Volume No:

8, Issue No: 1

ISSN No: 2582-0559

LIPOXINS – THE CRUCIAL FACTOR FOR RESOLUTION OF

INFLAMMATION

Dr. Jaishree Tukaram Kshirsagar, Dr. NarmathaDevi. N, Dr. Sangeetha S, Dr. Priyangha. P. T

Department of Periodontics, Tamilnadu Government Dental College and Hospital, Chennai 600003, Tamilnadu, India

Address for Correspondence

Dr. N. NarmathaDevi, Post Graduate Student,

Department of Periodontics,

Tamilnadu Government Dental College and Hospital,

Chennai 600003, Tamilnadu, India

Email id: narmathanatarajan1292@gmail.com

Received:

09.02.2021 First Published

13.03.2021

Accepted:

10.03.2021

Published:

27.03.2021

ABSTRACT

  Eliminating  offending  pathogens  from  the  site  of
infection is an effective host defense mechanism resulting
in subsequent resolution of inflammation restoring tissue
homeostasis.  Lipoxins  are  endogenous  proresolving
mediators which also have anti-inflammatory properties.
Lipoxins  play  a  crucial  role  in  suppressing  exaggerated
tissue  injury  and  chronic  inflammation.  Several  studies
demonstrated  that  synthesized  lipoxin  anolog  has  the
ability to inhibit neutrophil recruitment and alter vascular
permeability. This review explains lipoxins generation, its
actions at the site of inflammation, its role in periodontal
disease and how it could be used as a potential drug.

KEY

WORDS:

Lipoxins,

Defense

mechanism,

Inflammation, Resolution, Endogenous, Periodontal
Disease

REVIEW ARTICLE

DOI:1.37841/jidam_2021_V8_I1_06

Jaishree et al: Lipoxins for Resolution of Inflammation

Volume No:

8, Issue No: 1

ISSN No: 2582-0559

INTRODUCTION

Acute inflammation is a physiological innate immune
response and its primary role is protective to host which is
aimed to remove pathological noxious stimuli and to
restore homeostasis

. The process of inflammation is often

initiated by neutrophils in response to microbial challenge.

  The  fate  of  inflammation  is  determined  by  balance
between  the  proinflammatory  mediators  and  anti-
inflammatory  mediators  which  neither  amplifies  the
inflammation  nor  controls  the  inflammation.  Thus,
resolution is the ideal outcome of acute inflammation but
its  perpetuation  leads  to  pathology.  Resolution  of
inflammation  is  a  highly  ordered  process  regulated  by
numerous lipid mediators which are derived from essential
fatty acids. These lipid mediators or resolution agonists are
collectively  called  as  specialised  lipid  mediators  or
immunoresolvents. Lipoxin is one of these specialised lipid
mediators which is an acronym of lipoxygenase interaction
products, first discovered class of immunoresolvents and is
followed  by  lipoxin  epimers  called  Aspirin  triggered
lipoxins.  Evidence  states  that  resolution  is  mediated  by
mediators  like  Arachidonic  acid  derived  lipoxins,  aspirin
triggered  Lipoxins,  Resolvins  E  and  Dseries,  Maresins,
Protectins.

LIPOXINS

Lipoxins are the naturally occurring proresolving

molecules  produced  from  endogenous  fatty  acids  by  the
action  of  lipoxygenase  enzyme.  It  has  potent  anti-
inflammatory and resolution properties. Lipoxins also acts
as  inhibitors  of  neutrophils  recruitment  and  stimulated
macrophage recruitment.

HISTORY

Lipoxins were first described by Serhan, Hamberg,
Nobel lacerate Samuelson in 1984

1,2,3

. These are initially

reported in human blood neutrophils and when stimulated
produces two lipoxins namely LXA4, LXB4. Later several
studies have identified epimers of these two lipoxins, they
are epilipoxins – 15epi-LXA4 and 15epi-LXB4.

BIOCHEMISTRY

Lipoxins  are  arachidonic  acid  derived  metabolites
which  contains  3  hydroxyl  residues  and  4  double  bonds
and  contains  a  trihydroxy  tetraene  group.  This  structural
definition  is  distinguishing  character  from  the  other
specialised  lipid  mediators  such  as  resolvins  and
Maresins

SYNTHESIS

Lipoxins are produced in the vessel lumen primarily
through platelet and leukocyte transcellular biosynthesis

Lipoxin are produced via several different pathways, by
cell to cell interaction.

