Biomarkers for Acute Respiratory Distress syndrome and prospects for personalised medicine

Abstract

Acute lung injury (ALI) affects over 10% of patients hospitalised in critical care, with acute respiratory distress syndrome (ARDS) being the most severe form of ALI and having a mortality rate in the region of 40%. There has been slow but incremental progress in identification of biomarkers that contribute to the pathophysiology of ARDS, have utility in diagnosis and monitoring, and that are potential therapeutic targets (Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, Thompson T, Ware LB, Matthay MA, Lancet Respir Med 2014, 2:611–-620). However, a major issue is that ARDS is such a heterogeneous, multi-factorial, end-stage condition that the strategies for “lumping and splitting” are critical (Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX, Am J Respir Crit Care Med 2016, 194:147–-155). Nevertheless, sequencing of the human genome, the availability of improved methods for analysis of transcription to mRNA (gene expression), and development of sensitive immunoassays has allowed the application of network biology to ARDS, with these biomarkers offering potential for personalised or precision medicine (Sweeney TE, Khatri P, Toward precision medicine Crit Care Med; 2017 45:934-939).Biomarker panels have potential applications in molecular phenotyping for identifying patients at risk of developing ARDS, diagnosis of ARDS, risk stratification and monitoring. Two subphenotypes of ARDS have been identified on the basis of blood biomarkers: hypo-inflammatory and hyper-inflammatory. The hyper-inflammatory subphenotype is associated with shock, metabolic acidosis and worst clinical outcomes. Biomarkers of particular interest have included interleukins (IL-6 and IL-8), interferon gamma (IFN-γ), surfactant proteins (SPD and SPB), von Willebrand factor antigen, angiopoietin 1/2 and plasminogen activator inhibitor-1 (PAI-1). In terms of gene expression (mRNA) in blood there have been found to be increases in neutrophil-related genes in sepsis-induced and influenza-induced ARDS, but whole blood expression does not give a robust diagnostic test for ARDS.Despite improvements in management of ARDS on the critical care unit, this complex disease continues to be a major life-threatening event. Clinical trials of β2-agonists, statins, surfactants and keratinocyte growth factor (KGF) have been disappointing. In addition, monoclonal antibodies (anti-TNF) and TNFR fusion protein have also been unconvincing. However, there have been major advances in methods of mechanical ventilation, a neuromuscular blocker (cisatracurium besilate) has shown some benefit, and stem cell therapy is being developed. In the future, by understanding the role of biomarkers in the pathophysiology of ARDS and lung injury, it is hoped that this will provide rational therapeutic targets and ultimately improve clinical care (Seymour CW, Gomez H, Chang CH, Clermont G, Kellum JA, Kennedy J, Yende S, Angus DC, Crit Care 2017, 21:257).

A comparison of four different models of acute respiratory distress syndrome in sheep

“…In order to mimic the human clinical situation, we did not start the study at the time of inducing ARDS, but rather when all animals had met the criteria for ARDS. Our results are in line with human studies, in which the cytokines were elevated in all forms of ARDS (28,29); this supports the value of our models. Nevertheless, it is di cult to translate the results of our study to the human situation.…”

R-spondin 2 mediates neutrophil egress into the alveolar space through increased lung permeability

“…Excessive damage to alveolar structures can result in edema, gas-exchange compromise and death [9,10]. The loosening of endothelial cell junctions and the migration of inflammatory cells-including neutrophils-across the damaged endothelial barrier plays a key role in the pathophysiology of diseases such as acute respiratory distress syndrome (ARDS), cancer, and other inflammatory pathologies [11,12]. Although the canonical mechanisms governing diapedesis and leukocyte trafficking have been well described, mechanistic variations dependent on the organ milieu and inflammatory status can occur [12].…”

R-spondin 2 mediates neutrophil egress into the alveolar space through increased lung permeability.

“…Excessive damage to alveolar structures can result in edema, gas-exchange compromise and death (9,10). The loosening of endothelial cell junctions and the migration of inflammatory cells-including neutrophils -across the damaged endothelial barrier plays a key role in the pathophysiology of diseases such as acute respiratory distress syndrome (ARDS), cancer, and other inflammatory pathologies (11,12).…”