Key surfactant protein functions, such as lipid mixing, adsorption, and dynamic compression, that are associated with amphipathic domains are probably the most affected by surfactant inhibitors. Based on the known amino acid sequences of the surfactant proteins SP-A, SP-B, and SP-C, we will synthesize a family of peptides for use in characterizing the interactions of synthetic surfactant dispersions with surfactant inhibitors. These peptides will include short length, functional domains (eg. amphipathic and transmembrane sequences) of SP-A, SP-B, SP-C and full-length proteins representing SP-B (78 residues) and SP-C (35 residues). To evaluate the inhibitory actions of serum components such as serum albumin and anti-surfactant protein antibodies, synthetic peptides will be tested for their in vitro surface activity with and without inhibitors. Surfactant inhibitors will also be investigated for their effects on the mixing function of the surfactant dispersions using fluorescence vesicle assays. These studies will allow a better understanding of which surfactant protein functions (i.e., adsorption, spreading, dynamic compression and respreading, lipid mixing) are perturbed by inhibitors. With the information derived from these in vitro tests of surfactant inhibition, we will assess the interactions between surfactant peptides and inhibitors using physical-biochemical techniques, such as circular dichroism (CD), Fourier transform infrared (FTIR) and electron spin resonance (ESR) spectroscopy, to evaluate whether protein inhibitors (e.g., albumin, anti-surfactant protein antibodies) block surfactant activity by interacting with the amphipathic, surface-seeking domains of surfactant proteins. Finally, the effectiveness of synthetic peptide-lipid mixtures, with and without inhibitor proteins, in restoring lung function will be tested in two animal models of surfactant deficiency and inactivation. These experiments should provide information on dose-response relationships of synthetic surfactant preparations in vivo and identify those conditions under which the in vitro findings of the inhibitor studies predict the in vivo function of synthetic surfactants. This information may not only help in determining component(s) of a surfactant dispersion resist inhibitors, but also in designing synthetic surfactants that offer resistance against inhibition in the respiratory distress syndrome.
| Walther, Frans J; Gordon, Larry M; Waring, Alan J (2016) Design of Surfactant Protein B Peptide Mimics Based on the Saposin Fold for Synthetic Lung Surfactants. Biomed Hub 1: |
| Frey, Shelli L; Pocivavsek, Luka; Waring, Alan J et al. (2010) Functional importance of the NH2-terminal insertion sequence of lung surfactant protein B. Am J Physiol Lung Cell Mol Physiol 298:L335-47 |
| Pocivavsek, Luka; Frey, Shelli L; Krishan, Kapilanjan et al. (2008) Lateral stress relaxation and collapse in lipid monolayers. Soft Matter 4:2019-2029 |
| de Visser, Y P; Walther, F J; Laghmani, E H et al. (2008) Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury. Eur Respir J 31:633-44 |
| Walther, Frans J; Waring, Alan J; Sherman, Mark A et al. (2007) Hydrophobic surfactant proteins and their analogues. Neonatology 91:303-10 |
| Walther, Frans J; Waring, Alan J; Hernandez-Juviel, Jose M et al. (2007) Dynamic surface activity of a fully synthetic phospholipase-resistant lipid/peptide lung surfactant. PLoS One 2:e1039 |
| Sarker, Muzaddid; Waring, Alan J; Walther, Frans J et al. (2007) Structure of mini-B, a functional fragment of surfactant protein B, in detergent micelles. Biochemistry 46:11047-56 |
| ter Horst, Simone A J; Fijlstra, Margot; Sengupta, Sujata et al. (2006) Spatial and temporal expression of surfactant proteins in hyperoxia-induced neonatal rat lung injury. BMC Pulm Med 6:8 |
| Walther, Frans J; Hernandez-Juviel, Jose M; Gordon, Larry M et al. (2005) Comparison of three lipid formulations for synthetic surfactant with a surfactant protein B analog. Exp Lung Res 31:563-79 |
| Waring, A J; Walther, F J; Gordon, L M et al. (2005) The role of charged amphipathic helices in the structure and function of surfactant protein B. J Pept Res 66:364-74 |
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