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

Ann M Czyzewski,Annelise E Barron,Lauren A Broering,Lynda M Mccaig,Maruti K Didwania,Jennifer S Lin,Li-Juan Yao,Ruud Veldhuizen,Jim F Lewis,Michelle T Dohm,Nathan J Brown

doi:10.1038/s41598-018-25009-3

Ann M Czyzewski, Annelise E Barron + Show 9 more

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https://doi.org/10.1038/s41598-018-25009-3

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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.

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Lung surfactant is a complex lipid-protein mixture that coats alveolar surfaces and reduces surface tension at the air/liquid interface, enabling normal respiratory function[1]
For the 32 animals included in the study, the average baseline blood oxygen level (PaO2), normalized to the fraction of inspired oxygen (FiO2) (1.0 throughout all experiments), of 435.7 ± 4.9 mm Hg was reduced to 88.3 ± 2.5 mm Hg post-lavage, reflective of surfactant deficiency (Fig. 2A)
While the extensive alveolar network and capillary vasculature of the pulmonary parenchymal tissue are critical to achieving efficient gas exchange, these delicate structures are highly susceptible to systemic pathogens and environmental toxins[7]

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Lung surfactant is a complex lipid-protein mixture that coats alveolar surfaces and reduces surface tension at the air/liquid interface, enabling normal respiratory function[1]. Lung surfactant proteins B and C (SP-B and SP-C) are two hydrophobic proteins essential for the adsorption and spreading of the surfactant film at the air-liquid interface[15]. These proteins have proven challenging to synthesize in active form (either chemically or recombinantly), most research has focused on development of simpler analogs of these proteins that replicate key features for bioactivity[16,17,18]. Peptoid structure is advantageous for biomedical applications; their highly stable structure is protease-resistant, improving biostability and bioavailability while reducing immunogenic response; and they can be designed to form stable amphipathic helices[25]

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