

Impact of ventilation-induced lung injury on the structure and function of lamellar bodies.

Alterations to the pulmonary surfactant system have been observed consistently in ventilation-induced lung injury (VILI) including composition changes and impairments in the surface tension reducing ability of the isolated extracellular surfactant. However, there is limited information about the effects of VILI on the intracellular form of surfactant, the lamellar body. It is hypothesized that VILI leads to alterations of lamellar body numbers and function. To test this hypothesis, rats were randomized to one of three groups, nonventilated controls, control ventilation, and high tidal volume ventilation (VILI). Following physiological assessment to confirm lung injury, isolated lamellar bodies were tested for surfactant function on a constrained sessile drop surfactometer. A separate cohort of animals was used to fix the lungs followed by examination of lamellar body numbers and morphology using transmission electron microscopy. The results showed an impaired ability of reducing surface tension for the lamellar bodies isolated from the VILI group as compared with the two other groups. The morphological assessment revealed that the number, and the relative area covered by, lamellar bodies were significantly decreased in animals with VILI animals as compared with the other groups. It is concluded that VILI causes significant alterations to lamellar bodies. It is speculated that increased secretion causes a depletion of lamellar bodies that cannot be compensated by de novo synthesis of surfactant in these injured lungs.

Lack of matrix metalloproteinase 3 in mouse models of lung injury ameliorates the pulmonary inflammatory response in female but not in male mice.

BACKGROUND: The acute respiratory distress syndrome (ARDS) is a complex pulmonary disorder in which the local release of cytokines and chemokines appears central to the pathophysiology. OBJECTIVE: Based on the known role of matrix metalloproteinase-3 (MMP3) in inflammatory processes, the objective was to examine the role of MMP3 in the pathogenesis of ARDS through the modulation of pulmonary inflammation. MATERIALS AND METHODS: Female and male, wild type (MMP3+/+) and knock out (MMP3-/-) mice were exposed to two, clinically relevant models of ARDS including (i) lipopolysaccharide (LPS)-induced lung injury, and (ii) hydrochloric acid-induced lung injury. Parameters of lung injury and inflammation were assessed through measurements in lung lavage including total protein content, inflammatory cell influx, and concentrations of mediators such as TNF-α, IL-6, G-CSF, CXCL1, CXCL2, and CCL2. Lung histology and compliance were also evaluated in the LPS model of injury. RESULTS: Following intra-tracheal LPS instillation, all mice developed lung injury, as measured by an increase in lavage neutrophils, and decrease in lung compliance, with no overall effect of genotype observed. Increased concentrations of lavage inflammatory cytokines and chemokines were also observed following LPS injury, however, LPS-instilled female MMP3-/- mice had lower levels of inflammatory mediators compared to LPS-instilled female MMP3+/+ mice. This effect of the genotype was not observed in male mice. Similar findings, including the MMP3-related sex differences, were also observed after acid-induced lung injury. CONCLUSION: MMP3 contributes to the pathogenesis of ARDS, by affecting the pulmonary inflammatory response in female mice in relevant models of lung injury.

The effect of matrix metalloproteinase-3 deficiency on pulmonary surfactant in a mouse model of acute lung injury.

The acute respiratory distress syndrome (ARDS) is characterized by arterial hypoxemia accompanied by severe inflammation and alterations to the pulmonary surfactant system. Published data has demonstrated a protective effect of matrix metalloproteinase-3 (Mmp3) deficiency against the inflammatory response associated with ARDS; however, the effect of Mmp3 on physiologic parameters and alterations to surfactant have not been previously studied. It was hypothesized that Mmp3 deficient (Mmp3(-/-)) mice would be protected against lung dysfunction associated with ARDS and maintain a functional pulmonary surfactant system. Wild type (WT) and Mmp3(-/-) mice were subjected to acid-aspiration followed by mechanical ventilation. Mmp3(-/-) mice maintained higher arterial oxygenation compared with WT mice at the completion of ventilation. Significant increase in functional large aggregate surfactant forms were observed in Mmp3(-/-) mice compared with WT mice. These findings further support a role of Mmp3 as an attractive therapeutic target for drug development in the setting of ARDS.

