Printer Friendly

Anti-inflammatory mediators.


Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original result. Inflammation accomplishes its protective mission by diluting, destroying, or otherwise neutralizing harmful agents (e.g., microbes or toxins). It then sets into motion the events that eventually heal and reconstitute the sites of injury. Thus, inflammation is also intimately interwoven with repair processes. Vascular changes are important for the induction of the response and are characterized by redness, heat, and swelling, usually accompanied by pain and loss of function collectively represents the "cardinal signs" of inflammation. These signs of inflammation are the result of vasodilatation and increased vascular permeability, leading to exudation of fluid and plasma proteins and recruitment of leukocytes to the site of injury. (2)

Endogenous lipid-derived mediators have been demonstrated to moderate the host response and coordinate the resolution of inflammation. Recently, several lipid mediators have been described as potential anti-inflammatory molecules, illustrating the importance of endogenous generation of lipid mediators which have anti-inflammatory properties. An important example of lipid mediators with inflammation-resolving properties is the lipoxins (LX). Lipoxins contain a trihydroxytetraene group and are members of the eicosanoid family that are produced within the vascular lumen, primarily via platelet- leukocyte transcellular biosynthesis. Lipoxins can be generated by several different pathways. Normally cell-cell interactions result in the generation of lipoxins.

Bioactions of Lipoxins

1) Vasoactive actions

Lipoxins display vasodilatory and counterregulatory roles in vivo and in vitro models. (3) [LXA.sub.4] and [LXB.sub.4] promote vasorelaxation and relax the aorta and pulmonary arteries. [LXA.sub.4] reverses the precontraction of the pulmonary artery induced by prostaglandin [E.sub.2] and endothelin-1. The mechanisms of [LXA.sub.4]- and [LXB.sub.4]-induced vasodilatation involve endothelium--dependent vasorelaxation and involve prostaglandin-dependent and -independent pathways. (4)

2) Immunomodulatory actions

The actions of lipoxins contrast with those of most other lipid mediator proinflammators such as platelet-activating factor (PAF), Leukotrienes and prostanoids. Lipoxin A ([LXA.sub.4]) gives potent counterregulatory signals in vitro and in vivo for endogenous proinflammatory mediators like Leukotrienes, PAF and TNF-a, IL-6, thus inhibiting leukocyte-dependent inflammation. Lipoxins display selective actions on leukocytes inhibition of neutrophil chemotaxis. Recent studies have documented that lipoxins actions are closely linked with cytokine networks. Unlike PMN and eosinophils, lipoxins are potent stimuli for peripheral blood monocytes. While [LXA.sub.4] and [LXB.sub.4] stimulate monocyte chemotaxis and adherence, these cells do not degranulate or release reactive oxygen species in response to lipoxins, suggesting that the actions of these lipoxins are specific for locomotion and may be related to the recruitment of monocytes to sites of injury. Based on in vivo and in vitro studies, we can now associate Immunomodulatory and vasoactive protective roles with LXA4. For instance, in vivo Aspirin triggered lipoxin analogue (ATLa) inhibits PMN-trafficking in response to direct pro-inflammatory stimuli, as well as in second organ damage associated with ischemia-reperfusion injury (Qui et al. 2000). (5) It is increasingly appreciated that the resolution of inflammation is a dynamically regulated process and these different observations raise the possibility that lipoxins play pivotal roles in the resolution phase of PMN-mediated inflammation.

3) Anti-inflammatory signaling

Lipoxin actions are cell type, species and organ specific. These actions can be assigned to one or a combination of three mechanisms:

a) [LXA.sub.4] interacts with a subclass of the peptido-leukotriene ([LTC.sub.4] and [LTD.sub.4]) receptor that also binds [LXA.sub.4]. (4)

b) Lipoxins act at their own specific cell surface receptors ([LXA.sub.4] specific and separate [LXB.sub.4] receptor). (6)

c) Lipoxins can act on intracellular targets after lipoxin transport and uptake or within their cells of origin. (7) Many molecules play a counter regulatory role in this resolution stage of inflammatory response to control the magnitude and duration of the inflammatory response.

In several tissues and cell types other than leukocytes, results of pharmacological experiments have indicated that [LXA.sub.4] can also interact with a subclass of peptido-leukotriene receptors ([cysLT.sub.1]) as a partial agonist mediating their actions. The role of platelets in lipoxin generation during platelet-neutrophil interaction within the blood vessels might be an important factor in regulating the extravasation of neutrophils (Lehr et al., 1994). (8) In neutrophils lipoxins do not promote a sustained mobilization of intracellular [Ca.sub.2]+, acidification of the intracellular milieu or generation of cAMP. But, [LXA.sub.4] binding to its receptor triggers the activation of GTPase, phospholipase [A.sub.2] and phospholipase D, responses that are inhibited by pretreatment of the cells with peruses toxin. (9)

Lipoxin A4 (LX A4) actions

LX A4 is generated mainly by transcellular biosynthesis during cell to cell interactions. (1) The development of stable synthetic LXA4 and aspirin triggered lipoxin (ATL) mimetics has greatly facilitated studies on LXA4 functions and targets (Serhan 1994). (3) Since these compounds are less susceptible to metabolic inactivation and appear to be functionally equivalent to LXA4, they have proven be affective in the identification of novel mechanisms which lead to the resolution of an inflammation.


