RESUMO
Background: The discovery of biological subphenotypes in acute respiratory distress syndrome (ARDS) might offer a new approach to ARDS in general and possibly targeted treatment, but little is known about the underlying biology yet. To validate our recently described ovine ARDS phenotypes model, we compared a subset of messenger ribonucleic acid (mRNA) markers in leukocytes as reported before to display differential expression between human ARDS subphenotypes to the expression in lung tissue in our ovine ARDS phenotypes model (phenotype 1 (Ph1): hypoinflammatory; phenotype 2 (Ph2): hyperinflammatory). Methods: We studied 23 anesthetized sheep on mechanical ventilation with observation times between 6 and 24 h. They were randomly allocated to the two phenotypes (n = 14 to Ph1 and n = 9 to Ph2). At study end, lung tissue was harvested and preserved in RNAlater. After tissue homogenization in TRIzol, total RNA was extracted and custom capture and reporter probes designed by NanoString Technologies were used to measure the expression of 14 genes of interest and the 6 housekeeping genes on a nCounter SPRINT profiler. Results: Among the 14 mRNA markers, in all animals over all time points, 13 markers showed the same trend in ovine Ph2/Ph1 as previously reported in the MARS cohort: matrix metalloproteinase 8, olfactomedin 4, resistin, G protein-coupled receptor 84, lipocalin 2, ankyrin repeat domain 22, CD177 molecule, and transcobalamin 1 expression was higher in Ph2 and membrane metalloendopeptidase, adhesion G protein-coupled receptor E3, transforming growth factor beta induced, histidine ammonia-lyase, and sulfatase 2 expression was higher in Ph1. These expression patterns could be found when different sources of mRNA - such as blood leukocytes and lung tissue - were compared. Conclusion: In human and ovine ARDS subgroups, similar activated pathways might be involved (e.g., oxidative phosphorylation, NF-κB pathway) that result in specific phenotypes.
RESUMO
The acute respiratory distress syndrome (ARDS) is a severe lung disorder with a high morbidity and mortality which affects all age groups. Despite active research with intense, ongoing attempts in developing pharmacological agents to treat ARDS, its mortality rate remains unaltered high and treatment is still only supportive. Over the years, there have been many attempts to identify meaningful subgroups likely to react differently to treatment among the heterogenous ARDS population, most of them unsuccessful. Only recently, analysis of large ARDS cohorts from randomized controlled trials have identified the presence of distinct biological subphenotypes among ARDS patients: a hypoinflammatory (or uninflamed; named P1) and a hyperinflammatory (or reactive; named P2) subphenotype have been proposed and corroborated with existing retrospective data. The hyperinflammatory subphenotyope was clearly associated with shock state, metabolic acidosis, and worse clinical outcomes. Core features of the respective subphenotypes were identified consistently in all assessed cohorts, independently of the studied population, the geographical location, the study design, or the analysis method. Additionally and clinically even more relevant treatment efficacies, as assessed retrospectively, appeared to be highly dependent on the respective subphenotype. This discovery launches a promising new approach to targeted medicine in ARDS. Even though it is now widely accepted that each ARDS subphenotype has distinct functional, biological, and mechanistic differences, there are crucial gaps in our knowledge, hindering the translation to bedside application. First of all, the underlying driving biological factors are still largely unknown, and secondly, there is currently no option for fast and easy identification of ARDS subphenotypes. This narrative review aims to summarize the evidence in biological subphenotyping in ARDS and tries to point out the current issues that will need addressing before translation of biological subohenotypes into clinical practice will be possible.
