Patients with ARDS show improvement but not normalisation of alveolar surface activity with surfactant treatment: putative role of neutral lipids

Abstract

Background: Extensive biochemical and biophysical changes of the pulmonary surfactant system occur in the acute respiratory distress syndrome (ARDS). Methods: The effect of intrabronchial administration of a recombinant surfactant protein C-based surfactant preparation (Venticute) on gas exchange, surfactant composition and function was investigated in 31 patients with ARDS in a randomised controlled phase I/II clinical pilot trial. Bronchoalveolar lavage fluids for surfactant analysis were obtained 3 h before and 48 and 120 h after the first surfactant application. Potentially deleterious effects of surfactant neutral lipids in patients with ARDS were also identified. Results: Before treatment all patients had marked abnormalities in the surfactant phospholipid and protein composition. In response to surfactant treatment, gas exchange improved and surfactant phospholipid and protein content were almost normalised. Alveolar surface activity was dramatically impaired before treatment and only partially improved after surfactant administration. Further analysis of the bronchoalveolar lavage fluids revealed a twofold increase in neutral lipid content and altered neutral lipid profile in patients with ARDS compared with healthy controls. These differences persisted even after administration of large amounts of Venticute. Supplementation of Venticute or natural surfactant with a synthetic neutral lipid preparation, mimicking the profile in ARDS, caused a dose-dependent deterioration of surface activity in vitro. Conclusion: Intrabronchial surfactant treatment improves gas exchange in ARDS, but the efficacy may be limited by increased concentration and altered neutral lipid profile in surfactant under these conditions.

Role of cholesterol in the biophysical dysfunction of surfactant in ventilator-induced lung injury

“…The rationale was that 1) MV is known to contribute to the progression of lung injury in patients with ALI/ARDS (5), 2) the neutral lipid component of surfactant, which includes cholesterol, was increased in patients with ALI/ARDS (22) and in VILI (23), and 3) adding cholesterol to exogenous surfactant preparations inhibited surfactant function (12,13,18,20,33). Our study expanded on these studies by demonstrating, for the first time, that cholesterol-mediated inhibition of surfactant function occurred with samples from an in vivo model.…”

Anionic Pulmonary Surfactant Phospholipids Inhibit Inflammatory Responses from Alveolar Macrophages and U937 Cells by Binding the Lipopolysaccharide-interacting Proteins CD14 and MD-2

“…In idiopathic pulmonary fibrosis, ARDS, and asthma, several groups reported decreased unsaturated PG in surfactant (18,(52)(53)(54)(55)(56)(57). The issues of cause and effect in the above diseases remain unclear, but any condition that results in reduced levels of unsaturated PG pools within the lung is likely to increase the susceptibility to inflammatory processes elicited through TLR4 activation.…”

In vitro and in vivo comparison between poractant alfa and the new generation synthetic surfactant CHF5633

“…These preparations showed promising results in preclinical models of lung disease (20,21) and some of them were tested in clinical trials (19,(22)(23)(24). However, increased improvement of lung function by synthetic surfactants containing both SP-B and SP-C analogues, over that with a single surfactant protein, have previously been suggested (25,26).…”

“…Lusupultide is a mixture of phospholipids supplemented with 2% of human recombinant SP-C (19). These preparations showed promising results in preclinical models of lung disease (20,21) and some of them were tested in clinical trials (19,(22)(23)(24).…”