lipoxina a4 nueva terapia asma

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491ISSN 1744-666X © 2013 Expert Reviews Ltd10.1586/ECI.13.36www.expert-reviews.com

Editorial

Asthma continues to be a common andsignicant disease with substantial medi-cal and economic unmet needs despite

current therapies. In view of this medicaland social imperative, the pathobiologyof asthma is an area of active researchin both academic and industrial labora-tories. Perhaps most notably, 5–10% ofindividuals with asthma experience severeasthma that is refractory to current medi-cal treatment [1] . In addition, there areno therapies available to actively resolvethe uncontrolled immune responses inasthma.

Most individuals with asthma haveairway inammation that never com-pletely resolves. The nature and extentof this inammation varies by individualand by disease severity. In most cases,eosinophils and activated T cells accu-mulate in the lung. Th2 lymphocytesand eosinophils are increased in blood,lung tissue and bone marrow in mostasthma clinical phenotypes. Many othercell types are implicated in the patho-biology of asthma and are likely to playprominent roles. Along these lines, manyimportant functional responses have beenassigned to mast cells, neutrophils anddendritic cells, as well as epithelial andmesenchymal cells[2] . These cells releaseinflammatory mediators, includingTh2-associated cytokines, chemokines,growth factors and lipid mediators thatdrive the inammatory process. In someindividuals, changes in the airway epithe-lium, basement membrane and smoothmuscle remodel the airway, potentially

leading to a component of xed airowobstruction.

Innate lymphoid cells (ILCs) comprisea newly described family of hematopoieticeffectors that serve protective roles in:innate immune responses to infectiousmicroorganisms, lymphoid tissue for-mation, tissue remodeling after damageinicted by injury or infection and thehomeostasis of tissue stromal cells[3] .NK cells are prototypical members of theILC family. Potential roles for NK cellsin asthma and allergic disease have beenrecently dened in model systems, sug-gesting that NK cells can participate inthe downregulation of allergic airwayresponses, including clearance of eosino-phils and antigen-specic T cells[4] . Inaddition to NK cells, new ILC popula-tions have been described, including asubset that can produce the Th2 cell-associated cytokines IL-5 and IL-13 in anantigen-independent manner. These cellsare referred to as type 2 ILCs (ILC2s).They are involved in responses to hel-minth infection and murine models ofallergic asthma and can respond to theepithelial-derived cytokines IL-25 (alsoknown as IL-17E), IL-33 and thymicstromal lymphopoitein [5,6] . In addition,human ILC2s express the chemoattractant

Lipoxin A 4: a new direction in asthma

therapy?Expert Rev. Clin. Immunol. 9(6), 491–493 (2013)

“ Cell-specic effects of lipoxin A 4 … suggest that lipoxin A 4 canorchestrate the control of both early and late asthmatic

inammation and airway responses. ”

K EYWORDS : ALX/FPR2 receptors • asthma • innate lymphoid cells • lipoxin • proresolving mediators

• resolution

Cindy BarnigDepartment of ChestDisease, University Hospitalof Strasbourg, 1 Place del’Hôpital, Strasbourg 67091,France

Bruce D Levy Author for cor respondence:Pulmonary and Critical CareMedicine, Brigham & Women’sHospital, Boston, MA 02115,USATel.: +1 617 525 5407Fax: +1 617 525 [email protected]

“

…there are no therapiesavailable to actively resolve theuncontrolled immune responses

in asthma.”



492 Expert Rev. Clin. Immunol. 9(6), (2013)

Editorial

receptor-homologous molecule expressed on Th2 cells CRTH2,also known as prostaglandin D2 receptor 2 [7]. We have recentlyshown that ILCs are present in human lungs in close proxim-ity to mast cells and airway epithelial cells and that ILC2s gen-erate IL-13 in response to the mast cell product prostaglandin

D2, principally through prostaglandin D2 receptor 2 activation,and in a synergistic manner with the airway epithelial cytokinesIL-25 and IL-33 [8] . Given the potency of IL-5 and IL-13 toinitiate asthmatic immune responses in model systems, humanILC2s are likely to play important roles in allergen-independentinammation in asthma.

Natural resolution of inammation is an active host response. While it is driven, in part, by decrements in proinammatorymediators [9], the promotion of resolution is now recognized as anactive process with early signaling pathways engaging biosyntheticcircuits for the later formation of counter-regulatory mediators[10] .Failure of acute inammation to adequately resolve might contrib-

ute to the chronic airway inammation in asthma pathobiology.Several classes of counter-regulatory lipid mediators have beenrecently discovered that are generated from essential fatty acidsduring inammation to promote resolution [10] . Lipoxins (LXs)are the lead members of this new class of proresolving mediators.