Apolipoprotein E-deficient mice are susceptible to the development of acute lung injury.

BACKGROUND: Apolipoprotein E (apoE) has been shown to play a pivotal role in the development of cardiovascular disease, attributable to its function in lipid trafficking and immune modulating properties; however, its role in modulating inflammation in the setting of acute lung injury (ALI) is unknown. OBJECTIVE: To determine whether apoE-deficient mice (apoE-/-) are more susceptible to ALI compared to wild-type (WT) animals. METHODS: Two independent models of ALI were employed. Firstly, WT and apoE-/- mice were randomized to acid aspiration (50 µl of 0.1 N hydrochloric acid) followed by 4 h of mechanical ventilation. Secondly, WT and apoE-/- mice were randomized to 72 h of hyperoxia exposure or room air. Thereafter, the intrinsic responses of WT and apoE-/- mice were assessed using the isolated perfused mouse lung (IPML) setup. Finally, based on elevated levels of oxidized low-density lipoprotein (oxLDL) in apoE-/-, the effect of oxLDL on lung endothelial permeability and inflammation was assessed. RESULTS: In both in vivo models, apoE-/- mice demonstrated greater increases in lung lavage protein levels, neutrophil counts, and cytokine expression (p < 0.05) compared to WT mice. Experiments utilizing the IPML setup demonstrated no differences in intrinsic lung responses to injury between apoE-/- and WT mice, suggesting the presence of a circulating factor as being responsible for the in vivo observations. Finally, the exposure of lung endothelial cells to oxLDL resulted in increased monolayer permeability and IL-6 release compared to native (nonoxidized) LDL. CONCLUSIONS: Our findings demonstrate a susceptibility of apoE-/- animals to ALI that may occur, in part, due to elevated levels of oxLDL.

A technique for repeated blood and cerebrospinal fluid sampling from individual rats over time without the need for repeated anesthesia.

Ethical animal use follows the 3R's: Replacement, Reduction and Refinement. Here, we present the use of simultaneous jugular vein and cisterna magna catheterization via a port system in rats for repeated fluid sampling for 14 consecutive days without loss of catheter patency. This technique allows repeated intra-animal sampling without anesthesia and, if used with pooling samples from a cohort of animals, replaces the need for terminal collections for sufficient sample volumes.

Adaptation to low body temperature influences pulmonary surfactant composition thereby increasing fluidity while maintaining appropriately ordered membrane structure and surface activity.

The interfacial surface tension of the lung is regulated by phospholipid-rich pulmonary surfactant films. Small changes in temperature affect surfactant structure and function in vitro. We compared the compositional, thermodynamic and functional properties of surfactant from hibernating and summer-active 13-lined ground squirrels (Ictidomys tridecemlineatus) with porcine surfactant to understand structure-function relationships in surfactant membranes and films. Hibernating squirrels had more surfactant large aggregates with more fluid monounsaturated molecular species than summer-active animals. The latter had more unsaturated species than porcine surfactant. Cold-adapted surfactant membranes displayed gel-to-fluid transitions at lower phase transition temperatures with reduced enthalpy. Both hibernating and summer-active squirrel surfactants exhibited lower enthalpy than porcine surfactant. LAURDAN fluorescence and DPH anisotropy revealed that surfactant bilayers from both groups of squirrels possessed similar ordered phase characteristics at low temperatures. While ground squirrel surfactants functioned well during dynamic cycling at 3, 25, and 37 degrees C, porcine surfactant demonstrated poorer activity at 3 degrees C but was superior at 37 degrees C. Consequently the surfactant composition of ground squirrels confers a greater thermal flexibility relative to homeothermic mammals, while retaining tight lipid packing at low body temperatures. This may represent the most critical feature contributing to sustained stability of the respiratory interface at low lung volumes. Thus, while less effective than porcine surfactant at 37 degrees C, summer-active surfactant functions adequately at both 37 degrees C and 3 degrees C allowing these animals to enter hibernation. Here further compositional alterations occur which improve function at low temperatures by maintaining adequate stability at low lung volumes and when temperature increases during arousal from hibernation.

