Metabolomic profiling of parapneumonic effusion reveals a regulatory role of dipeptides in interleukin-8 production in neutrophil-like cells.

Bacterial pneumonia is a lethal condition, and approximately 40% of bacterial pneumonia patients experience parapneumonic effusion (PPE). Based on the severity of inflammation, PPEs can be categorized as early-stage uncomplicated PPE (UPPE), advanced-stage complicated PPE (CPPE) and, most seriously, thoracic empyema. Appropriate antibiotic treatment at the early stage of PPE can prevent PPE progression and reduce mortality, indicating that understanding PPE generation and components can help researchers develop corresponding treatment strategies for PPE. To this end, metabolomes of 73 PPE (38 UPPE and 35 CPPE samples) and 30 malignant pleural effusion (MPE) samples were profiled with differential 12C2-/13C2-isotope dansylation labeling-based mass spectrometry. We found that PPE is characterized by elevated levels of dipeptides, especially for PPEs at advanced stages. Furthermore, with integrated proteomic and transcriptomic analyses of PPEs, the levels of dipeptides were strongly associated with the production of interleukin-8 (IL-8), an inflammation-associated cytokine. The production of IL-8 indeed increased upon the treatment of HL-60-derived neutrophilic cells with dipeptides, Gly-Val and Gly-Tyr. Our findings help to elucidate the metabolic perturbations present in PPE and indicate for the first time that dipeptides may be involved in the immune regulation observed during PPE progression.