Polymer-Surfactant Treatment of Meconium-induced  Acute Lung Injury

Lu, Karen W.; Taeusch, H. William; Robertson, Bengt; Goerke, Jon; Clements, John A.

doi:10.1164/ajrccm.162.2.9909099

Cited by 66 publications

(73 citation statements)

References 26 publications

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“…The concentration of HA both in saline and in Survanta was 0.25% (wt/vol). The choice of 50 mg/kg Survanta was based on our previous studies of meconium lung injury in which we found that the addition of polyethylene glycol (PEG) to 50 mg/kg Survanta significantly improved measures of gas exchange and lung mechanics when compared with 50 mg/kg Survanta alone (15). We chose to use the same protocol with respect to injury model, surfactant, and dose as in the previous studies.…”

Section: Methodsmentioning

confidence: 99%

Hyaluronan Reduces Surfactant Inhibition and Improves Rat Lung Function after Meconium Injury

Goerke

Clements

et al. 2005

Pediatr Res

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Hyaluronan (HA), an ionic polymer, is normally present in the alveolar subphase and is known to decrease lung surfactant inactivation caused by serum in vitro. In this study, we examined whether HA can ameliorate the inactivating effects of meconium in vitro and in vivo. Surface activities of various mixtures of Survanta, HA, and meconium were measured using a modified pulsating bubble surfactometer. With meconium, almost all surface activity measures were improved by the addition of HA of several molecular weights at a concentration of 0.25%. Anesthetized, paralyzed rats were maintained on positive-pressure ventilation. After lung injury by instillation of meconium, they were treated with Survanta, Survanta with HA, or control mixtures. Serial measures of blood gases and peak inspiratory pressure were recorded for the duration of the experiment. When the Survanta plus HA group was compared with the Survanta alone group, arterial oxygen tension averaged 117% higher, peak inspiratory pressure was 27% lower at the end of the experiment, and lung compliance also showed significant improvement. These results indicate that HA added to Survanta decreases inactivation caused by meconium in vitro and improves gas exchange and pulmonary mechanics of animals with meconiuminduced acute lung injury. Abbreviations HA, hyaluronan (hyaluronic acid) PEG, polyethylene glycol PIP, peak inspiratory pressure PV, pressure-volume SA, surface area ⌬A 10 , percentage decrease in surface area from the maximum to reach a surface tension of 10 mN/m Hyaluronan (HA) is an ionic polymer of alternating Nacetylglucosamine and glucuronate units. It is one of the glycosaminoglycans that includes chondroitin, keratan, and heparan sulfates. Although HA has a simple chemical structure, it can assume a large number of conformations in aqueous solutions. These conformations allow HA to play many roles in biologic systems, such as being a space filler in the vitreous humor and serving as a viscoelastic substance in joints. In addition, HA interacts with cell surface receptors such as the receptor to HA-mediated motality RHAMM and CD44 (1-3). The biocompatibility of HA has led to many applications, including viscosurgery to allow the creation of space between tissues (4) and lubrication of arthritic joints.The role of HA in a variety of respiratory diseases has also been investigated by several groups. found that HA binds to elastic fibers, preventing elastolysis and limiting airspace enlargement in experimental models of emphysema induced by elastases. Forteza et al. (8) proposed that HA plays a major role in mucosal host defense by stimulating ciliary beating via the RHAMM. Because HA is secreted into the alveolar subphase by type II cells (9,10), it has been suggested that it may interact with lung surfactant (11).Our previous work has shown that adding HA to different lung surfactants improved the surface activity and decreased surfactant inactivation caused by serum (12). In this study, we investigated the effects of using HA Survanta mixtures i...

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Section: Methodsmentioning

confidence: 99%

Hyaluronan Reduces Surfactant Inhibition and Improves Rat Lung Function after Meconium Injury

Goerke

Clements

et al. 2005

Pediatr Res

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“…Both in vitro (1)(2)(3)(4)(5)(6) and in vivo (7)(8)(9) trials have shown that these nonionic polymers can significantly improve the surface activity of different therapeutic lung surfactants and effectively reverse inactivation due to a variety of inhibitory substances.…”

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Chitosan Enhances the In Vitro Surface Activity of Dilute Lung Surfactant Preparations and Resists Albumin-Induced Inactivation

