This multidisciplinary bioengineering research partnership (BRP) grant studies the molecular bioengineering, synthesis, surface activity, and pulmonary efficacy of novel fully-synthetic lipid/peptide lung surfactants. Also studied is the use of synthetic surfactants to facilitate the delivery of exogenous DNA to animals with lung injury for future gene therapy or multi-drug therapy applications. The primary goal of the BRP is to develop fully-synthetic lung surfactants with maximal activity, inhibition resistance, stability, purity, and production economy compared to existing animal-derived or synthetic clinical surfactant drugs for treating the neonatal respiratory distress syndrome (NRDS), acute lung injury (ALI), and the acute respiratory distress syndrome (ARDS). A highly-experienced, collaborative BRP team with expertise in bioengineering, physics, chemistry, biology, and medicine is assembled at three universities: the University of Rochester (primary institution), LA Biomedical Research Institute/Harbor-UCLA Medical Center, and the University of Guelph. Synthetic peptides studied in the BRP include compounds incorporating key molecular features of human surfactant protein (SP)-B, which has crucial functional activity in native surfactant. Peptides and lipopeptides related to human SP-C/SP-A are also studied and are bioengineered to have advantages in molecular stability relative to native apoproteins. The BRP also examines two types of lipids: synthetic lipids (L) modeled after those in native surfactant, and novel phospholipase-resistant lipids (RL) having enhanced adsorption and spreading plus the ability to resist degradation in inflammatory lung injury (ALI/ARDS).
Aims 1 and 2 study the bioengineering, proteomics, synthesis, purification, molecular biophysics, and scale-up of synthetic peptides/lipopeptides and novel RL compounds based on promising preliminary data on initial active compounds.
Aim 3 investigates the optimization of lipid/peptide composition in synthetic surfactants based on surface activity assessments in vitro (pulsating bubble, adsorption, Wilhelmy balance, captive bubble) and pulmonary activity studies in animals. Animal models studied include: (i) an excised lavaged rat lung mechanical model that is FDA-accepted for evaluating current clinical surfactant drugs for direct use in premature infants with NRDS;(ii) mice with ALI/ARDS in vivo from intratracheal instillation of lipopolysaccharide (LPS);(3) rabbits with ALI/ARDS in vivo from severe hyperoxic-exposure;and (4) ventilated rabbits with surfactant-deficiency and ALI/ARDS induced by in vivo lavage.
Aim 4 studies the shear viscosity, pulmonary distribution, and cytotoxicity of instilled synthetic surfactants, as well as their utility in facilitating the pulmonary delivery of DNA to LPS-mice for future applications involving gene- or multi-drug therapies for ALI/ARDS. This multidisciplinary BRP grant will enhance scientific understanding about the molecular behavior of peptides and lipids while using principles and methods of engineering, chemistry, physics, biology, physiology and medicine to bioengineer synthetic lung surfactants having maximum activity, inhibition resistance, pulmonary efficacy, and production economy.
This BRP research will develop and produce novel fully-synthetic lung surfactants having maximum activity and inhibition resistance for future use in treating severe and prevalent human pulmonary diseases involving acute respiratory failure. BRP surfactants will be bioengineered to be more active and inhibition-resistant than current synthetic surfactant drugs, and will also have significant potential advantages in activity, resistance, purity, reproducibility, stability, and production economy compared to existing animal-derived clinical surfactants. Specific therapeutic applications include not only the neonatal respiratory distress syndrome (NRDS) in premature infants, but also clinical acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) that affect hundreds of thousands of patients of all ages (infants to adults) each year in the United States and around the world. Added studies in the grant have further relevance to public health by examining synthetic surfactants not only for their primary activity in improving respiratory failure, but also for their ability to facilitate the pulmonary delivery of DNA for future gene therapy or multi-drug therapy approaches for treating ALI/ARDS and other lung diseases.
|Walther, Frans J; Waring, Alan J; Hernández-Juviel, José M et al. (2014) Surfactant protein C peptides with salt-bridges ("ion-locks") promote high surfactant activities by mimicking the ?-helix and membrane topography of the native protein. PeerJ 2:e485|
|Machado-Aranda, David; Wang, Zhengdong; Yu, Bi et al. (2013) Increased phospholipase A2 and lyso-phosphatidylcholine levels are associated with surfactant dysfunction in lung contusion injury in mice. Surgery 153:25-35|
|Holten-Andersen, Niels; Michael Henderson, J; Walther, Frans J et al. (2011) KL? peptide induces reversible collapse structures on multiple length scales in model lung surfactant. Biophys J 101:2957-65|
|Keating, Eleonora; Waring, Alan J; Walther, Frans J et al. (2011) A ToF-SIMS study of the lateral organization of lipids and proteins in pulmonary surfactant systems. Biochim Biophys Acta 1808:614-21|
|Raghavendran, Krishnan; Willson, D; Notter, R H (2011) Surfactant therapy for acute lung injury and acute respiratory distress syndrome. Crit Care Clin 27:525-59|
|Walther, Frans J; Waring, Alan J; Hernandez-Juviel, Jose M et al. (2010) Critical structural and functional roles for the N-terminal insertion sequence in surfactant protein B analogs. PLoS One 5:e8672|
|Chess, Patricia Rose; Benson, Randi Potter; Maniscalco, William M et al. (2010) Murine mechanical ventilation stimulates alveolar epithelial cell proliferation. Exp Lung Res 36:331-41|