The effects of exogenous surfactant administration on ventilation-induced inflammation in mouse models of lung injury.

BACKGROUND: Mechanical ventilation (MV) is an essential supportive therapy for acute lung injury (ALI); however it can also contribute to systemic inflammation. Since pulmonary surfactant has anti-inflammatory properties, the aim of the study was to investigate the effect of exogenous surfactant administration on ventilation-induced systemic inflammation. METHODS: Mice were randomized to receive an intra-tracheal instillation of a natural exogenous surfactant preparation (bLES, 50 mg/kg) or no treatment as a control. MV was then performed using the isolated and perfused mouse lung (IPML) set up. This model allowed for lung perfusion during MV. In experiment 1, mice were exposed to mechanical ventilation only (tidal volume =20 mL/kg, 2 hours). In experiment 2, hydrochloric acid or air was instilled intra-tracheally four hours before applying exogenous surfactant and ventilation (tidal volume =5 mL/kg, 2 hours). RESULTS: For both experiments, exogenous surfactant administration led to increased total and functional surfactant in the treated groups compared to the controls. Exogenous surfactant administration in mice exposed to MV only did not affect peak inspiratory pressure (PIP), lung IL-6 levels and the development of perfusate inflammation compared to non-treated controls. Acid injured mice exposed to conventional MV showed elevated PIP, lung IL-6 and protein levels and greater perfusate inflammation compared to air instilled controls. Instillation of exogenous surfactant did not influence the development of lung injury. Moreover, exogenous surfactant was not effective in reducing the concentration of inflammatory cytokines in the perfusate. CONCLUSIONS: The data indicates that exogenous surfactant did not mitigate ventilation-induced systemic inflammation in our models. Future studies will focus on altering surfactant composition to improve its immuno-modulating activity.

E-cigarette aerosol exposure of pulmonary surfactant impairs its surface tension reducing function.

INTRODUCTION: E-cigarette (EC) and vaping use continue to remain popular amongst teenage and young adult populations, despite several reports of vaping associated lung injury. One of the first compounds that EC aerosols comes into contact within the lungs during a deep inhalation is pulmonary surfactant. Impairment of surfactant's critical surface tension reducing activity can contribute to lung dysfunction. Currently, information on how EC aerosols impacts pulmonary surfactant remains limited. We hypothesized that exposure to EC aerosol impairs the surface tension reducing ability of surfactant. METHODS: Bovine Lipid Extract Surfactant (BLES) was used as a model surfactant in a direct exposure syringe system. BLES (2ml) was placed in a syringe (30ml) attached to an EC. The generated aerosol was drawn into the syringe and then expelled, repeated 30 times. Biophysical analysis after exposure was completed using a constrained drop surfactometer (CDS). RESULTS: Minimum surface tensions increased significantly after exposure to the EC aerosol across 20 compression/expansion cycles. Mixing of non-aerosolized e-liquid did not result in significant changes. Variation in device used, addition of nicotine, or temperature of the aerosol had no additional effect. Two e-liquid flavours, menthol and red wedding, had further detrimental effects, resulting in significantly higher surface tension than the vehicle exposed BLES. Menthol exposed BLES has the highest minimum surface tensions across all 20 compression/expansion cycles. Alteration of surfactant properties through interaction with the produced aerosol was observed with a basic e-liquid vehicle, however additional compounds produced by added flavourings appeared to be able to increase inhibition. CONCLUSION: EC aerosols alter surfactant function through increases in minimum surface tension. This impairment may contribute to lung dysfunction and susceptibility to further injury.

