Pro-resolving Actions Research Articles

Deciphering the role of n-3 polyunsaturated fatty acid-derived lipid mediators in health and disease

Accumulating evidence indicates that, analogous to n-6 PUFA, n-3 PUFA are enzymatically converted into diverse families of bioactive mediators that play numerous roles in physiology. These mediators, which include the resolvins, protectins and maresins, are particularly important in resolving acute inflammation and also appear to play a role in enhancing host defence. Given the protective actions of n-3 PUFA in human subjects and in animal models of disease, active generation of bioactive mediators may in part underlie these protective effects. Several studies have demonstrated that bioactive autacoids generated from n-3 PUFA have direct anti-inflammatory and pro-resolution actions, and the structures of many of these endogenous mediators have been elucidated. The diverse roles of these lipid mediators in health and disease, regulation of their biosynthesis, as well as identification of specific receptors and cellular targets, are emerging. This brief review will highlight the biosynthesis of resolvins, protectins and maresins, and discuss their receptor-mediated biological actions in promoting the resolution of inflammation. Their potential use as a new class of pro-resolution therapeutics, as well as gaps in knowledge and challenges for future research, will also be discussed. Overall, the identification of these novel families of lipid mediators has yielded insight into the protective actions of n-3 PUFA and may lead to the development of an entirely new class of therapeutics aimed at regulating inflammation and host defence.

Resolvin D1 reduces deterioration of tight junction proteins by upregulating HO-1 in LPS-induced mice

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is characterized by increased pulmonary permeability with high mortality. Resolvin D1 (RvD1), which has potent anti-inflammatory and pro-resolving activity, can attenuate pulmonary edema in the animal model of ALI. However, the mechanism underlying the protection of RvD1 on pulmonary edema is still unknown. Here we explore the effects and mechanism of RvD1 on the disruption of tight junction protein that results in the permeability edema in a model of lipopolysaccharide (LPS)-induced ALI. The severity of pulmonary edema was assessed by wet-to-dry rate and Evans blue infiltration; expressions of tight junction (TJ) proteins occludin and zona occludin-1 (ZO-1) were examined by immunofluorescence staining and western blot; mRNA in lung tissue was studied by real time-PCR; the TUNEL kit was performed for the detection of apoptosis of pulmonary barrier. Twenty-four hours after LPS inhalation by mice, wet-to-dry rate and Evans blue infiltration indicated that pretreatment with RvD1 relieved the pulmonary edema and pulmonary capillary permeability. Moreover, RvD1 attenuated the LPS-induced deterioration of TJ protein ZO-1 and occludin significantly. And we found that RvD1 increased heme oxygenase-1 (HO-1) expression contributed to the protection on the deterioration of TJs. In addition, we found that RvD1 could reduce pulmonary cellular apoptosis in LPS-induced mice. In conclusion, RvD1 possesses the ability that relieves the pulmonary edema and restores pulmonary capillary permeability and reduces disruption of TJs in LPS-induced ALI of mice, at least in part, by upregulating HO-1 expression.

Resolvin D1 protects periodontal ligament

Resolution agonists are endogenous mediators that drive inflammation to homeostasis. We earlier demonstrated in vivo activity of resolvins and lipoxins on regenerative periodontal wound healing. The goal of this study was to determine the impact of resolvin D1 (RvD1) on the function of human periodontal ligament (PDL) fibroblasts, which are critical for wound healing during regeneration of the soft and hard tissues around teeth. Primary cells were cultured from biopsies obtained from three individuals free of periodontal diseases. Peripheral blood mononuclear cells were isolated by density gradient centrifugation from whole blood of healthy volunteers. PGE2, leukotriene B4 (LTB4), and lipoxin A4 (LXA4) in culture supernatants were measured by ELISA. The direct impact of RvD1 on PDL fibroblast proliferation was measured and wound closure was analyzed in vitro using a fibroblast culture "scratch assay." PDL fibroblast function in response to RvD1 was further characterized by basic FGF production by ELISA. IL-1β and TNF-α enhanced the production of PGE2. Treatment of PDL cells and monocytes with 0.1-10 ng/ml RvD1 (0.27-27 M) reduced cytokine induced production of PGE2 and upregulated LXA4 production by both PDL cells and monocytes. RvD1 significantly enhanced PDL fibroblast proliferation and wound closure as well as basic FGF release. The results demonstrate that anti-inflammatory and proresolution actions of RvD1 with upregulation of arachidonic acid-derived endogenous resolution pathways (LXA4) and suggest resolution pathway synergy establishing a novel mechanism for the proresolution activity of the ω-3 docosahexaenoic acid-derived resolution agonist RvD1.

