Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: A prospective cohort study

Autor: Cabrera, CP, Manson, J, Shepherd, JM, Torrance, HD, Watson, D, Longhi, MP, Hoti, M, Patel, MB, O'Dwyer, M, Nourshargh, S, Pennington, DJ, Barnes, MR, Brohi, K
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: PLoS Medicine
PLoS Medicine, Vol 14, Iss 7, p e1002352 (2017)
ISSN: 1549-1676
1549-1277
Popis: Background Severe trauma induces a widespread response of the immune system. This “genomic storm” can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects long-term health outcomes. Contemporary management of MODS is entirely supportive, and no specific therapeutics have been shown to be effective in reducing incidence or severity. The pathogenesis of MODS remains unclear, and several models are proposed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflammatory pathways. We postulated that the hyperacute window after trauma may hold the key to understanding how the genomic storm is initiated and may lead to a new understanding of the pathogenesis of MODS. Methods and findings We performed whole blood transcriptome and flow cytometry analyses on a total of 70 critically injured patients (Injury Severity Score [ISS] ≥ 25) at The Royal London Hospital in the hyperacute time period within 2 hours of injury. We compared transcriptome findings in 36 critically injured patients with those of 6 patients with minor injuries (ISS ≤ 4). We then performed flow cytometry analyses in 34 critically injured patients and compared findings with those of 9 healthy volunteers. Immediately after injury, only 1,239 gene transcripts (4%) were differentially expressed in critically injured patients. By 24 hours after injury, 6,294 transcripts (21%) were differentially expressed compared to the hyperacute window. Only 202 (16%) genes differentially expressed in the hyperacute window were still expressed in the same direction at 24 hours postinjury. Pathway analysis showed principally up-regulation of pattern recognition and innate inflammatory pathways, with down-regulation of adaptive responses. Immune deconvolution, flow cytometry, and modular analysis suggested a central role for neutrophils and Natural Killer (NK) cells, with underexpression of T- and B cell responses. In the transcriptome cohort, 20 critically injured patients later developed MODS. Compared with the 16 patients who did not develop MODS (NoMODS), maximal differential expression was seen within the hyperacute window. In MODS versus NoMODS, 363 genes were differentially expressed on admission, compared to only 33 at 24 hours postinjury. MODS transcripts differentially expressed in the hyperacute window showed enrichment among diseases and biological functions associated with cell survival and organismal death rather than inflammatory pathways. There was differential up-regulation of NK cell signalling pathways and markers in patients who would later develop MODS, with down-regulation of neutrophil deconvolution markers. This study is limited by its sample size, precluding more detailed analyses of drivers of the hyperacute response and different MODS phenotypes, and requires validation in other critically injured cohorts. Conclusions In this study, we showed how the hyperacute postinjury time window contained a focused, specific signature of the response to critical injury that led to widespread genomic activation. A transcriptomic signature for later development of MODS was present in this hyperacute window; it showed a strong signal for cell death and survival pathways and implicated NK cells and neutrophil populations in this differential response.
In a prospective cohort study, Joanna Shepherd and colleagues use whole blood transcriptome and flow cytometry analyses to identify cell populations and genes associated with a focused immune response very early after injury that develops into a widespread immune dysregulation and multiple organ dysfunction.
Author summary Why was this study done? Multiple Organ Dysfunction Syndrome (MODS) is common in patients who survive critical injuries and is associated with poor patient outcomes, including death, infection, and prolonged critical care admission. MODS describes a failure of multiple organ systems (including lung, heart, kidney, and liver), and an excessive or dysfunctional immune response has been implicated in its development after trauma. The precise immune mechanisms leading to MODS are not fully understood, but the first minutes to hours after severe injury are likely to be pivotal to the development of a “normal” or “dysregulated” immune response. Our study was designed to investigate the very early immune responses to critical injury to determine whether a specific immune reaction occurs in the hyperacute timeframe that leads to widespread dysregulation and MODS. What did the researchers do and find? We studied 29,385 immune cell genes within whole blood samples obtained from 36 critically injured patients at admission (within 2 hours of injury) and compared these to samples obtained at 24 and 72 hours following injury. We analysed the differences between critically injured patient who developed MODS and those who did not and compared these to 6 patients who had minor injuries. We also used flow cytometry to analyse the numbers of circulating immune cell populations in 34 critically injured patients and compared these to healthy volunteers. Our study identified only 1,239 (4%) immune cell genes that were different between critical and control patients at admission; however, this subsequently developed into a widespread reaction by 24 hours postinjury. Comparing patients with MODS to those without MODS, we found 363 genes were different at admission, but by 24 hours postinjury, only 33 genes differentiated between the groups. Further analysis of the hyperacute timeframe demonstrated enrichment of gene pathways associated with cell death in patients with MODS and implicated neutrophils and natural killer immune cells in this response. What do these findings mean? The hyperacute timeframe is crucial to understanding the immune response to trauma and how this subsequently develops into MODS. There is a focused immune response to trauma in the hyperacute timeframe, which subsequently develops into a widespread immune reaction. The MODS signal was strongest in the hyperacute window and implicated cell death pathways and innate immune cells in this response.
Databáze: OpenAIRE
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