Alveolar epithelial glycocalyx degradation mediates surfactant dysfunction and contributes to acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure yet has few pharmacologic therapies, reflecting the mechanistic heterogeneity of lung injury. We hypothesized that damage to the alveolar epithelial glycocalyx, a layer of glycosaminoglycans interposed between the epithelium and surfactant, contributes to lung injury in patients with ARDS. Using mass spectrometry of airspace fluid noninvasively collected from mechanically ventilated patients, we found that airspace glycosaminoglycan shedding (an index of glycocalyx degradation) occurred predominantly in patients with direct lung injury and was associated with duration of mechanical ventilation. Male patients had increased shedding, which correlated with airspace concentrations of matrix metalloproteinases. Selective epithelial glycocalyx degradation in mice was sufficient to induce surfactant dysfunction, a key characteristic of ARDS, leading to microatelectasis and decreased lung compliance. Rapid colorimetric quantification of airspace glycosaminoglycans was feasible and could provide point-of-care prognostic information to clinicians and/or be used for predictive enrichment in clinical trials.

The biological effects of lung-derived mediators on the liver.

Despite the use of lung-protective mechanical ventilation (MV), the mortality of patients with acute lung injury remains at 30 to 40%, predominantly due to multiorgan failure. The objective of this study was to determine the biological significance of lung-derived mediators on peripheral organ inflammation. The authors utilized an isolated perfused mouse lung model of lipopolysaccharide (LPS)-induced lung inflammation and protective MV to collect lung-derived mediators. Aliquots of perfusate from these animals (or appropriate controls) were then injected intravenously into a cohort of normal animals whose livers were subsequently assessed in vivo using intravital video microscopy. Perfusate from LPS-inflamed lungs contained significantly higher concentrations of inflammatory mediators than perfusate from saline-instilled lungs. Assessment of livers in the second cohort of animals 120 minutes after perfusate injection revealed decreased sinusoidal blood flow, leukocytosis, and increased cell death in those receiving perfusate from LPS-inflamed lungs compared to perfusate from saline controls. There were no differences between control animals that received pure perfusate or pure LPS mixed with perfusate. These results showed that lung-derived mediators had a significant biological effect on nonpulmonary organs within a short period of time after administration. Therapies targeting these mediators may prevent multiorgan failure and death in patients with acute lung injury.

The impact of maternal protein restriction during perinatal life on the response to a septic insult in adult rats.

Although abundant evidence exists that adverse events during pregnancy lead to chronic conditions, there is limited information on the impact of acute insults such as sepsis. This study tested the hypothesis that impaired fetal development leads to altered organ responses to a septic insult in both male and female adult offspring. Fetal growth restricted (FGR) rats were generated using a maternal protein-restricted diet. Male and female FGR and control diet rats were housed until 150-160 d of age when they were exposed either a saline (control) or a fecal slurry intraperitoneal (Sepsis) injection. After 6 h, livers and lungs were analyzed for inflammation and, additionally, the amounts and function of pulmonary surfactant were measured. The results showed increases in the steady-state mRNA levels of inflammatory cytokines in the liver in response to the septic insult in both males and females; these responses were not different between FGR and control diet groups. In the lungs, cytokines were not detectable in any of the experimental groups. A significant decrease in the relative amount of surfactant was observed in male FGR offspring, but this was not observed in control males or in female animals. Overall, it is concluded that FGR induced by maternal protein restriction does not impact liver and lung inflammatory response to sepsis in either male or female adult rats. An altered septic response in male FGR offspring with respect to surfactant may imply a contribution to lung dysfunction.

Surfactant protein-A reduces translocation of mediators from the lung into the circulation.