Neutrophils are within the first line of host defense, and, by their ability to phagocytose microbes; they can protect the host from infection. The function of neutrophils (PMNs) is pivotal to the outcome of an acute inflammatory response. These cells respond and generate many lipid and protein mediators that exert pro-inflammatory and anti-inflammatory effects. They can also give rise to neutrophil-dependent vascular injury and contribute to increased vascular permeability, edema, and further release of chemoattractants, with a net pro-inflammatory effect. The working hypothesis is that cyclooxygenase isoform (COX-2) could have multiple role(s) in the development and progression of the periodontal disease. Major advances have been made in understanding signaling by arachidonic acid-derived lipid mediators. Eicosanoids are generated in small amounts (nano- to micro-molar quantities) and are rapidly inactivated. Even though these autocoids are short-lived, they are potent stimulators of bioactivity

The role of lipid mediators in the neutrophil response to Porphyromonas gingivalis was also characterized in an animal model. When P. gingivalis was introduced into murine dorsal air pouches, the leukocyte infiltration was initiated. Elevated [PGE.sub.2] levels in the cellular exudate and up-regulated COX-2 expression in the leukocyte infiltrate accompanied neutrophil accumulation. In addition, human neutrophils exposed to P. gingivalis also demonstrated up-regulation of COX-2 mRNA expression. (10) Metabolically stable analogues of lipoxin provide strong support for the notion that lipoxin can have a protective role in periodontitis, limiting further neutrophil recruitment and neutrophil-mediated tissue injury that can lead to loss of inflammatory barriers that prevent tissue invasion from oral microbial pathogens. Lipoxin generation and its relationship to [PGE.sub.2] and [LTB.sub.4] can be important markers for the pathogenesis of periodontal disease.


Lipoxins and Aspirin triggered lipoxins (ATL) appear to be the first recognized members of a new class of endogenous mediator that are anti-inflammatory or serve for the "pro-resolution" of inflammation. Since the integrated response of the host is essential to health and disease, it is important to achieve a more complete understanding of the molecular and cellular events governing the formation and actions of endogenous mediators of resolution that appear to control the magnitude and duration of inflammation. However, additional studies are needed to elucidate the role of lipoxins in the pathogenesis of periodontitis.


(1.) Ryan A, Godson C. Lipoxins regulators of resolution. Curr opin pharmacol 2010;10(2):166-172

(2.) Larsen GL, Henson PM. Mediators of inflammation. Annu Rev Immunol 1983; 1:335-359.

(3.) Serhan CN. Lipoxin biosynthesis and its impact in inflammatory and vascular events. Biochimica et Biophysica Acta 1994; 1212: 1-25.

(4.) Dahlen S-E & Serhan CN (1991). Lipoxins: bioactive lipoxygenases interaction products. In: Wong A & Crooke ST (Editors), Lipoxygenases and their Products, Academic Press, pg 235-276.

(5.) Qiu F-H, Wada K, Stahl GL, Serhan CN. IMP and AMP deaminase in reperfusion injury down-regulates neutrophil recruitment. Proc Natl Acad Sci USA2000; 97: 4267-4272.

(6.) Fiore S, Ryeom SW, Weller PF & Serhan CN. Lipoxin recognition sites. Specific binding of labeled lipoxin [A.sub.4] with human neutrophils. J Biol Chem 1992; 267: 16168-16176.

(7.) Simchowitz L, Fiore S & Serhan CN. Carrier-mediated transport of lipoxin A4 in human neutrophils. Am J Physiol Cell Physiol 1994; 267: C1525-C1534.

(8.) Lehr HA, Olofsson AM, Carew TE, Vajkoczy P, von Andrian UH, Hubner C et al. P-selectin mediates the interaction of circulating leukocytes with platelets and microvascular endothelium in response to oxidized lipoprotein in vivo. Lab Invest 1994; 71:380-386.

(9.) Kantarci A, Van Dyke TE Lipoxins in chronic inflammation. Crit rev oral biol med 2003: 14:4-12

(10.) Pouliot M, Clish CB, Petasis NA, Van Dyke TE, Serhan CN. Lipoxin A(4) analogues inhibit leukocyte recruitment to Porphyromonas gingivalis: a role for cyclooxygenase-2 and lipoxins in periodontal disease. Biochemistry 2000; 39(16):4761-4768.

Madhukar Neerudu [1], Rajababu [2], Harinath Reddy [3], Pradeep Koppolu [4]

Department of Periodontics Kamineni Institute of Dental Sciences, Narketpally, Andhra Pradesh.

Professor and HOD [2]

Professor [1&3]

PG student [4]

Article Info

Received: February 20, 2010

Review Completed: March 15, 2010

Accepted: March 25, 2010

Available Online: August, 2010

Email for correspondence:
COPYRIGHT 2010 National Academy of Dentistry
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2010 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Neerudu, Madhukar; Rajababu; Reddy, Harinath; Koppolu, Pradeep
Publication:Indian Journal of Dental Advancements
Article Type:Report
Date:Apr 1, 2010
Previous Article:Clinical considerations for cementation of implant retained crowns.
Next Article:Minor periodontal surgical procedures associated with orthodontic treatment.

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters