Treatment with recombinant tissue plasminogen activator (r-TPA) induces neutrophil degranulation in vitro via defined pathways

Federico Carbone, Nicolas Vuilleumier, Maria Bertolotto, Fabienne Burger, Katia Galan, Gloria Roversi, Carmine Tamborino, Ilaria Casetta, Silva Seraceni, Alessandro Trentini, Franco Dallegri, Analina Raquel da Silva, Aldo Pende, Nathan Artom, François Mach, Matteo Coen, Enrico Fainardi, Fabrizio Montecucco

Research output: Contribution to journalArticlepeer-review

Abstract

Thrombolysis is recommended for reperfusion following acute ischemic stroke (AIS), but its effects on stroke-associated injury remain to be clarified. Here, we investigated the effects of recombinant tissue plasminogen activator (r-tPA) on neutrophil pathophysiology in vitro and in a case-control study with AIS patients submitted (n. = 60) or not (n. = 30) to thrombolysis. Patients underwent radiological and clinical examination as well as blood sampling at admission and after 1, 7 and 90. days. In vitro, 30-min incubation with 0.1-1. mg/ml r-tPA induced neutrophil degranulation in different substrate cultures. Pre-incubation with kinase inhibitors and Western blot documented that degranulation was associated with activation of PI3K/Akt and ERK1/2 pathways in Teflon dishes and PI3K/Akt in polystyrene. In thrombolysed patients, a peak of neutrophil degranulation products (matrix metalloproteinase [MMP]-9, MMP-8, neutrophil elastase and myeloperoxidase), was shown during the first hours from drug administration. This was accompanied by serum augmentation of protective tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. An increased rate of haemorrhagic transformations on day 1 after AIS was shown in thrombolysed patients as compared to non-thrombolysed controls. In conclusion, r-tPA treatment was associated with in vitro neutrophil degranulation, indicating these cells as potential determinants in early haemorrhagic complications after thrombolysis in AIS patients.

Original languageEnglish
Pages (from-to)16-27
Number of pages12
JournalVascular Pharmacology
Volume64
DOIs
Publication statusPublished - Jan 1 2015

Keywords

  • Acute stroke
  • Cerebrovascular disease
  • Inflammation
  • Leukocytes
  • Thrombolysis

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Physiology
  • Medicine(all)

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