The objective of this study was to characterize a mouse model of lung inflammation and determine the effect of surfactant protein A (SP-A, or sftpa) on the transfer of inflammatory mediators from these injured lungs into the systemic circulation. Lung inflammation was induced in either sftpa-deficient (-/-) or wild-type (+/+) spontaneously breathing, adult mice via intranasal lipopolysaccharide (LPS). Four hours later, lungs were isolated, perfused, and mechanically ventilated for 2 hours. Perfusate was collected for analysis over the duration of ventilation and lung lavage was obtained in groups of animals immediately before and after mechanical ventilation (MV). Lavage analysis showed an increase in interleukin-6 (IL6) and tumor necrosis factor-alpha (TNFalpha) 4 hours after LPS, with a further increase in IL6 following MV. LPS and MV also caused an increase in total cell and neutrophil numbers as well as total protein in the lavage compared to controls. Perfusate analysis revealed a significant increase in IL6 and TNFalpha after LPS and MV, with significantly greater levels of these mediators in sftpa (-/-) versus (+/+) mice. The authors conclude that LPS followed by MV resulted in lung inflammation and injury, and that SP-A significantly influenced inflammatory mediator release from these inflamed lungs into the perfusate.

Protective effects of aerosolized pulmonary surfactant powder in a model of ventilator-induced lung injury.

Mechanical ventilation may contribute to the impairment of the pulmonary surfactant system, which is one of the mechanisms leading to the progression of acute lung injury. To investigate the potential protective effects of pulmonary surfactant in a rat model of ventilator-induced lung injury, the surfactant powder was aerosolized using an in-house made device designed to deliver the aerosolized powder to the inspiratory line of a rodent ventilator circuit. Rats were randomized to (i) administration of aerosolized recombinant surfactant protein C based pulmonary surfactant, (ii) intratracheally instillation of the same surfactant re-constituted in saline, and (iii) no treatment. Animals were monitored during 2 h of high-tidal volume mechanical ventilation, after which rats were sacrificed, and further analysis of lung mechanics and surfactant function were completed. Blood gas measurements during ventilation showed extended maintenance of oxygen levels above 400 mmHg in aerosol treated animals over non-treated and instilled groups, while total protein analysis showed reduced levels in the aerosol compared to non-treated groups. Dynamic captive bubble surface tension measurements showed the activity of surfactant recovered from aerosol treated animals is maintained below 1 mN/m. The prophylactic treatment of aerosolized surfactant powder reduced the severity of lung injury in this model.

Elevated endogenous surfactant reduces inflammation in an acute lung injury model.

Acute lung injury (ALI) is associated with severe pulmonary inflammation and alterations to surfactant, and often results in overwhelming systemic inflammation, leading to multiple organ failure. The objective of this study was to determine the effect of increased endogenous surfactant pools on pulmonary and systemic inflammation in a model of lipopolysaccharide (LPS)-induced ALI. Mice received an instillation of liposome-encapsulated (i) dichloromethylene diphosphonic acid (DMDP) to increase surfactant pools via depletion of alveolar macrophages, or (ii) phosphate-buffered saline (PBS). Seven days after instillation, mice received an intranasal administration of LPS or saline. Following a 4-hour recovery period, mice were sacrificed and their lungs were isolated, mechanically ventilated, and perfused with 8 mL of recirculated perfusate through the pulmonary circulation for 2 hours. Perfusate and lavage fluid were collected for analysis of inflammatory mediators. Lavage analysis revealed a 5-fold increase in surfactant pools in DMDP-treated mice compared to PBS-treated controls. Lavage and perfusate analyses showed significant decreases in the concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1alpha, and IL-1beta cytokines in DMDP-LPS mice compared to PBS-LPS controls. Elevated endogenous surfactant pools are protective against both LPS- and mechanical ventilation-induced inflammation, in addition to inflammation associated with the combination of these two insults.

Maternal protein restriction during perinatal life affects lung mechanics and the surfactant system during early postnatal life in female rats.

