Posts Tagged ‘Resolvins’

Can Resolvins Suppress Acute Lung Injury?

Reporter: Larry H Bernstein, MD, FCAP

Putting the brakes on acute lung injury: can resolvins suppress acute lung injury?

Cox RR Jr., Phillips O,and Kolliputi N Front.Physio. 2012;3:445.

The presence of resolvins, proresolving lipid mediators: their role in the resolution of ALI
Eickmeier et al.,
Mucosal Immunity 2012

conversion of DHA to RvD1 by

  • activation of RvD1 Receptor (ALX/FPR2) in pulmonary mucosa alleviates effects of inflammation in APALI

endogenous attenuation of inflammation in APALI

 Putting the brakes on acute lung injury: can resolvins suppress acute lung injury?
Ruan R. Cox Jr., Oluwakemi Phillips and Narasaiah Kolliputi*
Front Physiol. 2012;3:445.   doi: 10.3389/fphys.2012.00445. Epub 2012 Nov 29. the brakes on acute lung injury: can resolvins suppress acute lung injury?

A commentary on

Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury

by Eickmeier, O., Seki, H., Haworth, O., Hilberath, J. N., Gao, F., Uddin, M., et al. (2012). Mucosal Immunol. doi: 10.1038/mi.2012.66

Acute lung injury (ALI), a syndrome of respiratory failure, is a major clinical problem in the United States. With a high incidence rate, affecting nearly 200,000 annually and a significant morbidity and mortality rate, ALI represents a significant source of health care expenditure with a cost of 3.5–6 billion dollars annually (Treggiari et al., 2004; Rubenfeld et al., 2005; Raghavendran et al., 2011). Pneumocytes, unique cells in the alveolar epithelium, are responsible for

  • facilitating gas exchange,
  • regulating fluid transport, and
  • secreting surfactant to reduce alveolar surface tension.

When the alveolar barrier is disrupted, proteinaceous exudates and extracellular components of necrotic pneumocytes activate resident alveolar macrophages causing massive cytokine release (Ware and Matthay, 2000).  The inflammatory response, if left uncontrolled, can lead to further deterioration of the lung epithelium and the development of a fibroproliferative environment (Raghavendran et al., 2011).

In the July 2012 issue of Mucosal Immunity, Eickmeier et al., discuss the presence of

  1. resolvins,
  2. proresolving lipid mediators, and
  3. present exciting findings on their role in the natural resolution of ALI (Eickmeier et al., 2012).

Resolution phase interaction products (resolvins) are omega-3 polyunsaturated fatty acid derivatives of potent anti-inflammatory precursors, eicosapentaenoic acid (EPA), and docasahexaenoic acid (DHA) (Serhan et al., 2002). “E-series” and “D-series” resolvins are derived from EPA and DHA, respectively. The airway mucosa has been shown to be rich in DHA (Freedman et al., 2004), however, the conversion of DHA to D-series resolvins has not been shown. Resolvin D1 (RvD1), a derivative of DHA, has been found in murine resolving inflammatory peritoneal exudates (Serhan et al., 2002). To investigate the potential role that RvD1 may play in the resolution of ALI, Eickmeier et al. used a murine aspiration pneumonitis acute lung injury (APALI) model induced by hydrochloric acid (HCl) administration into the left lung. Picogram quantities of RvD1 were found using metabolipidomics analysis following HCl instillation. Immunohistochemical analysis showed enhanced expression of RvD1 receptor (ALX/FPR2) as early as 2 h post-APALI. This suggested that there was a conversion of DHA to RvD1 following lung injury. Activation of ALX/FPR2 dampens the inflammatory responses through blockage of proinflammatory MAP kinase and NF-κB signaling (Chiang et al., 2006).  Eickmeier et al. demonstrated that the conversion of DHA in pulmonary mucosa alleviates the effects of inflammation in APALI. AT-RvD1 showed therapeutic effects, and bronchio-alveolar lavage fluid (BALF) collected from AT-RvD1 treated mice contained decreased leukocytes and proinflammatory cytokines in comparison to control. AT-RvD1 treated mice demonstrated decreased lung resistance and improved lung mechanics in comparison to controls. The authors showed that AT-RvD1 restored barrier integrity in APALI mice in comparison to control. The anti-inflammatory effects of ALX/FPR2 activation were shown to be a result of

  • reduced activation and nuclear translocation of the transcription factor NF-κB.

Eickmeier et al., demonstrated that mice treated with AT-RvD1 demonstrated reduced

  • NF-κB phosphorylation, which is necessary for the activation,
  • translocation and DNA binding functions of this proinflammatory molecule.

The work of Eickmeier et al. revealed that RvD1 is a central mediator in the endogenous attenuation of inflammation seen in APALI. In most cases of ALI, the injury is indeed self-limiting and resolves on its own (Dos Santos and Slutsky, 2006). This work gives insight to the mechanism involved in the lung injury resolution process. A recent clinical study demonstrates that,
ALI progression is associated with

  • increased ventilator time and
  • longer intensive care unit (ICU) stays.

