SIGNALING MECHANISMS IN SEPSIS-INDUCED IMMUNE DYSFUNCTION

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Sepsis and subsequent organ failure remain the major cause of mortality in intensive care units in spite of significant research efforts. The lung is the most vulnerable organ affected by early hyper-inflammatory immune response in septic patients. On the other hand, the septic insult induces immune dysfunction in later phases of sepsis which in turn increases susceptibility to infections. The aim of this thesis was to investigate early and late inflammatory mechanisms in abdominal sepsis induced by cecal ligation and puncture (CLP). We observed that inhibition of CD44 not only reduced CLP-induced pulmonary accumulation of neutrophils but also protected against edema formation and tissue destruction in septic lung injury. We found that inhibition of geranylgeranyl transferase decreased CLP-induced pulmonary recruitment of neutrophils via reduction of CXC chemokine production in lung macrophages and neutrophil activation in the circulation. It was noted that Rho-kinase inhibitor reduced sepsis-induced pulmonary recruitment of neutrophils and tissue injury via regulation of CXC chemokines formation in the lung. Moreover, inhibition of Rho-kinase signaling decreased sepsis-induced T-cell apoptosis as well as enhanced T-cell proliferation and cytokine formation. In addition, Rho-kinase inhibition reduced sepsis-induced expansion of regulatory T-cells. Finally, it was noted that Rho-kinase inhibitor abolished CLP-induced increase in the plasma levels of HMGB1 and IL-6. Thus, these data identify new signaling mechanisms regulating pathological inflammation in septic lung injury and immune dysfunction, which may provide a basis for the development of more specific and effective treatment to ameliorate respiratory failure and improve T-cell-mediated host defense reactions in polymicrobial sepsis.

Details

Authors
  • Zirak Hasan
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Surgery

Keywords

  • abdominal sepsis, neutrophil, lung, chemokines, infection, T-cells, CD44, Rho-kinase, isoprenylation
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2013 Feb 25
Publisher
  • Surgery Research Unit
Print ISBNs978-91-87189-83-8
Publication statusPublished - 2013
Publication categoryResearch

Bibliographic note

Defence details Date: 2013-02-25 Time: 09:00 Place: Medelhavet, Wallenberg Neurocentrum, SUS, Malmö External reviewer(s) Name: Boros, Mihaly Title: professor Affiliation: Institute of Surgical Research ---

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Related research output

Zirak Hasan, Karzan Palani, Milladur Rahman & Henrik Thorlacius, 2011, In: Shock. 35, p. 567-572

Research output: Contribution to journalArticle

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