Abstract:BackgroundSecretory phospholipase A2 (sPLA2) is a group of enzymes involved in lung tissue inflammation and surfactant catabolism. sPLA2 plays a role in adults affected by acute lung injury and seems a promising therapeutic target. Preliminary data allow foreseeing the importance of such enzyme in some critical respiratory diseases in neonates and infants, as well. Our study aim is to clarify the role of sPLA2 and its modulators in the pathogenesis and clinical severity of hyaline membrane disease, infection r… Show more
“…The low compressibility of serum proteins does not allow for the extreme reduction in surface tensions that are required to prevent alveolar collapse. Other inflammation-associated proteins like CRP 25,26 or secretory phospholipase A2 24,27 also contribute, altogether, to inhibit surfactant performance. In our in vitro model, CBS results confirm a similar performance of CHF in the absence or presence of serum, including the possible exclusion of POPG that would be associated with the characteristic plateau of the isotherm during dynamic cycles.…”
CHF5633 is a novel synthetic clinical pulmonary surfactant preparation composed by two phospholipid species, dipalmitoyl phosphatidylcholine (Dppc) and palmitoyloleoyl phosphatidylglycerol (popG), and synthetic analogues of the hydrophobic surfactant proteins Sp-B and Sp-c. in this study, the interfacial properties of CHF5633 in the absence and in the presence of inhibitory serum proteins have been assessed in comparison with a native surfactant purified from porcine lungs and with poractant alpha, a widely used clinical surfactant preparation. The study of the spreading properties of CHF5633 in a Wilhelmy balance, its ability to adsorb and accumulate at air-liquid interfaces as revealed by a multiwell fluorescence assay, and its dynamic behavior under breathing-like compression-expansion cycling in a Captive Bubble Surfactometer (CBS), all revealed that CHF5633 exhibits a good behavior to reduce and sustain surface tensions to values below 5 mN/m. CHF5633 shows somehow slower initial interfacial adsorption than native surfactant or poractant alpha, but a better resistance to inhibition by serum proteins than the animal-derived clinical surfactant, comparable to that of the full native surfactant complex. Interfacial CHF5633 films formed in a Langmuir-Blodgett balance coupled with epifluorescence microscopy revealed similar propensity to segregate condensed lipid domains under compression than films made by native porcine surfactant or poractant alpha. This ability of CHF5633 to segregate condensed lipid phases can be related with a marked thermotropic transition from ordered to disordered membrane phases as exhibited by differential scanning calorimetry (DSC) of CHF5633 suspensions, occurring at similar temperatures but with higher associated enthalpy than that shown by poractant alpha. The good interfacial behavior of CHF5633 tested under physiologically meaningful conditions in vitro and its higher resistance to inactivation by serum proteins, together with its standardized and well-defined composition, makes it a particularly useful therapeutic preparation to be applied in situations associated with lung inflammation and edema, alone or in combined strategies to exploit surfactant-facilitated drug delivery. The presence of a surface-active lipid/protein complex at the respiratory air-liquid interface is essential to facilitate effortless breathing mechanics 1,2. Lack or dysfunction of this pulmonary surfactant is associated with severe, often lethal, respiratory pathologies 3. Babies born before their lungs have matured to produce surfactant are at risk of developing respiratory distress syndrome (RDS), with a high mortality unless these neonates are treated early with an exogenous surfactant material. In this sense, administration of a bolus of exogenous surfactant, typically obtained from extracts of animal-derived materials, has saved thousands of preterm baby lives 4,5. In other pathologies associated with lung injury and inflammation in children and adults, blood proteins and inflammatory mediators liber...
