Altered molecular specificity of surfactant phosphatidycholine synthesis in patients with acute respiratory distress syndrome.
BACKGROUND
Acute respiratory distress syndrome (ARDS) is a life-threatening critical illness, characterised by qualitative and quantitative surfactant compositional changes associated with premature airway collapse, gas-exchange abnormalities and acute hypoxic respiratory failure. The underlying mechanisms for this dysregulation in surfactant metabolisms are not fully explored. Lack of therapeutic benefits from clinical trials, highlight the importance of detailed in-vivo analysis and characterisation of ARDS patients according to patterns of surfactant synthesis and metabolism.


METHODS
Ten patients with moderate to severe ARDS were recruited. Most (90%) suffered from pneumonia. They had an infusion of methyl-D9-choline chloride and small volume bronchoalveolar lavage fluid (BALF) was obtained at 0,6,12,24,48,72 and 96 hours. Controls were healthy volunteers, who had BALF at 24 and 48 hours after methyl-D9-choline infusion. Compositional analysis and enrichment patterns of stable isotope labelling of surfactant phosphatidylcholine (PC) was determined by electrospray ionisation mass spectrometry.


RESULTS
BALF of patients with ARDS consisted of diminished total PC and fractional PC16:0/16:0 concentrations compared to healthy controls. Compositional analysis revealed, reductions in fractional compositions of saturated PC species with elevated levels of longer acyl chain unsaturated PC species. Molecular specificity of newly synthesised PC fraction showed time course variation, with lower PC16:0/16:0 composition at earlier time points, but achieved near equilibrium with endogenous composition at 48 hours after methyl-D9-choline infusion. The enrichment of methyl-D9-choline into surfactant total PC is nearly doubled in patients, with considerable variation between individuals.


CONCLUSIONS
This study demonstrate significant alterations in composition and kinetics of surfactant PC extracted from ARDS patients. This novel approach may facilitate biochemical phenotyping of ARDS patients according to surfactant synthesis and metabolism, enabling individualised treatment approaches for the management of ARDS patients in the future.
NIHR Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. adushianthan@gmail.com.|Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. adushianthan@gmail.com.|Critical Care Research & Anaesthesia Unit, CE 93, MP24, E-Level, Centre Block, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. adushianthan@gmail.com.|Department of Critical Care Unit, Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital, Southwick Hill Road, Cosham, PO6 3LY, UK. adushianthan@gmail.com.
Ahilanandan
A
Dushianthan
NIHR Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. v.ledger@soton.ac.uk.|Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. v.ledger@soton.ac.uk.
Victoria
V
Goss
NIHR Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. rebecca.cusack@uhs.nhs.uk.|Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. rebecca.cusack@uhs.nhs.uk.|Critical Care Research & Anaesthesia Unit, CE 93, MP24, E-Level, Centre Block, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. rebecca.cusack@uhs.nhs.uk.
Rebecca
R
Cusack
NIHR Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. mike.grocott@soton.ac.uk.|Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. mike.grocott@soton.ac.uk.|Critical Care Research & Anaesthesia Unit, CE 93, MP24, E-Level, Centre Block, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. mike.grocott@soton.ac.uk.
Michael P W
MP
Grocott
NIHR Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. a.d.postle@soton.ac.uk.|Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. a.d.postle@soton.ac.uk.
Anthony D
AD
Postle
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016022:Case-Control Studies; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000096:biosynthesis*; D010865:Pilot Projects; D012128:Respiratory Distress Syndrome / Q000175:diagnosis / Q000378:metabolism*; D012720:Severity of Illness Index; D021241:Spectrometry, Mass, Electrospray Ionization
D015415:Biomarkers; D010713:Phosphatidylcholines