et al. 2006

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ABSTRACT:Chitosan is a natural, cationic polysaccharide derived from fully or partially deacetylated chitin. Chitosan is capable of inducing large phospholipid aggregates, closely resembling the function of nonionic polymers tested previously as additives to therapeutic lung surfactants. The effects of chitosan on improving the surface activity of a dilute lung surfactant preparation, bovine lipid extract surfactant (BLES), and on resisting albumin-induced inactivation were studied using a constrained sessile drop (CSD) method. Also studied in parallel were the effects of polyethylene glycol (PEG, 10 kD) and hyaluronan (HA, 1240 kD). Both adsorption and dynamic cycling studies showed that chitosan is able to significantly enhance the surface activity of 0.5 mg/mL BLES and to resist albumin-induced inactivation at an extremely low concentration of 0.05 mg/mL, 1000 times smaller than the usual concentration of PEG and 20 times smaller than HA. Optical microscopy found that chitosan induced large surfactant aggregates even in the presence of albumin. Cytotoxicity tests confirmed that chitosan has no deleterious effect on the viability of lung epithelial cells. The experimental results suggest that chitosan may be a more effective polymeric additive to lung surfactant than the other polymers tested so far. (1) suggested the use of low-cost, water-soluble nonionic polymers, such as dextran, PEG, and polyvinylpyrrolidone (PVP), as additives to therapeutic lung surfactants. Both in vitro (1-6) and in vivo (7-9) trials have shown that these nonionic polymers can significantly improve the surface activity of different therapeutic lung surfactants and effectively reverse inactivation due to a variety of inhibitory substances.More recently, Lu et al. (10,11) reported the use of an anionic polymer, HA, as a surfactant additive. Both in vitro (10) and in vivo (11) tests showed that the addition of HA at different molecular weights to various therapeutic lung surfactants can effectively reverse serum-and meconium-induced inactivation. These studies, therefore, tentatively proved the feasibility of using an ionic polymer as a lung surfactant additive. Following these studies, we investigate here the use of a cationic polymer, chitosan, as a potential lung surfactant additive.Chitosan is a natural polysaccharide composed of linear ␤-(1¡4)-linked 2-amino-2-deoxy-␤-D-glucan combined with glycosidic linkages (12). It is derived from fully or partially deacetylated chitin, which is extracted from crustacean shells. Chitosan is also a polyelectrolyte with a positively charged backbone and is readily soluble in slightly acidic conditions (12). Chitosan was proven to be biodegradable, biocompatible, bioadhesive, and nontoxic in a range of toxicity tests (13). Because of these desirable properties, it has been extensively used in a variety of food, cosmetic, and pharmaceutical fields. Specifically, chitosan has been extensively used in drug delivery (13), including pulmonary drug delivery (12).Chan and co-workers (14 -17) have recently...

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“…We and others have found that the addition of nonionic polymers [principally polyethylene glycol (PEG), or dextran] further reduces surfactant inactivation by serum, meconium, or other substances in vitro (10 -12). In vivo studies also demonstrate that the addition of nonionic polymers to therapeutic surfactants improves pulmonary function after lung injury caused by meconium, albumin, hydrochloric acid, milk acid, or endotoxin (11,(13)(14)(15)(16).The successful experiments with nonionic polymers led us to consider using ionic polymers. In this study, we investigated whether hyaluronan (HA) has effects on pulmonary surfactants that are similar to those described for dextran and PEG.…”

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confidence: 99%

Hyaluronan Decreases Surfactant Inactivation In Vitro

Goerke

Clements

et al. 2005

Pediatr Res

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Hyaluronan (HA) is an anionic polymer and a constituent of alveolar fluid that can bind proteins, phospholipids, and water. Previous studies have established that nonionic polymers improve the surface activity of pulmonary surfactants by decreasing inactivation of surfactant. In this work, we investigate whether HA can also have beneficial effects when added to surfactants. We used a modified pulsating bubble surfactometer to measure mixtures of several commercially available pulmonary surfactants or native calf surfactant with and without serum inactivation. Surface properties such as equilibrium surface tension, minimum and maximum surface tensions on compression and expansion of a surface film, and degree of surface area reduction required to reach a surface tension of 10 mN/m were measured. In the presence of serum, addition of HA dramatically improved the surface activities of all four surfactants and in some cases in the absence of serum as well. These results indicate that HA reduces inactivation of surfactants caused by serum and add evidence that endogenous HAs may interact with alveolar surfactant under normal and abnormal conditions. Over the past decade, pulmonary surfactant replacement has revolutionized the therapy of respiratory distress syndrome of premature infants (1-3). However, effects of surfactant therapy are less dramatic when used to treat lung diseases associated with acute lung injury and acute respiratory distress syndrome (4 -7). The less successful clinical response in these diseases may be due in part to surfactant inactivation caused by leakage of plasma and inflammatory products into the alveoli. In the presence of inactivating substances, surface activity of alveolar surfactant is adversely affected, worsening overall lung function (8,9).Variation in susceptibility to inactivation exists among therapeutic surfactants. Many studies have reported that surfactantassociated proteins help resist inactivation caused by a variety of factors (6). We and others have found that the addition of nonionic polymers [principally polyethylene glycol (PEG), or dextran] further reduces surfactant inactivation by serum, meconium, or other substances in vitro (10 -12). In vivo studies also demonstrate that the addition of nonionic polymers to therapeutic surfactants improves pulmonary function after lung injury caused by meconium, albumin, hydrochloric acid, milk acid, or endotoxin (11,(13)(14)(15)(16).The successful experiments with nonionic polymers led us to consider using ionic polymers. In this study, we investigated whether hyaluronan (HA) has effects on pulmonary surfactants that are similar to those described for dextran and PEG. HA is a nonsulfated, polymeric glycosaminoglycan (mucopolysaccharide) of N-acetyl-glucosamine linked ␤-1, 4 to glucuronic acid, which is linked ␤-1, 3 to N-acetylglucosamine, etc. Unlike PEG or dextran, HA, an anionic polymer, is a natural, ubiquitous substance in the body. However, HA (like PEG and dextran) shares the ability to bind water but has much greater bind...

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Polymer-Surfactant Treatment of Meconium-induced Acute Lung Injury

Cited by 66 publications

References 26 publications

Hyaluronan Reduces Surfactant Inhibition and Improves Rat Lung Function after Meconium Injury

Hyaluronan Reduces Surfactant Inhibition and Improves Rat Lung Function after Meconium Injury

Chitosan Enhances the In Vitro Surface Activity of Dilute Lung Surfactant Preparations and Resists Albumin-Induced Inactivation

Hyaluronan Decreases Surfactant Inactivation In Vitro

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