The biological activity of the LXs in asthma and allergic diseasehas been dened over the past two decades. Bioactive, LXA 4 stableanalogs have been prepared that in animal models block airwayhyper-responsiveness and allergic inammation, including eosino-phil trafcking and tissue accumulation[11] . In humans, LXA 4 isgenerated during asthmatic responses[12] and, when administeredto asthmatic subjects via nebulization, LXA 4 attenuates leukotrieneC

4-induced bronchoconstriction [13] . In addition, treatment of aller-

gic eczema in infants with topical 15(R/S)-methyl-LXA 4 decreaseseczema severity and duration and improves patients’ quality of life with similar efcacy to topical corticosteroids[14] . More severe vari-ants of asthma, including aspirin-exacerbated respiratory disease,are associated with diminished LX biosynthesis compared withmilder asthma [15–17] , suggesting that the chronic inammatoryresponse in asthma may be due, in part, to defective generation ofproresolving mediators leading to inadequate counter-regulation.

LXs are enzyme-derived products of arachidonic acid metabo-lism. They are rapidly generated via biosynthetic circuits engagedduring cell–cell interactions at sites of inammation, act locallyand then are rapidly inactivated by metabolic enzymes via pathways shared with other eicosanoids. LX A 4 is an agonist for ALX/FPR2 receptors, which are expressed on both human airway epithelial cells and leukocytes and can be induced by specicinammatory mediators [10] . LXs demonstrate cell type-specicactions in vitro, including inhibition of granulocyte activationand locomotion, promotion of monocyte-derived macrophagephagocytosis of apoptotic granulocytes, blockade of T lympho-cyte cytokine release and epithelial proinammatory cytokine

and chemokine release. More recently, we described new cell-specic biological actions of LXA 4 on ILCs that would decreaseinammation in asthma [8]. First, we observed that both NK cellsand ILC2s express the proresolving receptors ALX/FPR2 andCMKLR1 and that NK cells from subjects with severe asthma

have increased ALX/FPR2 expression. When NK cells wereexposed to LXA 4, the cells displayed an increase in NK cell-medi-ated apoptosis of both eosinophils and neutrophils. In addition,LX A 4 prevented prostaglandin D2-stimulated release of IL-13from ILC2s. These properties of LXA 4 are consistent with potentanti-inammatory (ILC2) and proresolving (NK cell) effects onILCs and highlight new putative mechanisms for the pathogen-esis of severe asthma that links earlier observations of defectiveLXA 4 generation in severe asthma to the increased eosinophiliaand chronic airway inammation that characterize the disease.

Cell-specic effects of LXA 4 on eosinophils, macrophages, NKcells and ILC2 suggest that LXA 4 can orchestrate the control ofboth early and late asthmatic inammation and airway responses.These potentially benecial properties of LXs in the airway and inview of defective LX generation in uncontrolled asthma raise thepossibility that LXA 4 or LXA 4 stable analogs could be useful inasthma therapy. Most of the biological asthma therapies currentlyunder development target proinammatory cytokines that areimportant during the onset of the asthmatic inammatory response[2]. Variable responses have been observed among patients, probablybecause of substantial differences among the types of inamma-tion in asthma clinical phenotypes. Developing therapies based onendogenous mediators that are anti-inammatory and proresolv-ing agonists would represent a new and distinct drug developmentstrategy. Although the two published human clinical studies withLXs show intriguing therapeutic promise for asthma and allergicdiseases, more clinical trials of LXA 4 or stable analogs are needed todetermine the potential utility of promoting endogenous resolutionmechanisms in the treatment of asthma patients. The recent devel-opment of new LX stable analogs that are topically and orally activeshould enable further investigation of LX regulation in asthma.

In conclusion, innate immunity can play an important rolein regulating asthmatic inammation and airway responses andILCs, including NK cells and ILC2s, can serve as targets forthe counter-regulatory and proresolving actions of LXA 4, whichdisplays potential as a new therapeutic strategy in asthma.

AcknowledgementsThe work has been funded in part by AI068084 (BD Levy), HL107166(BD Levy), HL109172 (BD Levy) and Fonds de dotation ‘Recherche enSanté Respiratoire’ 2011 (C Barnig).