These cell to cell interactions may

also  stimulate  transcellular  biosynthetic  pathways  and
subsequent  amplification  signals  like  leukotrienes  and
prostaglandins  or  breaking  signals  involving  novel
compounds

. Generation of lipoxins is a rapid process

which is activated by inflammation, thrombosis and
atherosclerosis (levy et al).

I5-Lipoxygenase – initiated pathway

Insertion of oxygen molecule into 15-carbon

position (C15) of arachidonic acid is the essential step for
lipoxin  generation  and  this  pathway  requires  the  enzyme
15 lipoxygenase. Once the C15 position gets oxygenated;
Arachidonic  acid  is  converted  into  15-hydroperoxy
eicosatetraenoic acid (15-HPETE), which is a substrate for
5-lipoxygenase  present  in  the  leukocytes.  This  was
demonstrated  by  Serhan  et  al  1984,  Ford  Hut  Chinsro
1991

This HPETE molecule is quickly converted into 15s

epoxytetraene by hydrolases. This forms the major route
for Lipoxin generation.

5 Lipoxygenase-Initiated Pathway

The second route of lipoxin synthesis occurs by the

interaction of neutrophils and platelets in the blood vessels.
This cell to cell interaction involves 5-LO in neutrophils
and 12-LO in platelets for the insertion of oxygen
molecules into Arachidonic acid.

Additional pathways for Lipoxin synthesis:

Neutrophils synthesized LIA4 that is converted in

epithelial cells by 15LO, especially in tracheal epithelial
cells can also produce lipoxins by LIA4 dependant
mechanism.

Another

route

often

involves

5,6

dihydroxyeicosane which are the substrates for the

Jaishree et al: Lipoxins for Resolution of Inflammation

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ISSN No: 2582-0559

conversion of lipoxin which include both 15-LO and 12-
LO enhanced by cell to cell adhesion interactions

Aspirin triggered lipoxins:

In transcellular biosynthesis with the presence of

aspirin, COX- switches its catalytic activity and generates
15R-HETE  instead  of  prostaglandins.  Thereby  Aspirin
inhibits prostaglandin synthesis by both COX-1and COX-
2 pathways. When COX- acetylated by aspirin in epithelial
or  endothelial  cells,  arachidonic  acid  converts  into  15R-
HETE,  which  is  transformed  via  transcellular  routes  to
produce  15-epilipoxins  by  leukocytes.  The  activated  and
adherent  leukocytes  releases  its  5-LO  and  converts  15R
HETE  into  5-epoxytetraene  within  leukocytes.  This
conversion results in generation of 15-epi-LXA4 and 15-
epi-LXB4. 15epi-LXA4 is highly potent than native LXA4
in  inhibiting  the  adhesion  of  neutrophils.  This  ATL  can
serve as a potent endogenous anti-inflammatory signals or
mediators of some aspirin related beneficial actions like MI
prevention.

LIPOXINS AT THE SITE OF INFLAMMATION

Neutrophils play a critical role in the acute immune

response  against  microbial  challenge.  Recruitment  of
neutrophils  to  the  inflammation  site  and  subsequent
clearance helps to resolve inflammation. Lipoxins help in
neutrophil migration to the inflammation site by increasing
levels of cytosolic calcium which helps the neutrophils to
put  out  their  pseudopods  and  initiates  the  migration  of
neutrophils. Lipoxins also help in neutrophil clearance at
the  site  of  infection  there  by  resolving  the  inflammation.

Myeloperoxidase  rescues  the  PMNs  from  constitutive
apoptosis thereby prolongs the lifespan of PMNs through
adhesion  molecule  cluster  differentiation  CD11b/CD18.
Lipoxins  reduce  IL-8  and  nitrous  oxide  which  helps  in
prevention of tissue injury and attenuates the accumulation
of nuclear factor activator protein-1 in the nucleus which
further  reduces  IL-8  production  thereby  reduces
neutrophils accumulation & activation

Lipoxins often promotes resolution of inflammation

by delaying the apoptosis of macrophages  and stimulates
rapid  activation  of  P13K/Akt  &  ECK/Nrf2  pathways
which has a relevant role in macrophage apoptosis.

