Lipoteichoic acid upregulates plasminogen activator inhibitor‐1 expression in parapneumonic effusions

Abstract

Background and objective: Parapneumonic effusion (PPE) is commonly caused by Gram-positive bacteria (GPB) and often presents with pleural loculation, which is characterized by overproduction of plasminogen activator inhibitor (PAI)-1. Lipoteichoic acid (LTA), a surface adhesion molecule of GPB, binds to the pleural mesothelium and triggers inflammation. However, the effects of LTA on PAI-1 expression in PPE and underlying mechanisms remain unclear. Methods: Thirty consecutive patients with PPE were enrolled, including uncomplicated culture negative (CN, n = 11), Gram-negative bacteria (GNB, n = 7) and GPB (n = 12) groups stratified by pleural fluid characteristics and bacteriology, and the effusion PAI-1 levels were measured. In addition, human pleural mesothelial cells (PMC) were treated with LTA and the expression of PAI-1 and activation of signalling pathways were assayed. Results: The median levels of PAI-1 were significantly higher in GPB (160.5 ng/mL) and GNB (117.0 ng/mL) groups than in the uncomplicated CN (58.0 ng/mL) group. In human PMC, LTA markedly upregulated PAI-1 mRNA and protein expression and enhanced elaboration of Toll-like receptor 2 (TLR2). Furthermore, LTA increased c-Jun N-terminal kinase (JNK) phosphorylation, induced activating transcription factor 2 (ATF2)/cJun nuclear translocation and activated PAI-1 promoter activity. Pretreatment with TLR2 siRNA significantly inhibited LTA-induced JNK phosphorylation and PAI-1 protein expression. Conclusion: Culture-positive PPE, especially that caused by GPB, has a significantly higher level of PAI-1 than uncomplicated CN PPE. LTA upregulates PAI-1 expression through activation of TLR2/JNK/activator protein 1 (AP-1) pathway in human PMC. Better understanding of the modulation of PAI-1 synthesis by LTA in PPE may provide potential therapies for infected pleural effusions.

Pleural infection: a closer look at the etiopathogenesis, microbiology and role of antibiotics

“…[34] Moreover, in patients referred for decortication, pleural fluid culture positivity was associated with longer duration of hospital stay. [55] This is likely to be supported by the recent finding that PAI-1 levels are higher in pleural effusions from gram positive bacteria, compared to gram negative and uncomplicated culture negative parapneumonic effusions [56] 4 Pleural infection diagnostics…”

Recent developments in the management of pleural infection: A comprehensive review

“…This interaction is amenable to medical intervention (see below). Lipoteichoic acid (LTA), a surface molecule found on gram positive bacteria, was found to cause upregulation of PAI‐1 expression in mesothelial cells . Whether this is an “inhibitable” target that can play a role in hampering fibrin deposition in the infected pleural space is yet to be explored.…”

Medical and Surgical Management of Empyema

“…88 Finally, culture positivity does not appear to predict success or failure of fibrinolytic therapy. 89 In preclinical studies different bacteria may differentially affect pleural mesothelial cells 90 or upregulate fibrin deposition, 91 but clinical evidence does not demonstrate that specific bacteria are associated with worse outcomes. Although increased mortality with Gram-negative and Staph infections (irrespective of CAE or HCAE) was shown in one posthoc analysis of the bacteriology from a large, wellcharacterized randomized trial cohort, 61 subsequent (multivariate) analyses controlling for other factors showed that mortality is primarily dependent on patient factors and setting (CAE or HCAE) and not specific organisms.…”