The RAGE Signaling Pathway in Sepsis Induced ARDS: Role of HMGB1 and MMPs
Journal: American Journal of Respiratory and Critical Care Medicine
Publication Date: 01/01/2015
Authors: Martin GS, Martin RT, Esper AM, Harris F, Brown LA
Cite As: Martin RT, Martin GS, Harris F, Brown LA, Esper AM. The RAGE Signaling Pathway in Sepsis Induced ARDS: Role of HMGB1 and MMPs. Am J Respir Crit Care Med 2015;191: A2372.
Rationale: Acute respiratory distress syndrome (ARDS) is a life threatening condition characterized by lung inflammation, increased pulmonary alveolar-capillary permeability and the accumulation of pulmonary edema. There are currently no sufficiently accurate biomarkers to predict development or outcomes of ARDS. Soluble RAGE (sRAGE) is increased in patients with ARDS, and other markers such as HMGB1 and the MMPs have been implicated in the RAGE signaling pathway. Data on these biomarkers in sepsis-induced ARDS is limited; therefore, we sought to examine the association of sRAGE, HMGB1, MMP3 and MMP13 with ARDS development and survival status in patients with sepsis. Methods: Prospective cohort of adult ICU patients at Grady Memorial Hospital meeting the ACCP/SCCM definition of severe sepsis or septic shock. Each subject underwent blood sampling and bronchoscopy with BAL. We collected patient demographics, sepsis sources, co-morbid conditions, APACHE and SOFA scores, length of stay and 28-day mortality. The primary outcome was development of ARDS, defined using the American-European Consensus Conference definition. RAGE, HMGB1 and MMPs were measured by ELISA. Statistical analysis employed two-sided t-tests or Wilcoxon rank-sum tests for continuous variables, chi-squared analysis for categorical variables and biomarker association using the Pearson correlation coefficient; P-values < 0.05 were considered significant. Results: Analysis was performed on 69 severe sepsis/septic shock patients; 36 had ARDS. The mean age of the cohort was 53.9 years, 59 % male, and 68% black. The overall mortality for the cohort was 46%. There was no mortality difference between ARDS and non-ARDS patients (42.9% vs. 54.1%, p=0.32). sRAGE was found to be significantly higher in the BALF of ARDS compared to non-ARDS patients (median 17.3 pg/ml (IQR 10.75-20.89) vs 6.76 pg/ml (IQR 3.69-10.16), p=0.0009) and there was a correlation with plasma sRAGE (r=0.39, p=0.005). Levels of plasma sRAGE, HMGB1 and MMPs were not statistically different between ARDS vs non- ARDS patients. There was no difference in either the sepsis or ARDS patient groups with respect to sRAGE, MMP or HMGB1 between survivors and non-survivors. Correlation analysis revealed no significant correlation between sRAGE and the other measured biomarkers in BALF or in plasma. Conclusions: BALF sRAGE is increased in patients with sepsis-induced ARDS and was associated with plasma sRAGE. There was no difference in the levels of HMGB1 and MMPs between ARDS and non-ARDS patients nor did the biomarkers distinguish survivors from non-survivors. HMGB1 and MMP were not associated with sRAGE.