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Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients.

ABSTRACT: Danger-associated molecular patterns (DAMPs) released of trauma could contribute to an immune suppressed state that renders patients vulnerable towards nosocomial infections. We investigated DAMP release in trauma patients, starting in the prehospital phase, and assessed its relationship with immune suppression and nosocomial infections.Blood was obtained from 166 adult trauma patients at the trauma scene, emergency room (ER), and serially afterwards. Circulating levels of DAMPs and cytokines were determined. Immune suppression was investigated by determination of HLA-DRA gene expression and ex vivo lipopolysaccharide-stimulated cytokine production.Compared with healthy controls, plasma levels of nuclear DNA (nDNA) and heat shock protein-70 (HSP70) but not mitochondrial DNA were profoundly increased immediately following trauma and remained elevated for 10 days. Plasma cytokines were increased at the ER, and levels of anti-inflammatory IL-10 but not of pro-inflammatory cytokines peaked at this early time-point. HLA-DRA expression was attenuated directly after trauma and did not recover during the follow-up period. Plasma nDNA (r = -0.24, p = 0.006) and HSP70 (r = -0.38, p < 0.0001) levels correlated negatively with HLA-DRA expression. Ex vivo cytokine production revealed an anti-inflammatory phenotype already at the trauma scene which persisted in the following days, characterized by attenuated TNF-? and IL-6, and increased IL-10 production. Finally, higher concentrations of nDNA and a further decrease of HLA-DRA expression were associated with infections.Plasma levels of DAMPs are associated with immune suppression, which is apparent within minutes/hours following trauma. Furthermore, aggravated immune suppression during the initial phase following trauma is associated with increased susceptibility towards infections.

SUBMITTER: Timmermans K

PROVIDER: S-EPMC5413532 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients.

Timmermans Kim K Kox Matthijs M Vaneker Michiel M van den Berg Maarten M John Aaron A van Laarhoven Arjan A van der Hoeven Hans H Scheffer Gert Jan GJ Pickkers Peter P

Intensive care medicine 20160224 4

<h4>Purpose</h4>Danger-associated molecular patterns (DAMPs) released of trauma could contribute to an immune suppressed state that renders patients vulnerable towards nosocomial infections. We investigated DAMP release in trauma patients, starting in the prehospital phase, and assessed its relationship with immune suppression and nosocomial infections.<h4>Methods</h4>Blood was obtained from 166 adult trauma patients at the trauma scene, emergency room (ER), and serially afterwards. Circulating ...[more]

PMID: 26912315

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Project description:ObjectivesTrauma predisposes to systemic sterile inflammation (systemic inflammatory response syndrome) as well as infection, but the mechanisms linking injury to infection are poorly understood. Mitochondrial debris contains formyl peptides. These bind formyl peptide receptor-1, trafficking neutrophils to wounds, initiating systemic inflammatory response syndrome, and wound healing. Bacterial formyl peptides, however, also attract neutrophils via formyl peptide receptor-1. Thus, mitochondrial formyl peptides might suppress neutrophils antimicrobial function. Also, formyl peptide receptor-1 blockade used to mitigate systemic inflammatory response syndrome might predispose to sepsis. We examined how mitochondrial formyl peptides impact neutrophils functions contributing to antimicrobial responses and how formyl peptide receptor-1 antagonists affect those functions.DesignProspective study of human and murine neutrophils and clinical cohort analysis.SettingUniversity research laboratory and level 1 trauma center.PatientsTrauma patients, volunteer controls.Animal subjectsC57Bl/6, formyl peptide receptor-1, and formyl peptide receptor-2 knockout mice.InterventionsHuman and murine neutrophils functions were activated with autologous mitochondrial debris, mitochondrial formyl peptides, or bacterial formyl peptides followed by chemokines or leukotrienes. The experiments were repeated using formyl peptide receptor-1 antagonist cyclosporin H, "designer" human formyl peptide receptor-1 antagonists (POL7178 and POL7200), or anti-formyl peptide receptor-1 antibodies. Mouse injury/lung infection model was used to evaluate effect of formyl peptide receptor-1 inhibition.Measurements and main resultsHuman neutrophils cytosolic calcium, chemotaxis, reactive oxygen species production, and phagocytosis were studied before and after exposure to mitochondrial debris, mitochondrial formyl peptides, and bacterial formyl peptides. Mitochondrial formyl peptide and bacterial formyl peptides had similar effects on neutrophils. Responses to chemokines and leukotrienes were suppressed by prior exposure to formyl peptides. POL7200 and POL7178 were specific antagonists of human formyl peptide receptor-1 and more effective than cyclosporin H or anti-formyl peptide receptor-1 antibodies. Formyl peptides inhibited mouse neutrophils responses to chemokines only if formyl peptide receptor-1 was present. Formyl peptide receptor-1 blockade did not inhibit neutrophils bacterial phagocytosis or reactive oxygen species production. Cyclosporin H increased bacterial clearance in lungs after injury.ConclusionsFormyl peptides both activate and desensitize neutrophils. Formyl peptide receptor-1 blockade prevents desensitization, potentially both diminishing systemic inflammatory response syndrome and protecting the host against secondary infection after tissue trauma or primary infection.

Project description:The idea that cellular stress (including that precipitated by stretch), plays a significant role in the mechanisms initiating parturition, has gained considerable traction over the last decade. One key consequence of this cellular stress is the increased production of Danger Associated Molecular Patterns (DAMPs). This diverse family of molecules are known to initiate inflammation through their interaction with Pattern Recognition Receptors (PRRs) including, Toll-like receptors (TLRs). TLRs are the key innate immune system surveillance receptors that detect Pathogen Associated Molecular Patterns (PAMPs) during bacterial and viral infection. This is also seen during Chorioamnionitis. The activation of TLR commonly results in the activation of the pro-inflammatory transcription factor Nuclear Factor Kappa-B (NF-kB) and the downstream production of pro-inflammatory cytokines. It is thought that in the human fetal membranes both DAMPs and PAMPs are able, perhaps via their interaction with PRRs and the induction of their downstream inflammatory cascades, to lead to both tissue remodeling and weakening. Due to the high incidence of infection-driven Pre-Term Birth (PTB), including those that have preterm Premature Rupture of the Membranes (pPROM), the role of TLR in fetal membranes with Chorioamnionitis has been the subject of considerable study. Most of the work in this field has focused on the effect of PAMPs on whole pieces of fetal membrane and the resultant inflammatory cascade. This is important to understand, in order to develop novel prevention, detection, and therapeutic approaches, which aim to reduce the high number of mothers suffering from infection driven PTB, including those with pPROM. Studying the role of sterile inflammation driven by these endogenous ligands (DAMPs) activating PRRs system in the mesenchymal and epithelial cells in the amnion is important. These cells are key for the maintenance of the integrity and strength of the human fetal membranes. This review aims to (1) summarize the knowledge to date pertinent to the role of DAMPs and PRRs in fetal membrane weakening and (2) discuss the clinical potential brought by a better understanding of these pathways by pathway manipulation strategies.

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Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients.

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Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients.

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