Resolution phase lipid mediators of inflammation: agonists of resolution.

Lipid mediators are appreciated for their roles in leukocyte traffic required in host defense. With identification of novel resolution phase mediators, resolvins, protectins and maresins, these three families and their aspirin-triggered forms, given their potent stereoselective actions with human cells and animal disease models, are coined specialized pro-resolving mediators (SPM). Stereochemistries of key SPM are established and several groups reported organic synthesis. Given increased availability, this two-year-review period expands their potent pro-resolving and non-redundant actions. Collectively, they support the concept that return of acute inflammation involves active biosynthesis and SPM signaling toward homeostasis.

Maresin-1 reduces the pro-inflammatory response of bronchial epithelial cells to organic dust

BackgroundExposure to organic dust causes detrimental airway inflammation. Current preventative and therapeutic measures do not adequately treat resulting disease, necessitating novel therapeutic interventions. Recently identified mediators derived from polyunsaturated fatty acids exhibit anti-inflammatory and pro-resolving actions. We tested the potential of one of these mediators, maresin-1 (MaR1), in reducing organic dust-associated airway inflammation.MethodsAs bronchial epithelial cells (BECs) are pivotal in initiating organic dust-induced inflammation, we investigated the in vitro effects of MaR1 on a human BEC cell line (BEAS-2B). Cells were pretreated for 1 hour with 0–200 nM MaR1, followed by 1–24 hour treatment with 5% hog confinement facility-derived organic dust extract (HDE). Alternatively, a mouse lung slice model was utilized in supportive cytokine studies. Supernatants were harvested and cytokine levels determined via enzyme-linked immunosorbent assays. Epithelial cell protein kinase C (PKC) isoforms α and ϵ, and PKA activities were assessed via radioactivity assays, and NFκB and MAPK-related signaling mechanisms were investigated using luciferase vector reporters.ResultsMaR1 dose-dependently reduced IL-6 and IL-8 production following HDE treatment of BECs. MaR1 also reduced HDE-stimulated cytokine release including TNF-α in a mouse lung slice model when given before or following HDE treatment. Previous studies have established that HDE sequentially activates epithelial PKCα and PKCϵ at 1 and 6 hours, respectively that regulated TNF-α, IL-6, and IL-8 release. MaR1 pretreatment abrogated these HDE-induced PKC activities. Furthermore, HDE treatment over a 24-hour period revealed temporal increases in NFκB, AP-1, SP-1, and SRE DNA binding activities, using luciferase reporter assays. MaR1 pretreatment did not alter the activation of NFκB, AP-1, or SP-1, but did reduce the activation of DNA binding at SRE.ConclusionsThese observations indicate a role for MaR1 in attenuating the pro-inflammatory responses of BECs to organic dust extract, through a mechanism that does not appear to rely on reduced NFκB, AP-1, or SP-1-related signaling, but may be mediated partly through SRE-related signaling. These data offer insights for a novel mechanistic action of MaR1 in bronchial epithelial cells, and support future in vivo studies to test MaR1’s utility in reducing the deleterious inflammatory effects of environmental dust exposures.

