Serhan CN, Savill JResolution of inflammation: the beginning programs the end. Nat Immunol 6:1191-1197

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature Immunology (Impact Factor: 20). 01/2006; 6(12):1191-7. DOI: 10.1038/ni1276
Source: PubMed


Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, granulocytes promote the switch of arachidonic acid-derived prostaglandins and leukotrienes to lipoxins, which initiate the termination sequence. Neutrophil recruitment thus ceases and programmed death by apoptosis is engaged. These events coincide with the biosynthesis, from omega-3 polyunsaturated fatty acids, of resolvins and protectins, which critically shorten the period of neutrophil infiltration by initiating apoptosis. Consequently, apoptotic neutrophils undergo phagocytosis by macrophages, leading to neutrophil clearance and release of anti-inflammatory and reparative cytokines such as transforming growth factor-beta1. The anti-inflammatory program ends with the departure of macrophages through the lymphatics. Understanding these and further details of the mechanism required for inflammation resolution may underpin the development of drugs that can resolve inflammatory processes in directed and controlled ways.


Available from: Charles N Serhan
    • "The ability of MDM⌽ to phagocytose neutrophils is an important step in the resolution of inflammation and the progress of wound healing (Serhan and Savill 2005). The hypothesis behind the present study was that oxidative stress induced by hyperbaric oxygen (HBO) contributes to the apoptosis of neutrophils and that this augments clearance by macrophages through their recognition of the apoptotic neutrophils. "
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    ABSTRACT: Neutrophil apoptosis and clearance by macrophages are essential for wound healing. Evidence suggests that hyperbaric oxygen (HBO) exposure may enhance neutrophil apoptosis, but HBO effects leading to neutrophil clearance by macrophages are still unclear. In the current study, bovine neutrophils and monocyte-derived macrophages (MDMΦ) were co-cultured under HBO (97.9% O2, 2.1% CO2 at 2.4 atm absolute (ATA)) (1 atm = 101.325 kPa), hyperbaric normoxia (8.8% O2 at 2.4 ATA), normobaric hyperoxia (95% O2, 5% CO2), normoxia (air), and normobaric hypoxia (5% O2, 5% CO2). Phagocytosis of fresh and 22 h aged neutrophils by MDMΦ was increased after HBO pre-treatment, assessed using flow cytometry and light microscopy. Enhanced clearance of neutrophils was accompanied by an increase in H2O2 levels following HBO pre-treatment with upregulation of IL-10 (anti-inflammatory cytokine) mRNA expression in LPS-stimulated MDMΦ that had ingested aged neutrophils. TNF-α (pro-inflammatory cytokine) gene expression did not change in LPS-stimulated MDMΦ that had ingested fresh or aged neutrophils after HBO, pressure, and hyperoxia. These findings suggest that HBO-activated MDMΦ participate in the clearance of apoptotic cells. Uptake of neutrophils by MDMΦ exposed to HBO may contribute to resolution of inflammation, because HBO induced up-regulation of IL-10 mRNA expression.
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    • "Normally, this process attempts to remove the harmful stimuli and promotes wound healing. However, prolonged inflammation can be harmful, contributing to the pathogenesis of many diseases (Medzhitov & Janeway, 1997; Serhan & Savill, 2005). Macrophages are largely responsible for initiating the immune defense and inflammatory reactions (Li et al., 2011; Li & Xu, 2011). "
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    • "Prostaglandin E2 (PGE2) is an important mediator of pain, swelling , and inflammatory responses [51] and plays a key role in immune suppression [52]. In a variety of cells including macrophages , COX-2 is induced by LPS, and this induction results in the release of huge amounts of PGE2 at areas of inflammation [53]. "
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