“…The low compressibility of serum proteins does not allow for the extreme reduction in surface tensions that are required to prevent alveolar collapse. Other inflammation-associated proteins like CRP 25,26 or secretory phospholipase A2 24,27 also contribute, altogether, to inhibit surfactant performance. In our in vitro model, CBS results confirm a similar performance of CHF in the absence or presence of serum, including the possible exclusion of POPG that would be associated with the characteristic plateau of the isotherm during dynamic cycles.…”
CHF5633 is a novel synthetic clinical pulmonary surfactant preparation composed by two phospholipid species, dipalmitoyl phosphatidylcholine (Dppc) and palmitoyloleoyl phosphatidylglycerol (popG), and synthetic analogues of the hydrophobic surfactant proteins Sp-B and Sp-c. in this study, the interfacial properties of CHF5633 in the absence and in the presence of inhibitory serum proteins have been assessed in comparison with a native surfactant purified from porcine lungs and with poractant alpha, a widely used clinical surfactant preparation. The study of the spreading properties of CHF5633 in a Wilhelmy balance, its ability to adsorb and accumulate at air-liquid interfaces as revealed by a multiwell fluorescence assay, and its dynamic behavior under breathing-like compression-expansion cycling in a Captive Bubble Surfactometer (CBS), all revealed that CHF5633 exhibits a good behavior to reduce and sustain surface tensions to values below 5 mN/m. CHF5633 shows somehow slower initial interfacial adsorption than native surfactant or poractant alpha, but a better resistance to inhibition by serum proteins than the animal-derived clinical surfactant, comparable to that of the full native surfactant complex. Interfacial CHF5633 films formed in a Langmuir-Blodgett balance coupled with epifluorescence microscopy revealed similar propensity to segregate condensed lipid domains under compression than films made by native porcine surfactant or poractant alpha. This ability of CHF5633 to segregate condensed lipid phases can be related with a marked thermotropic transition from ordered to disordered membrane phases as exhibited by differential scanning calorimetry (DSC) of CHF5633 suspensions, occurring at similar temperatures but with higher associated enthalpy than that shown by poractant alpha. The good interfacial behavior of CHF5633 tested under physiologically meaningful conditions in vitro and its higher resistance to inactivation by serum proteins, together with its standardized and well-defined composition, makes it a particularly useful therapeutic preparation to be applied in situations associated with lung inflammation and edema, alone or in combined strategies to exploit surfactant-facilitated drug delivery. The presence of a surface-active lipid/protein complex at the respiratory air-liquid interface is essential to facilitate effortless breathing mechanics 1,2. Lack or dysfunction of this pulmonary surfactant is associated with severe, often lethal, respiratory pathologies 3. Babies born before their lungs have matured to produce surfactant are at risk of developing respiratory distress syndrome (RDS), with a high mortality unless these neonates are treated early with an exogenous surfactant material. In this sense, administration of a bolus of exogenous surfactant, typically obtained from extracts of animal-derived materials, has saved thousands of preterm baby lives 4,5. In other pathologies associated with lung injury and inflammation in children and adults, blood proteins and inflammatory mediators liber...
“…The role of secretory phospholipases (e.g. sPLA2) in surfactant degradation and lung inflammation is well known and these lipases also add another layer of complexity to surfactant balance; secretory lipases also mediate surfactant dysfunction and augment acute lung injury [237]. …”
Section: Regulation Of Surfactant Degradation and Recyclingmentioning
Pulmonary surfactant is essential for life and is comprised of a complex lipoprotein-like mixture that lines the inner surface of the lung to prevent alveolar collapse at the end of expiration. The molecular composition of surfactant depends on highly integrated and regulated processes involving its biosynthesis, remodeling, degradation, and intracellular trafficking. Despite its multicomponent composition, the study of surfactant phospholipid metabolism has focused on two predominant components, disaturated phosphatidylcholine that confers surface-tension lowering activities, and phosphatidylglycerol, recently implicated in innate immune defense. Future studies providing a better understanding of the molecular control and physiological relevance of minor surfactant lipid components are needed.
“…Secreted PLA 2 is a known mechanism of surfactant degradation that has been implicated in respiratory diseases (43,44). PLA 2 activity in lavage fluid from LCAD Ϫ/Ϫ and wild-type mice was very low in both genotypes and could not be accurately determined.…”
Section: Amount and Function Of Pulmonary Surfactant Is Reduced In Lcadmentioning
Background:The contribution of long-chain acyl-CoA dehydrogenase (LCAD) to human fatty acid oxidation is not understood. Results: LCAD localizes to lung alveolar type II cells, which produce pulmonary surfactant; LCAD-deficient mice have surfactant dysfunction. Conclusion: LCAD is important for lung energy metabolism and lung function. Significance: LCAD may play a role in human lung disease and unexplained sudden infant death.
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