LIPOXINS AND DISEASE:

The lipoxins in clinical inflammation was initially

demonstrated by  Lee et al 1990 in bronchial lavage. The
LXA4 and LXB4 have been formed in nasal polyps.  The
LXA4 is  found in the  nasal lavage obtained from aspirin
sensitive asthmatics. Lipoxins serves as a useful biomarker
of  asthma  and  for  long  term  clinical  improvement  in
arthritis  patients.  During  chronic  myeloblastic  leukemia,
platelets  lose  1-lipoxygenase  and  lose  their  ability  to
produce  lipoxins  which  may  be  related  to  blast  crisis
(Stenke  et  al).  A  reduction  and  alteration  in  lipoxin
synthesis  has  been  found  in  chronic  liver  disease  &  in
chronic myelogenous leukemia.

LIPOXINS IN PERIODONTAL DISEASE

Inducible cycloxygenase isoform involvement and

the  novel  role  of  lipid  mediators  are  studied  and  data
derived from these studies have showed that COX-2 may
have  multiple  role  in  development  and  progression  of
periodontal  diseases  which  has  been  demonstrated  by
Pouliol  et  al  2000.  Samples  from  crevicular  fluid  of
localised  aggressive  periodontitis  patients  exhibits
prostaglandins  E

, 5LO derived products, LTB4 and

biosynthesis products like LXA4. The neutrophils have
found to generate significant arachidonic acid metabolite.
These findings suggest that neutrophils influences the
pathogenesis of periodontal disease in several ways

10.

The role of lipid mediators in the neutrophils

response  to  P.gingivalis  was  studied  in  animal  model.
When  P.gingivalis  was  injected  into  murine  dorsal  air
pouches  1-  leukocytes  was  stimulated,  2-  levels  of  PGE

increased. In addition upregulation of COX-2 mRNA
expression was also demonstrated

Metabolically stable lipoxin analogs administration

potentially blocked the neutrophils trafficking into dorsal
pouch cavity and also reduced PGE

levels within the

exudates without allowing the spread of infections. These

Jaishree et al: Lipoxins for Resolution of Inflammation

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results suggest that neutrophils may provide an important
source of PGE

in periodontal tissues

. Moreover these

data also provide strong evidence that lipoxins may have a
protective  role  in  periodontitis  by  limiting  further
recruitment  of  neutrophils,  neutrophils  mediated  injuries
and subsequent reduction of inflammatory responses that
prevent  tissue  invasion  by  periodontal  pathogens.  It  has
been proposed that lipoxin generation and its relationship
to  PGE

and LTX

can be a significant marker in

periodontal disease and also suggest that activated
neutrophils from localised aggressive periodontitis patients
produced it

LIPOXINS AS A POTENTIAL DRUG

Several studies have demonstrated that lipoxins and

synthetic analogues protects tissues from acute and chronic
inflammation and the mechanism include downregulation
of  pro-inflammatory  cytokines  and  chemokines  (  e.g.,
interleukin- 1β and tumor necrosis factor- α), inhibition of
activation  of  the  master  proinflammatory  pathway(e.g
nuclear factor κ-light chain – enhancer of activated B cell
pathway)  and  increased  release  of  the  pro-resolving
cytokines (e.g., interleukin – 10). Three generations of LXs
analogues  are  well  described  in  the  literature,  and  more
recently fourth generation has been generated that appears
to show enhanced potency. In this review, we will briefly
discuss  the  potential  therapeutic  opportunity  provided  by
lipoxin  A

as a novel approach to treat chronic

inflammatory disorders

Lipoxin stable analogs were analysed for their

clinical  inhibition  of  inflammation  and  are  produced  by
means of recombinant dehydrogenous screen assay which
is  an  inexpensive  and  rapidly  to  design.  These  analogs
synthesized  were  tested  for  their  ability  to  inhibit  the
neutrophil  recruitment  and  alteration  in  vascular
permeability in several murine models.

An experimental study was done by Serhan et al

where they used rabbit models, 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

Lipoxin and ATL are the first recognized members

of a new class of endogenous mediators which has anti-
inflammatory properties and serves for the preresolution of
inflammation. PGE

may appear to have antiinflammatory

properties  in  certain  conditions.  But  in  most  cases  it
enhances  inflammation  in-vivo.  This  is  may  be  due  to
presence  of  numerous  receptor  isoforms  and  differential
coupled  mechanisms  of  PGE

and its diversity in human

physiology. Because the integrated response of the host is
necessary to health and disease, it is essential to achieve a
more complete understanding of the molecular and cellular
events, their formation, the actions of endogenous
mediators of inflammation to control the intensity and
duration of inflammation.

FINANCIAL SUPPORT AND SPONSORSHIP

Nil

CONFLICTS OF INTEREST

There are no conflicts of interest.

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