Resolvin E1 enhances phagocytosis‐induced neutrophil apoptosis

Resolvin E1 (RvE1) is an endogenous lipid mediator derived from the ω‐3 polyunsaturated fatty acid eicosapentaenoic acid that displays potent pro‐resolving actions in experimental models of inflammation. However, little is known about the impact of RvE1 on neutrophil apoptosis, a critical control point in the resolution of inflammation. Culture of human neutrophils with RvE1 did not affect neutrophil longevity, RvE1 accelerated apoptosis evoked by phagocytosis of opsonized Escherichia coli or yeast. RvE1 through the leukotriene B4 receptor BLT1 enhanced ROS generation by NADPH oxidase, leading to subsequent activation of caspase‐8 and caspase‐3. Moreover, RvE1 mitigated phagocytosis‐induced ERK activation. RvE1 also attenuated myeloperoxidase (through Mac‐1), serum amyloid A (through the formyl peptide receptor 2) and bacterial DNA (through TLR9)‐evoked concurrent ERK and phosphatidylinositol 3‐kinase/Akt‐mediated apoptosis‐suppressing signals. These led to reductions in the expression of the antiapoptotic protein Mcl‐1, collapse of mitochondrial transmembrane potential and activation of caspase‐3. Our results identify a novel BLT1 receptor‐mediated mechanism, promotion of phagocytosis‐induced neutrophil apoptosis by which RvE1 could enhance neutrophil apoptosis and subsequently promote inflammation resolution. (Grant support: CIHR MOP‐97742).

BML-111 attenuates hemorrhagic shock-induced acute lung injury through inhibiting activation of mitogen-activated protein kinase pathway in rats

BackgroundHemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. Mitogen-activated protein kinase (MAPK) acts as a sensor of tissue injury in models of ischemia-reperfusion injury. Lipoxins are endogenous lipid mediators with potent anti-inflammatory and pro-resolving actions. We hypothesized that BML-111 (a lipoxin A4-receptor agonist) attenuates hemorrhagic shock-induced acute lung injury (ALI) through inhibiting activation of the MAPK pathway. MethodsWe randomized Sprague-Dawley rats into four groups: sham, hemorrhagic shock–resuscitation (HS), HS plus BML-111 (BML-111), and HS plus BML-111 and BOC-2 (BOC-2). Two hours after resuscitation, we collected samples of lung. We obtained bronchoalveolar lavage fluid for neutrophil count. We performed optical microscopy to examine pathologic changes in lungs. Wet/dry ratios, myeloperoxidase expression, interleukin (IL)-1β and IL-6 levels in lung were measured. We evaluated MAPK activation and the DNA binding activity of activator protein-1 in lung. ResultsTreatment with BML-111 reduced the lung damage and wet/dry ratio, neutrophil count in bronchoalveolar lavage fluid, expression of myeloperoxidase, and production of IL-1β and IL-6 in lung. Phosphorylation of MAPK was also decreased by BML-111 in lung. Furthermore, the DNA binding activity of activator protein-1 was blocked by BML-111. An antagonist of the lipoxin A4-receptor, BOC-2, reversed the protective effect of BML-111 on ALI induced by hemorrhagic shock. ConclusionsThis study indicates that BML-111 attenuated hemorrhagic shock-induced ALI via the MAPK/activator protein-1 signaling pathway. Therefore, BML-111 may have therapeutic potential for hemorrhagic shock-induced ALI.

Development and in vivo efficacy of targeted polymeric inflammation-resolving nanoparticles

Excessive inflammation and failed resolution of the inflammatory response are underlying components of numerous conditions such as arthritis, cardiovascular disease, and cancer. Hence, therapeutics that dampen inflammation and enhance resolution are of considerable interest. In this study, we demonstrate the proresolving activity of sub-100-nm nanoparticles (NPs) containing the anti-inflammatory peptide Ac2-26, an annexin A1/lipocortin 1-mimetic peptide. These NPs were engineered using biodegradable diblock poly(lactic-co-glycolic acid)-b-polyethyleneglycol and poly(lactic-co-glycolic acid)-b-polyethyleneglycol collagen IV-targeted polymers. Using a self-limited zymosan-induced peritonitis model, we show that the Ac2-26 NPs (100 ng per mouse) were significantly more potent than Ac2-26 native peptide at limiting recruitment of polymononuclear neutrophils (56% vs. 30%) and at decreasing the resolution interval up to 4 h. Moreover, systemic administration of collagen IV targeted Ac2-26 NPs (in as low as 1 µg peptide per mouse) was shown to significantly block tissue damage in hind-limb ischemia-reperfusion injury by up to 30% in comparison with controls. Together, these findings demonstrate that Ac2-26 NPs are proresolving in vivo and raise the prospect of their use in chronic inflammatory diseases such as atherosclerosis.

Stereocontrolled Total Synthesis of the Potent Anti-inflammatory and Pro-resolving Lipid Mediator Resolvin D3 and Its Aspirin-Triggered 17R-Epimer

The first total synthesis of stereochemically pure resolvin D3 and aspirin-triggered resolvin D3 is reported. These enzymatic metabolites of docosahexaenoic acid (DHA) have potent anti-inflammatory and pro-resolving actions. The convergent synthetic strategy is based on enantiomerically pure starting materials, and it is highly stereocontrolled.

The novel 13S,14S‐epoxy‐maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4hydrolase (LTA4H), and shifts macrophage phenotype

Maresins are produced by macrophages from docosahexaenoic acid (DHA) and exert potent proresolving and tissue homeostatic actions. Maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid) is the first identified maresin. Here, we investigate formation, stereochemistry, and precursor role of 13,14-epoxy-docosahexaenoic acid, an intermediate in MaR1 biosynthesis. The 14-lipoxygenation of DHA by human macrophage 12-lipoxygenase (hm12-LOX) gave 14-hydro(peroxy)-docosahexaenoic acid (14-HpDHA), as well as several dihydroxy-docosahexaenoic acids, implicating an epoxide intermediate formation by this enzyme. Using a stereo-controlled synthesis, enantiomerically pure 13S,14S-epoxy-docosa-4Z,7Z,9E,11E,16Z,19Z-hexaenoic acid (13S,14S-epoxy-DHA) was prepared, and its stereochemistry was confirmed by NMR spectroscopy. When this 13S,14S-epoxide was incubated with human macrophages, it was converted to MaR1. The synthetic 13S,14S-epoxide inhibited leukotriene B4 (LTB4) formation by human leukotriene A4 hydrolase (LTA4H) ∼40% (P<0.05) to a similar extent as LTA4 (∼50%, P<0.05) but was not converted to MaR1 by this enzyme. 13S,14S-epoxy-DHA also reduced (∼60%; P<0.05) arachidonic acid conversion by hm12-LOX and promoted conversion of M1 macrophages to M2 phenotype, which produced more MaR1 from the epoxide than M1. Together, these findings establish the biosynthesis of the 13S,14S-epoxide, its absolute stereochemistry, its precursor role in MaR1 biosynthesis, and its own intrinsic bioactivity. Given its actions and role in MaR1 biosynthesis, this epoxide is now termed 13,14-epoxy-maresin (13,14-eMaR) and exhibits new mechanisms in resolution of inflammation in its ability to inhibit proinflammatory mediator production by LTA4 hydrolase and to block arachidonate conversion by human 12-LOX rather than merely terminating phagocyte involvement.

Understanding Resolvin Signaling Pathways to Improve Oral Health

The discovery of resolvins has been a major breakthrough for understanding the processes involved in resolution of inflammation. Resolvins belong to a family of novel lipid mediators that possess dual anti-inflammatory and pro-resolution actions. Specifically, they protect healthy tissue during immune-inflammatory responses to infection or injury, thereby aiding inflammation resolution and promoting tissue healing. One of the major concerns in modern medicine is the management and treatment of oral diseases, as they are related to systemic outcomes impacting the quality of life of many patients. This review summarizes known signaling pathways utilized by resolvins to regulate inflammatory responses associated with the oral cavity.

Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Potent Immunoresolvents

Resolvins are a family of n-3 lipid mediators initially identified in resolving inflammatory exudates that temper inflammatory responses to promote catabasis. Here, temporal metabololipidomics with self-limited resolving exudates revealed that resolvin (Rv) D3 has a distinct time frame from other lipid mediators, appearing late in the resolution phase. Using synthetic materials prepared by stereocontrolled total organic synthesis and metabololipidomics, we established complete stereochemistry ofRvD3 and its aspirin-triggered 17R-epimer (AT-RvD3). Both synthetic resolvins potently regulated neutrophils and mediators, reducing murine peritonitis and dermal inflammation. RvD3 and AT-RvD3 displayed leukocyte-directed actions, e.g., blocking human neutrophil transmigration and enhancing macrophage phagocytosis and efferocytosis. These results position RvD3 uniquely within the inflammation-resolution time frame to vantage and contribute to the beneficial actions of aspirin and essential n-3 fatty acids.

Novel Biphasic Role of Resolvin D1 on Expression of Cyclooxygenase-2 in Lipopolysaccharide-Stimulated Lung Fibroblasts Is Partly through PI3K/AKT and ERK2 Pathways

Fibroblasts, far frombeing merely bystander cells, are known to play a specific role in inflammation resolution after an acute injury. As the endogenous “braking signal,” resolvins possess potent anti-inflammatory and proresolution actions. We demonstrated that the expression of COX-2 protein was significantly peaked initially at 6 hours but then also at 48 hours after LPS stimulation in lung fibroblasts. PGE2 levels also peaked at 6 hours, and PGD2 levels were increased and peaked at 48 hours. However, no significant change in the protein expression of COX-1 was observed after treatment with LPS in lung fibroblasts. Exogenous resolvin D1 inhibited the first peak of COX-2 expression as well as the production of PGE2 induced by LPS. In contrast, exogenous resolvin D1 increased the second peak of COX-2 expression as well as the production of PGD2 induced by LPS. In addition, resolvin D1 inhibited COX-2 expression at 6 hours, which was partly through PI3K/AKT and ERK2 signalling pathways.

Lipoxins and aspirin-triggered lipoxin alleviate bone cancer pain in association with suppressing expression of spinal proinflammatory cytokines

BackgroundThe neuroinflammatory responses in the spinal cord following bone cancer development have been shown to play an important role in cancer-induced bone pain (CIBP). Lipoxins (LXs), endogenous lipoxygenase-derived eicosanoids, represent a unique class of lipid mediators that possess a wide spectrum of anti-inflammatory and pro-resolving actions. In this study, we investigated the effects of intrathecal injection with lipoxin and related analogues on CIBP in rats.MethodsThe CIBP model was induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. Mechanical thresholds were determined by measuring the paw withdrawal threshold to probing with a series of calibrated von Frey filaments. Lipoxins and analogues were administered by intrathecal (i.t.) or intravenous (i.v.) injection. The protein level of LXA4 receptor (ALX) was tested by western blot. The localization of lipoxin receptor in spinal cord was assessed by fluorescent immunohistochemistry. Real-time PCR was carried out for detecting the expression of pro-inflammatory cytokines.ResultsOur results demonstrated that: 1) i.t. injection with the same dose (0.3 nmol) of lipoxin A4 (LXA4), lipoxin B4 (LXB4) or aspirin-triggered-15-epi-lipoxin A4 (ATL) could alleviate the mechanical allodynia in CIBP on day 7 after surgery. ATL showed a longer effect than the others and the effect lasted for 6 hours. ATL administered through i.v. injection could also attenuate the allodynia in cancer rats. 2) The results from western blot indicate that there is no difference in the expression of ALX among the naive, sham or cancer groups. 3) Immunohistochemistry showed that the lipoxin receptor (ALX)-like immunoreactive substance was distributed in the spinal cord, mainly co-localized with astrocytes, rarely co-localized with neurons, and never co-localized with microglia. 4) Real-time PCR analysis revealed that, compared with vehicle, i.t. injection with ATL could significantly attenuate the expression of the mRNA of proinflammatory cytokines (IL-1β and TNF-α) in the spinal cord in CIBP.ConclusionsTaken together, the results of our study suggest that LXs and analogues exert strong analgesic effects on CIBP. These analgesic effects in CIBP are associated with suppressing the expression of spinal proinflammatory cytokines.

Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation

Inappropriate neutrophil activation contributes to the pathogenesis of acute lung injury (ALI). Apoptosis is essential for removal of neutrophils from inflamed tissues and timely resolution of inflammation. Resolvin E1 (RvE1) is an endogenous lipid mediator derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid that displays proresolving actions. Because the balance of prosurvival and proapoptosis signals determines the fate of neutrophils, we investigated the impact of RvE1 on neutrophil apoptosis and the outcome of neutrophil-mediated pulmonary inflammation in mice. Culture of human neutrophils with RvE1 accelerated apoptosis evoked by phagocytosis of opsonized Escherichia coli or yeast. RvE1 through the leukotriene B(4) receptor BLT1 enhanced NADPH oxidase-derived reactive oxygen species generation and subsequent activation of caspase-8 and caspase-3. RvE1 also attenuated ERK and Akt-mediated apoptosis-suppressing signals from myeloperoxidase, serum amyloid A, and bacterial DNA, shifting the balance of pro- and anti-survival signals toward apoptosis via induction of mitochondrial dysfunction. In mice, RvE1 treatment enhanced the resolution of established neutrophil-mediated pulmonary injury evoked by intratracheal instillation or i.p. administration of live E. coli or intratracheal instillation of carrageenan plus myeloperoxidase via facilitating neutrophil apoptosis and their removal by macrophages. The actions of RvE1 were prevented by the pan-caspase inhibitor zVAD-fmk. These results identify a mechanism, promotion of phagocytosis-induced neutrophil apoptosis and mitigation of potent anti-apoptosis signals, by which RvE1 could enhance resolution of acute lung inflammation.

Role of the membrane receptor ALXR in polymicrobial sepsis

Sepsis is a leading cause of death in the ICU. It is characterized by a systemic inflammatory response following bacterial infection. Inflammatory dysregulation affects multiple organs through effects on endothelial, epithelial and immune cells, which can lead to irreversible damage and death of the host. Although exacerbated inflammation plays a pivotal role in sepsis evolution, anti-inflammatory drugs fail to treat this disease. In addition, anti-inflammatory therapy may inhibit clearance of infection or favor secondary infections. Therefore, it is of interest to resolve excessive inflammation without compromising host defense mechanisms. In accordance, it has been shown that treatment with LXA4, a endogenous anti-inflammatory agent with pro-resolution activity, increased survival in experimental sepsis by reducing systemic inflammation as well as bacterial spread. We therefore aimed to evaluate the role of a nonspecific LXA4 receptor, ALXR, in host response to sepsis induction by cecal ligation and puncture in mice (CLP).

Resolvins attenuate cigarette smoke-induced lung inflammation and injury (120.31)

Abstract Cigarette smoke induced chronic obstructive pulmonary disease (COPD) is a major global health issue with an increasing incidence worldwide. Inflammation plays an integral role in the development of chronic lung diseases such as COPD. Unresolved inflammatory responses in COPD can lead to tissue damage and dysfunction. Current therapies for COPD only treat symptoms and do not alter the course of the disease. Resolution of inflammatory responses was once believed to be passive, however, recent studies have shown that resolution is a biosynthetically active process involving endogenous pro-resolving lipid mediators, derived from omega-3 and omega-6 polyunsaturated fatty acids that control and limit inflammatory responses. Resolvin D1 (RvD1) is an endogenous lipid mediator that displays potent anti-inflammatory and pro-resolving actions without being immunosuppressive. We hypothesized that RvD1 would be beneficial in a smoke-induced lung injury model. Cigarette smoke-exposed mice treated with RvD1 exhibited a greater than 50% reduction in neutrophil accumulation in the lung lavage fluid, coupled with significant reductions in the neutrophil chemoattractants KC and MIP-2. IL-6 and IL-1β were also reduced. RvD1 treated mice also had enhanced phagocytosis of apoptotic neutrophils by macrophages. Interestingly, RvD1 drives polarization of alternatively activated macrophages (M2) that may facilitate resolution of inflammation and attenuate tissue damage.

