Microvesicles in Acute Respiratory Distress Syndrome

There is an urgent and compelling need to better understand the fundamental mechanisms of ARDS and associated MOF in both ICU and perioperative patients, to identify targets from entirely novel perspectives, which allow development of more specific and effective therapies. We hypothesise that MVs, released within the lungs and into the circulation, play crucial roles in the evolution of ARDS as well as in transmitting inflammation to peripheral organs, producing AKI/MOF. 

By investigating the previously un-tested body compartment "extracellular MVs", we will identify a novel alternative inflammatory pathway/target that is closely linked with key pathophysiology of ARDS/MOF, to aid diagnosis, phenotype differentiation, prognostication and treatment personalisation.

Most recently, we have demonstrated a dynamic production of MVs from multiple intra-alveolar cells early in the inflammatory course of acute lung injury (ALI) particularly from alveolar macrophages. When instilled into murine lungs, these MVs induced lung injury via a TNF dependent mechanism. We found that TNF is released within MVs via an unconventional endoplasmic reticulum/Golgi-independent route (similar to IL-1β), despite being a classical, golgi-dependant cytokine. Interestingly, we demonstrated that this switch in cellular TNF trafficking is mediated via acid sphingomyelinase.

We also characterised MV populations within bronchoalveolar lavage taken from COPD patients and found that neutrophil-derived MVs strongly correlated with disease severity. We have similarly characterised MVs populations in bronchoalveolar lavage fluid taken from patients post lung tranplantation with Primary Graft Dysfunction (PGD) and in patients with ARDS.

Currently we are also running a large multi-centre clinical translational study ’multi-organ failure in SARS-CoV-2: identifying mechanisms and potential therapeutic targets’.

• Academy of Medical Sciences (P86239)
• British Journal of Anaesthesia, National Institute of Academic Anaesthesia (P89938)
• Medical Research Council (P54008)

Internal 

Professor Fan Chung

External

• Professor Wolfgang Kuebler
• Professor Pallav Shah

Imperial College NHS Trust

Koh MW, Baldi RF, Soni S, Handslip R, Tan YY, O'Dea KP, Malesevic M, McAuley DF, O'Kane CM, Patel BV, Takata M, Wilson MR. Secreted Extracellular Cyclophilin A is a Novel Mediator of Ventilator Induced Lung Injury. Am J Respir Crit Care Med. 2021 Apr 13. doi: 10.1164/rccm.202009-3545OC.

Soni S, Garner J, O;dea K, Koh, M, Tirlapur N, Srikanthan K, Tenda R, Faelkady A, Singh S, Wilson MR, Kemp S, Usmani O, Shah P, Takata M. Intra-alveolar neutrophil-derived microvesicles are associated with disease severity in COPD. Am J Physiol Lung Cell Mol Physiol. 2021 Jan 1;320(1): L73-L83.

 Chia G, Barrett H, Patel P, Soni S. One hundred eighteen days on a ventilator: a COVID-19 success story against all odds. BMJ Case Rep. 2021 Mar 29;14(3):e239631.

Chaggar RS, Shah SV, Berry M, Saini R, Soni S, Vaughan D. The Video Classification of Intubation (VCI) score: a new description tool for tracheal intubation using videolaryngoscopy: A pilot study. Eur J Anaesthesiol. 2021 Mar 1;38(3):324-326.

Stephens JR, Wong JLC, Broomhead R, Stümpfle R, Waheed U, Patel P, Brett SJ, Soni S. Raised serum amylase in patients with COVID-19 may not be associated with pancreatitis. Br J Surg. 2021 Apr 30;108(4):e152-e153.

Gasparini M, Khan S, Patel J, Parekh D, Bangash M, Stumpfle R, Shah A, Baharlo B and Soni S. Renal impairment and its impact on clinical outcomes in critically ill patients with COVID-19: a UK multicentre observational study. Anaesthesia 2021.

Stephens J, Stumpfle R, Patel P, Brett S, Broomhead R, Baharlo B and Soni S. Analysis of critical care severity of illness scoring systems in patients with COVID-19: a retrospective analysis of three UK intensive care units. Crit Care Med 2021.

Soni S, Shah S, Chaggar R, Saini R, James E, Elliot J, Stephens J, McCormack T, Hartle A. Surgical cancellation rates due to peri-operative hypertension: Implementation of multi-disciplinary guidelines across primary and secondary care. Anaesthesia 2020;75(10):1314-1320

O'Dea KP, Tan YY, Shah S, V Patel B, C Tatham K, Wilson MR, Soni S, Takata M. Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low grade systemic inflammation. Journal of extracellular vesicles. 2020; 5;9(1):1706708 2nd senior author

Soni S, Tirlapur N, O'Dea KP, Takata M, Wilson MR. Microvesicles as new therapeutic targets for the treatment of the acute respiratory distress syndrome (ARDS). Expert Opin Ther Targets. 2019;23(11):931-941

Oakley C, Koh M, Baldi R, Soni S, O'Dea K, Takata M, Wilson M. Ventilation following established ARDS: a preclinical model framework to improve predictive power. Thorax. 2019;74(12):1120-1129.

Soni S, O'Dea KP, Tan YY, Cho K, Abe E, Romano R, Cui J, Ma D, Sarathchandra P, Wilson MR, Takata M. Danger signals redirect cytokine trafficking and promote novel membrane TNF signalling via microvesicles. FASEB J. 2019:fj201802386R.

Soni S, Wilson MR, O'Dea KP, Yoshida M, Katbeh U, Woods SJ, Takata M. Alveolar macrophage-derived microvesicles mediate acute lung injury. Thorax. 2016 Nov;71(11):1020-1029.