Molecular and biophysical mechanisms behind the enhancement of lung surfactant function during controlled therapeutic hypothermia

C Autilio,M Echaide,D De Luca,E Da Silva,Jorid B Sørli,J Pérez-Gil,A Hidalgo,A Cruz,C García-Mouton

doi:10.1038/s41598-020-79025-3

Abstract

Therapeutic hypothermia (TH) enhances pulmonary surfactant performance in vivo by molecular mechanisms still unknown. Here, the interfacial structure and the composition of lung surfactant films have been analysed in vitro under TH as well as the molecular basis of its improved performance both under physiological and inhibitory conditions. The biophysical activity of a purified porcine surfactant was tested under slow and breathing-like dynamics by constrained drop surfactometry (CDS) and in the captive bubble surfactometer (CBS) at both 33 and 37 °C. Additionally, the temperature-dependent surfactant activity was also analysed upon inhibition by plasma and subsequent restoration by further surfactant supplementation. Interfacial performance was correlated with lateral structure and lipid composition of films made of native surfactant. Lipid/protein mixtures designed as models to mimic different surfactant contexts were also studied. The capability of surfactant to drastically reduce surface tension was enhanced at 33 °C. Larger DPPC-enriched domains and lower percentages of less active lipids were detected in surfactant films exposed to TH-like conditions. Surfactant resistance to plasma inhibition was boosted and restoration therapies were more effective at 33 °C. This may explain the improved respiratory outcomes observed in cooled patients with acute respiratory distress syndrome and opens new opportunities in the treatment of acute lung injury.

Highlights

Therapeutic hypothermia (TH) enhances pulmonary surfactant performance in vivo by molecular mechanisms still unknown
ML) under slow (2 cycles/min) and quick (20 cycles/min) dynamic cycles by Constrained Drop Surfactometer (CDS) and Captive Bubble Surfactometer (CBS), respectively (Fig. 1).PS initial adsorption did not change among conditions (Fig. 1a), whereas dynamic activity significantly depended on sample concentration
There was a significant difference in γmin comparing cycle 5 and 10 for material tested at 37 °C, but it was not the case for PS assayed at 33 °C (Supplementary Fig. S1a)

Summary

Introduction

Therapeutic hypothermia (TH) enhances pulmonary surfactant performance in vivo by molecular mechanisms still unknown. The interfacial structure and the composition of lung surfactant films have been analysed in vitro under TH as well as the molecular basis of its improved performance both under physiological and inhibitory conditions. Surfactant resistance to plasma inhibition was boosted and restoration therapies were more effective at 33 °C. This may explain the improved respiratory outcomes observed in cooled patients with acute respiratory distress syndrome and opens new opportunities in the treatment of acute lung injury. Dipalmitoylphosphatidylcholine (DPPC), unsaturated phospholipids and hydrophobic surfactant proteins B (SP-B) and C (SP-C) are essential for its function in a healthy l ung[12] Oedema proteins, such as albumin, increase in ARDS p

Methods

Results

Conclusion