ReviewResolvins: Natural agonists for resolution of pulmonary inflammation
Introduction
Acute inflammation is an essential host response to danger signals, including potential infection, noxious stimulus or tissue injury [1]. However, non-resolving inflammation is linked to many chronic inflammatory diseases, including asthma, rheumatoid arthritis, inflammatory bowel disease, and psoriasis (reviewed in [2]). In association with clinical symptoms in these chronic inflammatory diseases are elevated levels of pro-inflammatory mediators [3]. The overall magnitude and duration of inflammation depends on competing physiological processes, namely pro-phlogistic mechanisms that amplify inflammation and endogenous braking programs that control the resolution of inflammation (reviewed in [4]). In health, progression through the resolution phase of inflammation is primarily driven by the orderly phagocytic clearance of apoptotic granulocytes and debris by macrophages [5], [6]. It is now established that resolution of inflammation is an active coordinated process that is spatiotemporally controlled by endogenously generated autacoids at sites of inflammation [4], [7], [8]. The enzymatic transformation of polyunsaturated fatty acids (PUFAs) during inflammation leads to the generation of specific endogenous mediators that act as potent agonists for resolution by exhibiting anti-inflammatory, pro-resolving, anti-fibrotic, anti-angiogenic and anti-infective actions (reviewed in [4]). The discovery that PUFAs are indispensable for health and dietary deficiencies can lead to clinical symptoms of diseases was first established in the late 1920s [9]. Such pioneering work suggested a specific relationship between the immunoregulatory role of PUFAs and the pathogenesis of major human diseases. As such, the identification of PUFA-derived mediators generated locally during the resolution of inflammation has led to a rapidly advancing understanding of the cellular and molecular mechanisms that are fundamental to resolution. Here, we review recent insights into the resolution of airway inflammation, and in particular, highlight anti-inflammatory and pro-resolving roles for resolvins in inflammation and pulmonary diseases.
Section snippets
Resolution of acute inflammation
Resolution is now appreciated to be an active process that terminates acute inflammation. At present, we know that efficient restoration of inflamed tissues to their basal state requires that inflammatory cells are effectively cleared and further neutrophil recruitment is abrogated. During this process, tissue neutrophils undergo apoptosis and are recognised and subsequently engulfed by phagocytic macrophages in a non-inflammatory manner [5], [6]. Clearance of apoptotic neutrophils leads to the
PUFA-derived mediators regulate inflammation
PUFAs are essential for mammalian health. The ω − 6 PUFA, arachidonic acid (AA; 20:4n − 6) is incorporated into cellular phospholipids, and upon cell activation, specific phospholipase A2 enzymes hydrolyze the sn-2 fatty acyl bond of phospholipids to liberate AA. Once released, enzymatic metabolism of AA via COX or LOX give rise to bioactive mediators, such as prostaglandins, leukotrienes and lipoxins [50]. The ω − 3 PUFAs, eicosapentaenoic acid (EPA; 20:5n − 3) and docosahexaenoic acid (DHA; 22:6n − 3)
Resolvins: ω − 3 PUFA-derived pro-resolving mediators
Two molecular series of resolvins have been identified and characterized, namely E- and D-series resolvins that are enzymatically derived from ω − 3 PUFAs EPA and DHA, respectively. They were originally identified by physical methods during unbiased lipidomic analyses of resolving exudates [8], [58]. It is now appreciated that resolvins elicit a range of cell-type specific responses that collectively block inflammation and promote resolution (reviewed in [4]). These catabatic actions in vitro and
Resolvin receptors
Details of pharmacological properties of resolvins are emerging and there are multiple receptors that transduce the potent pro-resolving actions of these compounds in a cell- and tissue-specific manner.
Nuclear factor kappa B (NF-κB)
The transcription factor NF-κB is a critical regulator of innate immune responses. A wide range of pro-inflammatory cytokines, chemokines, adhesion molecules and enzymes are regulated by the NF-κB pathway [122]. In addition, NF-κB repression has been identified as a major inducer of granulocyte apoptosis [123], [124], an integral part of the resolution of inflammation and is linked to the pathogenesis of chronic inflammatory lung diseases, including asthma and chronic obstructive pulmonary
Pro-resolving actions of resolvins in experimental models of lung disease
E- and D-series resolvins display potent bioactivities in vivo in a wide range of experimental models of ocular, oral, dermal, gastrointestinal, renal and vascular inflammation, as well as in regulating angiogenesis, ischemia–reperfusion and hyperalgesia in vivo (Table 1). Recently, experimental models of lung disease have provided insights into cellular and molecular pro-resolving actions for resolvins in pulmonary inflammation and infection, which will be highlighted in this section.
Resolvin stable analogs
PUFA-derived mediators are rapidly formed and rapidly inactivated by local metabolic pathways (reviewed in [4]). These compounds thus serve as autacoids with largely autocrine and paracrine effects. The pivotal metabolic pathways for resolvins have been uncovered, informing the development of stable analogs. In addition to natural resolvins, their mimetics may serve useful to enhance the compound’s bioavailability, pharmacokinetics and pharmacodynamics. For example, 19-(p-fluorophenoxy)-RvE1 is
Conclusions
The recent discovery of resolvins, endogenously generated from essential ω − 3 PUFAs, has helped to redefine our understanding of events that terminate inflammation by uncovering their pro-resolving roles in driving inflamed tissues to a non-inflammatory state. There is now substantial evidence that these stereospecific molecules play a vital role in governing the resolution of inflammation. Resolvins are enzymatically generated during cell-cell interactions and serve as mediators of resolution
Acknowledgements
This work was supported in part by US National Institutes of Health Grants AI068084, HL68669 and P50-DE016191. The authors gratefully thank Tania A. Uddin MRPharmS and Nan Chiang PhD for their assistance with the illustrations and Anna Maria Recupero for expert assistance in preparation of the manuscript.
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