|Year : 2019 | Volume
| Issue : 1 | Page : 45-48
Role of lipoxins in the resolution of inflammation
Supritha S Pai, Nina Shenoy
Department of Periodontics, A.B Shetty Memorial Institute of Dental Sciences, Nitte (Deemed to be) University, Mangalore, Karnataka, India
|Date of Web Publication||11-Oct-2019|
Dr. Nina Shenoy
Department of Periodontics, A.B Shetty Memorial Institute of Dental Sciences, Nitte (Deemed to be) University, Deralakatte, Mangalore, Karnataka
Source of Support: None, Conflict of Interest: None
Periodontal disease is initiated by a group of oral bacteria that stimulate local inflammatory responses, leading to bleeding on probing, loss of periodontal attachment, and bone and ultimately tooth loss. In periodontitis , host bacterial interactions that initiate as an acute inflammatory response develop into a chronic stage which is ruled by macrophages , B-lyphocytes, intense T-Lymphocytes and finally causes the destruction of periodontium. Over the past decade, understanding of pathways of inflammation has matured, and better understanding of the molecular basis of resolution of inflammation has emerged. Resolution of inflammation is an active, agonist-mediated, well-orchestrated return of tissue homeostasis. The mediators that are involved in the resolution of inflammation are lipoxins (LXs), resolvins, maresins, and protectins. This article reviews recent findings and new concepts pertaining to the generation of LXs and their impact on the resolution of inflammation.
Keywords: Lipoxins; periodontitis; resolution
|How to cite this article:|
Pai SS, Shenoy N. Role of lipoxins in the resolution of inflammation. Indian J Multidiscip Dent 2019;9:45-8
| Introduction|| |
Periodontitis is an inflammatory disease which is primarily triggered due to microbial origin, by bacteria such as Porphyromonas gingivalis, Tannerella forsythus, and Actinobacillus actinomycetemcomitans, resulting in damage to the supporting structures of the dentition. To heal the periodontal tissues, a series of inflammatory events are induced by the host.
Complete resolution of an acute inflammatory response and the body's return to homeostasis is necessary for on-going health. The ideal outcome of resolution of inflammation should result in the complete removal of leukocytes, without leaving behind the remnants of invading microbes that cause inflammation. A novel class of proresolving lipid molecules facilitates resolution of inflammation which is considered as an active process. Potential use of these proresolving molecules could result in the neutralization and elimination of inflammatory leukocytes and prevention of periodontal pathology. Tissue remodeling and repair are the final outcomes of resolution of inflammation, and if the repair is not controlled properly, it results in fibrosis and tissue scarring.
| Resolution and Repair|| |
Pro-resolving molecules are readily generated in host tissues.
[Figure 1] depicts the mechanisms of action proresolving molecules.
| Lipoxins|| |
Lipoxins (LXs) are the naturally occurring proresolving molecules which were first illustrated in human leukocytes. They are produced by bovine, porcine, and rat cells, including basophils and macrophage. An initiation of inflammatory response results in the production of LXs from arachidonic acid, which is an omega-6 fatty acid through an enzymatically derived lipooxygenase (LO) pathway. LXs initiate mononuclear cell infiltration without stimulating proinflammatory chemokine release or activation of these cells. They also stimulate and enhance the uptake of apoptotic polymorphonuclear (PMNs) and antimicrobial defense mechanisms as well as clearance on mucosal surfaces. They are essentially a “braking” signal for PMN and PMN-mediated tissue injury.
A study done by Samuelsson et al. revealed that LXs possess dual actions, i.e., anti-inflammatory and resolution actions. Numerous studies have identified three main pathways of LX synthesis. The first pathway describes that LXA4 and LXB4 which is formed by the eicosanoid products of 15-lipoxygenase (15-LO), i.e., 15 S-hydroperoxyeicosatetraenoic acid (15 S-H(p)ETE), or the reduced alcohol form. 15 S-hydroxyeicosatetraenoic acid present in the airway epithelial cells or monocytes, which serves as a substrate for neutrophil 5-LO [Figure 2].
|Figure 2: The three main pathways for lipoxin formation. Initiation of all three pathways is done by arachidonic acid. All the three pathways are independent of each other|
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The second pathway for LX biosynthesis mainly involves the interaction between 5-LO present in myeloid cells and 12-LO present in platelets. Leukotriene A4 (LTA4) product of 5-LO (LTA4) is rapidly taken up by the platelets and converted to LXs via a 12-LO-dependent mechanism to LXs [Figure 2].
The third major pathway for LX synthesis, which was recently discovered, is aspirin-triggered 15-epi-lipoxin (ATL) pathway. This pathway involves the interaction between aspirin and action of cyclooxygenase (COX) 2 and 5-LO. Exposure to diverse stimuli such as cytokine hypoxia and bacterial infection cause the endothelial cells endothelial and epithelial cells to start expressing COX-2. Acetylation of COX-2 occurs by aspirin, which eventually leads to catalytic conversion of C20:4-15 R-hydroxyeicosatetraenoic (15 R-HETE) [Figure 2].
Further, any cell activation will generate 15 R-HETE that is transformed by the 5-LO of adhering neutrophils (PMN) to 15-epi-lipoxins. In the absence of aspirin, enzyme such as cytochrome P450 can result in the formation of 15 epi-lipoxins as depicted in [Figure 2].
| Therapeutical Use of Lipoxins|| |
LXs possess a major role in the restoration of tissue homeostasis. However, LXs were discovered to be short-lived as they were rapidly metabolized. To overcome this, stable LX analogs were discovered. The LX receptors which are present on the neutrophils interact with aspirin trigerred lipoxin analogs (ATLa). The role of ATLa was detected in tissue injury in animal models which was mediated by PMN. In a study done by Takano et al., 1997, LTB4 was intravenously induced in mouse ears which resulted in peripheral vasodilatation and leakage of blood from capillaries, initiating stasis of blood in tissues.
In the same study done by Takano et al., 1997, before the injection of LTB4, ATLa was topically applied to one ear and vehicle alone to the other. The ear which was treated with ATLa did not turn blue demonstrating the possible role of ATLa for preventing inflammation.
| Detection of Lipoxins|| |
Due to the LXA4s unique overall three-dimensional conformation, detection of LXs could be done through ELISA. Furthermore, recently, a selective Elisa was developed for ATL.
| Inactivation of Lipoxin|| |
LX inactivation is a metabolic process which is initiated by dehydrogenation of the 15-hydroxyl group, to yield 15-oxo-LXA4. This product formed is biologically inactive which leads to the reduction of the 13,14 double bond of 15-oxo-LXA4 to 13,14-dihydro-15-oxo-LXA4 [Figure 3].
|Figure 3: Lipoxin inactivation is a metabolic process which is initiated by dehydrogenation of the 15-hydroxyl group, to yield 15-oxo-lipoxin A4. This product formed is biologically inactive which leads to the reduction of the 13,14 double bond of 15-oxo-lipoxin A4|
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| Role of Lipoxins in the Management of Periodontal Diseases|| |
Serhan et al. in 2002 raised a hypothesis that management of periodontitis with LXs and their analogs could result in deterrence of periodontal disease. An experimental study was done by Serhan et al. where they used rabbit models. In this study, P. gingivalis was inoculated on the rabbit teeth that were ligatured three times a week. When these animals were evaluated after 6 weeks, 50% bone loss was noticed in the ligatured teeth. The study demonstrates the infectious nature of the lesion because when the rabbit teeth were ligatured without the inoculation of P. gingivalis or when the rabbit teeth were treated with metronidazole it did not result in bone loss.
In a similar design experiment, animals were allocated into two groups, and both the groups were ligatured and were inoculated with P. gingivalis. One group received LX (6microgram in 6microL) three times a week applied topically and the other group received ethanol alone. At 6 weeks, animals were sacrificed and jaws were harvested for analysis of bone loss which was done using an X-ray. Statistically significant reduction in all disease parameters including bone loss was noticed in the group which was treated with LX. Van Dyke and Serhan concluded that application of LX in the management of periodontitis could inhibit more than 90% of bone loss.
| Conclusion|| |
According to the recent research, LXs, which belong to the class of eicosanoids, are considered to be the molecules that are responsible for resolving the inflammation. Cell-to-cell interactions lead to the production of LXs and they also serve as anti-inflammatory mediators.
LXs possess an ability to halt the signals that are involved in resolution of inflammation. Thus, they are considered as important molecules in a variety of disease processes. Furthermore, it has been established that resolution of inflammation in periodontitis through LX-mediated pathways offers better results for prevention of periodontal lesions. Hence, future studies should focus on utilizing these molecules in prevention and treatment of the periodontal diseases in humans.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]