Limited information is available on how fetal growth retardation (FGR) affects the lung in the neonatal period in males and females. This led us to test the hypothesis that FGR alters lung mechanics and the surfactant system during the neonatal period. To test this hypothesis a model of FGR was utilized in which pregnant rat dams were fed a low protein diet during both the gestation and lactation period. We subsequently analyzed lung mechanics using a FlexiVent ventilator in male and female pups at postnatal day 7 and 21. Lung lavage material was obtained at postnatal day 1, 7 and 21, and was used for analysis of the surfactant system which included measurement of the pool size of surfactant and its subfraction as well as the surface tension reducing ability of the surfactant. The main result of the study was a significantly lower lung compliance and higher tissue elastance which was observed in FGR female offspring at day 21 compared to control offspring. In addition, female LP offspring exhibited lower surfactant pool sizes at postnatal day 1compared to controls. These changes were not observed in the male offspring. It is concluded that FGR has a different impact on pulmonary function and on surfactant in female, as compared to male, offspring.

The effects of long-term conventional mechanical ventilation on the lungs of adult rats.

BACKGROUND: Ventilation-induced lung injury is often studied in animal models by using ventilation strategies with high-tidal volumes and high-oxygen concentration over a relatively short period of time. The injury induced by these ventilation strategies includes alterations to the surfactant system and up-regulation of inflammatory markers. Whether these responses to ventilation occur with more clinically relevant ventilation strategies is not known. OBJECTIVE: To assess how healthy adult rats respond to 24 hrs of conventional mechanical ventilation with respect to lung physiology, markers of inflammation, and alterations to pulmonary surfactant, and how this is affected by the oxygen concentration. INTERVENTIONS: Adult rats were mechanically ventilated for 24 hrs with a tidal volume of 8 mL/kg, 5 cm H2O positive end-expiratory pressure, at 60 breaths/min with either 21% or 100% oxygen. Animals were monitored for blood oxygenation and other physiologic parameters. After ventilation, lungs were lavaged and analyzed for inflammatory markers and pulmonary surfactant. These outcomes were compared with measurements obtained from spontaneously breathing rats exposed to either 21% or 100% oxygen for 24 hrs. MAIN RESULTS: Twenty-four hours of ventilation did not result in significant changes in blood oxygenation. Inflammatory markers, such as interleukin-6 concentration and the number of neutrophils in the lavage, were increased in ventilated animals compared with the nonventilated controls, regardless of the level of inspired oxygen. The amount of active surfactant was increased after ventilation; however, the surface activity of this material was impaired as compared with controls. CONCLUSION: Prolonged mechanical ventilation of health lungs with a physiologically benign strategy can contribute to the inflammatory response and cause alterations to pulmonary surfactant.

Effective in vivo treatment of acute lung injury with helical, amphipathic peptoid mimics of pulmonary surfactant proteins.

Acute lung injury (ALI) leads to progressive loss of breathing capacity and hypoxemia, as well as pulmonary surfactant dysfunction. ALI's pathogenesis and management are complex, and it is a significant cause of morbidity and mortality worldwide. Exogenous surfactant therapy, even for research purposes, is impractical for adults because of the high cost of current surfactant preparations. Prior in vitro work has shown that poly-N-substituted glycines (peptoids), in a biomimetic lipid mixture, emulate key biophysical activities of lung surfactant proteins B and C at the air-water interface. Here we report good in vivo efficacy of a peptoid-based surfactant, compared with extracted animal surfactant and a synthetic lipid formulation, in a rat model of lavage-induced ALI. Adult rats were subjected to whole-lung lavage followed by administration of surfactant formulations and monitoring of outcomes. Treatment with a surfactant protein C mimic formulation improved blood oxygenation, blood pH, shunt fraction, and peak inspiratory pressure to a greater degree than surfactant protein B mimic or combined formulations. All peptoid-enhanced treatment groups showed improved outcomes compared to synthetic lipids alone, and some formulations improved outcomes to a similar extent as animal-derived surfactant. Robust biophysical mimics of natural surfactant proteins may enable new medical research in ALI treatment.