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Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS.

ABSTRACT: The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS.

SUBMITTER: Kangelaris KN

PROVIDER: S-EPMC4451399 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS.

Kangelaris Kirsten Neudoerffer KN Prakash Arun A Liu Kathleen D KD Aouizerat Bradley B Woodruff Prescott G PG Erle David J DJ Rogers Angela A Seeley Eric J EJ Chu Jeffrey J Liu Tom T Osterberg-Deiss Thomas T Zhuo Hanjing H Matthay Michael A MA Calfee Carolyn S CS

American journal of physiology. Lung cellular and molecular physiology 20150320 11

The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission ...[more]

PMID: 25795726

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Project description:BackgroundARDS may occur after either septic or nonseptic injuries. Sepsis is the major cause of ARDS, but little is known about the differences between sepsis-related and non-sepsis-related ARDS.MethodsA total of 2,786 patients with ARDS-predisposing conditions were enrolled consecutively into a prospective cohort, of which 736 patients developed ARDS. We defined sepsis-related ARDS as ARDS developing in patients with sepsis and non-sepsis-related ARDS as ARDS developing after nonseptic injuries, such as trauma, aspiration, and multiple transfusions. Patients with both septic and nonseptic risks were excluded from analysis.ResultsCompared with patients with non-sepsis-related ARDS (n = 62), patients with sepsis-related ARDS (n = 524) were more likely to be women and to have diabetes, less likely to have preceding surgery, and had longer pre-ICU hospital stays and higher APACHE III (Acute Physiology and Chronic Health Evaluation III) scores (median, 78 vs 65, P < .0001). There were no differences in lung injury score, blood pH, Pao(2)/Fio(2) ratio, and Paco(2) on ARDS diagnosis. However, patients with sepsis-related ARDS had significantly lower Pao(2)/Fio(2) ratios than patients with non-sepsis-related ARDS patients on ARDS day 3 (P = .018), day 7 (P = .004), and day 14 (P = .004) (repeated-measures analysis, P = .011). Compared with patients with non-sepsis-related ARDS, those with sepsis-related had a higher 60-day mortality (38.2% vs 22.6%; P = .016), a lower successful extubation rate (53.6% vs 72.6%; P = .005), and fewer ICU-free days (P = .0001) and ventilator-free days (P = .003). In multivariate analysis, age, APACHE III score, liver cirrhosis, metastatic cancer, admission serum bilirubin and glucose levels, and treatment with activated protein C were independently associated with 60-day ARDS mortality. After adjustment, sepsis-related ARDS was no longer associated with higher 60-day mortality (hazard ratio, 1.26; 95% CI, 0.71-2.22).ConclusionSepsis-related ARDS has a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, and higher mortality than non-sepsis-related ARDS. Worse clinical outcomes in sepsis-related ARDS appear to be driven by disease severity and comorbidities.

Project description:BackgroundAcute Respiratory Distress Syndrome (ARDS) is a devastating pulmonary inflammatory disorder, commonly precipitated by sepsis. Glucocorticoids are immunomodulatory steroids that can suppress inflammation. Their anti-inflammatory properties within tissues are influenced by their pre-receptor metabolism and amplification from inactive precursors by 11β-hydroxysteroid dehydrogenase type-1 (HSD-1). We hypothesised that in sepsis-related ARDS, alveolar macrophage (AM) HSD-1 activity and glucocorticoid activation are impaired, and associated with greater inflammatory injury and worse outcomes.MethodsWe analysed broncho-alveolar lavage (BAL) and circulating glucocorticoid levels, AM HSD-1 reductase activity and Receptor for Advanced Glycation End-products (RAGE) levels in two cohorts of critically ill sepsis patients, with and without ARDS. AM HSD-1 reductase activity was also measured in lobectomy patients. We assessed inflammatory injury parameters in models of lung injury and sepsis in HSD-1 knockout (KO) and wild type (WT) mice.ResultsNo difference in serum and BAL cortisol: cortisone ratios are shown between sepsis patients with and without ARDS. Across all sepsis patients, there is no association between BAL cortisol: cortisone ratio and 30-day mortality. However, AM HSD-1 reductase activity is impaired in patients with sepsis-related ARDS, compared to sepsis patients without ARDS and lobectomy patients (0.075 v 0.882 v 0.967 pM/hr/106 AMs, p=0.004). Across all sepsis patients (with and without ARDS), impaired AM HSD-1 reductase activity is associated with defective efferocytosis (r=0.804, p=0.008) and increased 30-day mortality. AM HSD-1 reductase activity negatively correlates with BAL RAGE in sepsis patients with ARDS (r=-0.427, p=0.017). Following intra-tracheal lipopolysaccharide (IT-LPS) injury, HSD-1 KO mice demonstrate increased alveolar neutrophil infiltration, apoptotic neutrophil accumulation, alveolar protein permeability and BAL RAGE concentrations compared to WT mice. Caecal Ligation and Puncture (CLP) injury in HSD-1 KO mice results in greater peritoneal apoptotic neutrophil accumulation compared to WT mice.ConclusionsAM HSD-1 reductase activity does not shape total BAL and serum cortisol: cortisone ratios, however impaired HSD-1 autocrine signalling renders AMs insensitive to the anti-inflammatory effects of local glucocorticoids. This contributes to the decreased efferocytosis, increased BAL RAGE concentrations and mortality seen in sepsis-related ARDS. Upregulation of alveolar HSD-1 activity could restore AM function and improve clinical outcomes in these patients.

Dataset Information

Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS.

Publications

Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS.

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