Financial & competing interests disclosureBD Levy is a co-inventor on patents related to lipoxin A4 and asthmathat have been licensed by the Brigham and Women’s Hospital for clinical

“Most individuals with asthma have airway

inammation that never completely resolves.”

“Natural resolution of inammation is an active

host response.”

Barnig & Levy



493www.expert-reviews.com

Editorial

References1 Busse WW, Lemanske RF Jr. Asthma.

N. Engl. J. Med. 344(5), 350–362 (2001).2 Pelaia G, Vatrella A, Maselli R. The

potential of biologics for the treatmentof asthma. Nat. Rev. Drug Discov. 11(12),958–972 (2012).

3 Spits H, Di Santo JP. The expanding familyof innate lymphoid cells: regulators andeffectors of immunity and tissue remodeling.Nat. Immunol. 12(1), 21–27 (2011).

4 Haworth O, Cernadas M, Levy BD.NK cells are effectors for resolvin E1 in

the timely resolution of allergic airwayinammation. J. Immunol. 186(11),6129–6135 (2011).

5 Halim TY, Krauss RH, Sun AC, Takei F.Lung natural helper cells are a critical sourceof Th2 cell-type cytokines in proteaseallergen-induced airway inammation.Immunity 36(3), 451–463 (2012).

6 Klein Wolterink RG, Kleinjan A,van Nimwegen Met al. Pulmonary innatelymphoid cells are major producers of IL-5 andIL-13 in murine models of allergic asthma.Eur. J. Immunol. 42(5), 1106–1116 (2012).

7 Mjösberg JM, Trifari S, Crellin NKet al. Human IL-25- and IL-33-responsivetype 2 innate lymphoid cells are denedby expression of CRTh2 and CD161. Nat.Immunol. 12(11), 1055–1062 (2011).

8 Barnig C, Cernadas M, Dutile S et al. Lipoxin A 4 regulates natural killer cell andtype 2 innate lymphoid cell activation inasthma. Sci. Transl. Med. 5(174), 174ra26(2013).

9 Henson PM. Dampening inammation.Nat. Immunol. 6(12), 1179–1181 (2005).

10 Serhan CN, Chiang N, Van Dyke TE.Resolving inammation: dual anti-inammatory and pro-resolution lipidmediators. Nat. Rev. Immunol. 8(5),349–361 (2008).

11 Levy BD, De Sanctis GT, Devchand PRet al. Multi-pronged inhibition of airwayhyper-responsiveness and inammationby lipoxin A 4. Nat. Med. 8(9), 1018–1023(2002).

12 Lee TH, Crea AE, Gant Vet al. Identicationof lipoxin A 4 and its relationship to thesuldopeptide leukotrienes C4, D4, and E4 in the bronchoalveolar lavage uids obtainedfrom patients with selected pulmonary

diseases. Am. Rev. Respir. Dis. 141(6),1453–1458 (1990).

13 Christie PE, Spur BW, Lee TH. Theeffects of lipoxin A 4 on airway responsesin asthmatic subjects. Am. Rev. Respir. Dis. 145(6), 1281–1284 (1992).

14 Wu SH, Chen XQ, Liu B, Wu HJ, Dong L.Efcacy and safety of 15(R/S)-methyl-lipoxin A 4 in topical treatment of infantileeczema.Br. J. Dermatol. 168(1), 172–178(2013).

15 Levy BD, Bonnans C, Silverman ES,Palmer LJ, Marigowda G, Israel E; Severe Asthma Research Program, National Heart,Lung, and Blood Institute. Diminishedlipoxin biosynthesis in severe asthma. Am. J. Respir. Crit. Care Med. 172(7), 824–830(2005).

16 Planagumà A, Kazani S, Marigowda Get al. Airway lipoxin A 4 generation and lipoxin A 4 receptor expression are decreased insevere asthma. Am. J. Respir. Crit. Care Med. 178(6), 574–582 (2008).

17 Sanak M, Levy BD, Clish CBet al. Aspirin-tolerant asthmatics generate morelipoxins than aspirin-intolerant asthmatics.Eur. Respir. J. 16(1), 44–49 (2000).

development, and receives a share of licensing income through Brigham andWomen’s Hospital. The authors have no other relevant afliations or nan-cial involvement with any organization or entity with a nancial interest

in or nancial conict with the subject matter or materials discussed in tmanuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscrip

Lipoxin A 4: a new direction in asthma therapy?

lipoxina a4 nueva terapia asma

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