These patients show an enhanced proinflammatory cytokine profile which was also correlated with increased morbidity (Dolinay et al., 2012). Previous reports have also demonstrated that ALI/ARDS patients represent 34% of yearly costs for all ICU trauma patients (Treggiari et al., 2004). In the case that the ALI does not resolve, the patient is at risk for developing acute respiratory distress syndrome in as little as 3 days (Marshall et al., 1998). Finding endogenous mediators that may control the ungoverned inflammation seen in ALI is a pivotal step to finding a treatment for this disease that entails more than just supportive care (Marshall et al., 1998). The work of Eickmeier et al. has paved the way for the exploration of the beneficial effects of resolvins in the incidences of other sterile injuries, such as atherosclerosis, gout, Alzheimer’s disease, and diabetes.

Br J Pharmacol. 2008 March; 153(S1): S200–S215.
Published online 2007 October 29. doi:  10.1038/sj.bjp.0707489
PMCID: PMC2268040

Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus

C N Serhan1,2,* and N Chiang1
This article has been cited by other articles in PMC.


Complete resolution of an acute inflammatory response and its return to homeostasis are essential for healthy tissues. We here consider work to characterize cellular and molecular mechanisms that govern the resolution of self-limited inflammation. Systematic temporal analyses of evolving inflammatory exudates using

  1. mediator lipidomics-informatics,
  2. proteomics, and
  3. cellular trafficking with murine resolving exudates demonstrate
    • novel endogenous pathways of local-acting mediators that share both anti-inflammatory and pro-resolving properties.

In murine systems, resolving-exudate leukocytes switch their phenotype to actively generate new families of mediators from major omega-3 fatty acids EPA and DHA termed resolvins and protectins. Recent advances on their biosynthesis and actions are reviewed with a focus on the E-series resolvins (RvE1, RvE2), D series resolvins (RvD1, RvD2) and the protectins including neuroprotectin D1/protectin D1 (NPD1/PD1) as well as their aspirin-triggered epimeric forms.  These endogenous agonists of resolution pathways constitute a novel genus of chemical mediators that possess

  • pro-resolving,
  • anti-inflammatory, and
  • antifibrotic as well as
  • host-directed antimicrobial actions.
    These may be useful in the design of new therapeutics and treatments for diseases with the underlying trait of uncontrolled inflammation and redox organ stress.
Keywords: leukocytes, eicosanoids, resolvins, acute inflammation, ω-3 fatty acids, protectins


Acute inflammation has several outcomes that include

  • progression to chronic inflammation,
  • scarring and fibrosis or
  • complete resolution (Cotran et al., 1999).

With the isolation of endogenous anti-inflammatory and pro-resolving mediators and their characterization, it became clear that resolution is an active process involving biochemical circuits that

The resolution phase has emerged as a new terrain for drug design and resolution-directed therapeutics (Gilroy et al., 2004Lawrence et al., 2005). A pro-resolving small molecule can, in addition to serving as

  • an agonist of anti-inflammation, also
  • promote the uptake and clearance of apoptotic neutrophils (polymorphonuclear leukocyte, PMN)

A recent consensus report from investigators at the forefront of this emerging area has addressed these definitions to help delineate this new terrain (Serhan et al., 2007). Some agents such as the widely used COX-2 inhibitors proved to be resolution toxic (Gilroy et al., 1999Bannenberg et al., 2005Serhan et al., 2007), whereas others can possess pro-resolving actions, such as

Interest in natural resolving mechanisms has been heightened in recent years (Henson, 2005Luster et al., 2005Serhan and Savill, 2005) because inflammation (characterized by the cardinal symptoms dolor, calor, rubor and loss of function) is now recognized as a central feature in the pathogenesis of many prevalent diseases in modern Western civilization, such as

  1. stroke,
  2. Alzheimer’s and
  3. Parkinson’s diseases (Majno and Joris, 1996;Nathan, 2002Erlinger et al., 2004Hansson et al., 2006).

Resolution of inflammation is required for the return from inflammatory disease to health, that is, catabasis (Bannenberg et al., 2005). New evidence from this laboratory and others indicates that the catabasis from inflammation to the ‘normal’ noninflamed state is not merely passive termination of inflammation but rather an actively regulated program of resolution (Serhan et al., 2007). This event is accompanied by lipid mediator class switching from pro-inflammatory prostaglandins (PGs) and leukotrienes (LT) to the biosynthesis of anti-inflammatory mediators, such as lipoxins (LXs) (Levy et al., 2001), as well as the appearance of new families of pro-resolving mediators biosynthesized in exudates from ω-3 polyunsaturated fatty acid (PUFA) precursors (Serhan et al., 20002002Hong et al., 2003) (Figure 1a).

