Article

Oxidative stress generated by hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages.

Department of Surgery, St. Michael's Hospital and University Health Network, Toronto, Ontario, Canada.
Journal of Experimental Medicine (Impact Factor: 13.21). 09/2006; 203(8):1951-61. DOI: 10.1084/jem.20060943
Source: PubMed

ABSTRACT Oxidative stress generated by ischemia/reperfusion is known to prime inflammatory cells for increased responsiveness to subsequent stimuli, such as lipopolysaccharide (LPS). The mechanism(s) underlying this effect remains poorly elucidated. These studies show that alveolar macrophages recovered from rodents subjected to hemorrhagic shock/resuscitation expressed increased surface levels of Toll-like receptor 4 (TLR4), an effect inhibited by adding the antioxidant N-acetylcysteine to the resuscitation fluid. Consistent with a role for oxidative stress in this effect, in vitro H2O2 treatment of RAW 264.7 macrophages similarly caused an increase in surface TLR4. The H2O2-induced increase in surface TLR4 was prevented by depleting intracellular calcium or disrupting the cytoskeleton, suggesting the involvement of receptor exocytosis. Further, fluorescent resonance energy transfer between TLR4 and the raft marker GM1 as well as biochemical analysis of the raft components demonstrated that oxidative stress redistributes TLR4 to lipid rafts in the plasma membrane. Preventing the oxidant-induced movement of TLR4 to lipid rafts using methyl-beta-cyclodextrin precluded the increased responsiveness of cells to LPS after H2O2 treatment. Collectively, these studies suggest a novel mechanism whereby oxidative stress might prime the responsiveness of cells of the innate immune system.

0 Bookmarks
 · 
110 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Innate immune cells including macrophages, dendritic cells, and granulocytes are resident within or patrol very different microenvironments in the host. Their activity or responsiveness to antigen is dictated by site-specific factors. Because of the constant exposure to environmental antigens and commensal microorganisms, mucosal immunity needs to be more constrained than peripheral counterparts to prevent unnecessary inflammation. The epithelial surfaces that dominate all mucosal tissues provide an ideal regulator since innate immune cells are often in intimate contact with, or lie immediately beneath, them and a breach in epithelial integrity would signal a damaging event and release innate immunity from their influence. We discuss the role of the respiratory epithelium in raising the threshold of innate immune cell activation at homoeostasis, how its absence triggers innate immunity, and how inflammatory resolution often produces an altered homoeostatic environment that can affect the next inflammatory event at this site.
    The Lancet Infectious Diseases 05/2010; 10(5):360-6. · 19.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nuclear factor erythroid 2-related factor 2 (NRF2) has been shown to protect against experimental sepsis in mice and lipopolysaccharide (LPS)-induced inflammation in ex vivo white blood cells from healthy subjects by upregulating cellular antioxidant genes. The objective of this study was to test the hypothesis that ex vivo CDDO-Me activates NRF2-regulated antioxidant genes in white blood cells from patients with septic shock and protects against LPS-induced inflammation and reactive oxidative species production.
    Shock (Augusta, Ga.) 08/2014; · 2.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The idea of protecting the heart from ischemic insult during heart surgery to allow elective cardiac arrest is as old as the idea of cardiac surgery itself. The current gold standard in clinical routine is a high potassium regimen added either to crystalloid or blood cardioplegic solutions inducing depolarized arrest. Ongoing patient demographic changes with increasingly older, comorbidly ill patients and increasing case complexity with increasingly structurally abnormal hearts as morphological correlate paired with evolutions in pediatric cardiac surgery allowing more complex procedures than ever before redefine requirements for cardioprotection. Many, in part adversarial, regimens to protect the myocardium from ischemic insults have entered clinical routine; however, functional recovery of the heart is still often impaired due to perfusion injury. Myocardial reperfusion damage is a key determinant of postoperative organ functional recovery, morbidity, and mortality in adult and pediatric patients. There is a discrepancy between what current protective strategies are capable of and what they are expected to do in a rapidly changing cardiac surgery community. An increased understanding of the molecular players of ischemia reperfusion injury offers potential seeds for new cardioprotective regimens and may further displace boundaries of what is technically feasible.
    BioMed Research International 01/2014; 2014:325725. · 2.71 Impact Factor

Full-text (4 Sources)

View
10 Downloads
Available from
Jul 24, 2014