E-prostanoid 2 receptor signaling suppresses lung innate immunity against Streptococcus pneumoniae

Pneumonia is a major global health problem. Prostaglandin (PG) E2 is an immunomodulatory lipid with anti-inflammatory, immunosuppressive, and pro-resolving actions. Data suggest that the E-prostanoid (EP) 2 receptor mediates immunomodulatory effects of PGE2, but the extent to which this occurs in Streptococcus pneumoniae infection is unknown. Intratracheal lung infection of C57BL/6 mice possessing (EP2+/+) or lacking (EP2−/−) the EP2 receptor was performed, as were in vitro studies of alveolar macrophage (AM) host defense functions. Bacterial clearance and survival were significantly improved in vivo in EP2−/− mice and it correlated with greater neutrophilic inflammation and higher lung IL-12 levels. Upon ex vivo challenge with pneumococcus, EP2−/−cells expressed greater amounts of TNF-α and MIP-2 than did EP2+/+ AMs, and had improved phagocytosis, intracellular killing, and reactive oxygen intermediate generation. These data suggest that PGE2-EP2 signaling may provide a novel pharmacological target for treating pneumococcal pneumonia in combination with antimicrobials.

Resolvins are potent analgesics for arthritic pain

Arthritis-associated inflammatory pain represents a serious medical problem worldwide. Current treatments for arthritic pain are not very effective and cause unwanted side effects. Resolvins, including the resolvin D and resolvin E series, are a family of novel endogenous lipid mediators derived from ω-3 polyunsaturated fatty acids and display potent anti-inflammatory and pro-resolution actions in animal models of inflammation. Emerging evidence also points to a potent anti-hyperalgesic role of resolvins in animal models of inflammatory pain. The study by Lima-Garcia et al. in this issue of the BJP demonstrated that systemic treatment with 17(R)-hydroxy-docosahexaenoic acid (17(R)HDoHE), the precursor of resolvin D series and its product, aspirin-triggered resolvin D1 (AT-RvD1), at very low doses (1 µg·kg(-1)), reduced inflammatory pain in an adjuvant-induced arthritis model. Particularly 17(R)HDoHE reduced joint stiffness but not paw and joint oedema. Given their potency and safety profile, resolvins may represent a new class of analgesics well suited to treating inflammatory pain associated with arthritis. LINKED ARTICLE This article is a commentary on Lima-Garcia et al., pp. 278-293 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2011.01345.x.

The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats

Resolution of inflammation is mediated by endogenous molecules with anti-inflammatory and pro-resolving activities and they have generated new possibilities for the treatment of inflammatory diseases. Here, we have investigated the possible anti-hyperalgesic effects of two lipids, aspirin-triggered resolvin D1 (AT-RvD1) and its precursor, 17(R)-hydroxy-4Z,7Z,10Z,13Z,15E,17R,19Z-docosahexaenoic acid (17(R)HDoHE). The anti-hyperalgesic effects of both lipid mediators were evaluated, using mechanical and thermal stimuli, at different time-points in adjuvant-induced arthritis in rats. Cytokine levels were measured, and immunohistochemistry and real-time PCR for pro-inflammatory mediators were also performed. The precursor of resolvin D series, 17(R)HDoHE, given systemically, inhibited the development and the maintenance of mechanical hyperalgesia in acute inflammation. Such effects were likely to be associated with modulation of both NF-κB and COX-2 in dorsal root ganglia and spinal cord. 17(R)HDoHE was also effective against sub-chronic pain. Unexpectedly, repeated treatment with 17(R)HDoHE did not modify paw and joint oedema in the sub-chronic model, while joint stiffness was prevented. Notably, AT-RvD1 exhibited marked anti-hyperalgesic effects in acute inflammation when given systemically. The efficacy of long-term treatment with either 17(R)HDoHE or AT-RvD1 was partly related to decreased production of TNF-α and IL-1β in rat hind paw. Our findings provide fresh evidence for the anti-hyperalgesic properties of 17(R)HDoHE and its pro-resolution metabolite AT-RvD1. Such lipid mediators might be useful for treating pain associated with acute or chronic inflammation. LINKED ARTICLE This article is commented on by Xu and Ji, pp. 274-277 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01348.x.