The essential roles of omega-3 PUFAs in preventing disease in rodents were established in 1929 (Burr and Burr, 1929). In humans, the beneficial actions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major omega-3 PUFA, remains a topic of interest because structure–activity relationships remained to be established.  One theory suggests that the omega-3 PUFA compete with the storage of arachidonic acid (AA),

  • replacing it and blocking the production of pro-inflammatory eicosanoids (Lands, 1987).

Along with the pro-inflammatory PGs and LT, the n−6 essential fatty acid AA is precursor to LX and aspirin-triggered LX, which possess potent anti-inflammatory and pro-resolving actions. Therefore, the popular view of essential n−6 and n−3 PUFA actions in inflammation and homeostasis was incomplete.

The evidence available to date  indicates that

The term resolvins (resolution-phase interaction products) was first introduced to signify that the new structures were endogenous mediators possessing potent anti-inflammatory and immunomodulatory actions demonstrated in the nanogram dose range in vivo(Serhan et al., 2002). These include

  • reducing neutrophil traffic and pro-inflammatory cytokines, as well as
  • lowering the magnitude of the inflammatory response in vivo (Serhan et al., 20002002).

The terms protectin and neuroprotectin (when generated in neural tissues) (Serhan et al., 2006a) were introduced given the anti-inflammatory (Hong et al., 2003) as well as the protective actions of the
DHA-derived mediator NPD1/PD1 in neural systems (Mukherjee et al., 2004),

RvE1 possesses an interesting and novel distinct structure consisting of

  • a conjugated diene plus
  • conjugated diene chromophore present within the same molecule.

Both biogenic (Serhan et al., 2000) and total organic syntheses were achieved and its complete stereochemical assignment was established along with that of several related natural isomers (Arita et al., 2005a). RvE1 proved to be 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoicacid.

Human recombinant 5-LOX generates resolvin E2 (RvE2) from a common precursor of E-series resolvins, namely 18-HEPE. RvE2, which is 5S,18-dihydroxyeicosapentaenoic acid, stopped zymosan-induced PMN infiltration, displaying potent anti-inflammatory properties in murine peritonitis (Tjonahen et al., 2006). In addition, RvE1 and RvE2, when given together, displayed additive action in controlling PMN infiltration. These results demonstrate that RvE2, together with RvE1, may contribute to the beneficial actions of ω-3 fatty acids in human diseases. Moreover, they indicate that the 5-LOX, in human leukocytes, is a pivotal enzyme that is temporally and spatially regulated in vivo to produce either pro- or anti-inflammatory local chemical mediators.

Resolvins of the E-series comprise several molecules. Among them, RvE1 was the first isolated and studied in depth. RvE1 displayed potent stereoselective actions in vivo and with isolated cells.
At nanomolar levels in vitro, RvE1 dramatically reduced

  1. human PMN transendothelial migration,
  2. dendritic cell (DC) migration and
  3. interleukin (IL)-12 production
    (Serhan et al., 2002Arita et al., 2005a).

These new findings provide evidence for

  • endogenous mechanism(s) that may account for some of the widely touted beneficial actions noted with dietary supplementation with ω-3 PUFA (EPA and DHA),
  • thereby providing new approaches for the treatment of gastrointestinal mucosal and oral inflammation.

The new families of EPA- and DHA-derived chemical mediators, namely the resolvins and protectins, qualify as ‘resolution agonists’ along with the n−6 derived agonists of resolution, the LX, in this new arena of immunomodulation and tissue protection. These are conserved structures in evolution, because rainbow trout biosynthesize resolvins and protectins, which are present in their neural and hematopoietic tissues (Hong et al., 2005). Their functional roles in fish and lower phyla remain to be established, but are likely to involve

  1. cell trafficking,
  2. motility and
  3. protection.

Additionally, they now open new avenues to design ‘resolution-targeted’-based therapies where aberrant uncontrolled inflammation and/or impaired resolution are components of the disease pathophysiology.

Lipoxin A4 Regulates Natural Killer Cell and Type 2 Innate Lymphoid Cell Activation in Asthma
C Barnig, M Cernadas, S Dutile,…BR Levy.
Sci Transl Med 27 Feb 2013: 5(174) 174ra26

Asthma is a prevalent disease of chronic inflammation in which endogenous counterregulatory signaling pathways are dysregulated. Recent evidence suggests that innate lymphoid cells (ILCs), including natural killer (NK) cells and type 2 ILCs (ILC2s), can participate in the regulation of allergic airway responses, in particular airway mucosal inflammation.
Both NK cells and ILC2s expressed

Lipoxin A4, a natural pro-resolving ligand for ALX/FPR2 receptors, significantly

Together, these findings indicate that ILCs are targets for lipoxin A4 to decrease airway inflammation and mediate the catabasis of eosinophilic inflammation

Neutrophil granulocyte migrates from the blood...

Neutrophil granulocyte migrates from the blood vessel to the matrix, sensing proteolytic enzymes, in order to determine intercellular connections (to the improvement of its mobility) and envelop bacteria through Phagocytosis. (Photo credit: Wikipedia)


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