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The need for Group IIA secretory phospholipase A2 (sPLA2-IIA) inhibitors in inflammatory ocular disease treatment

Michael X Liu

Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Chao LV

Yantaishan Hospital, Yantai, Shandong Province, China 264001

Jennifer S Feng

Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029

Penny A Asbell

Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029

Yi Wei

Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029

DOI: 10.15761/MDR.1000106

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Abstract

The highly cationic nature of sPLA2-IIA allows the enzyme to bind and hydrolyze an anionic phospholipid on the cell membrane, especially when damaged and stressed, causing the release of lysophospholipid and free fatty acid. These products are eventually converted into eicosanoids such as arachidonic acid, leukotrienes, and prostaglandins, leading to inflammation. Recent studies have shown that a high level of sPLA2-IIA is associated with ocular inflammatory diseases, including dry eye disease, chronic blepharitis and allergic conjunctivitis. Therefore, inhibition of sPLA2-IIA may serve as a promising strategy to alleviate ocular inflammation. In this review, we survey the current literature of sPLA2-IIA on inflammatory diseases and aim to provide new insight into the study of sPLA2-IIA inhibition for inflammatory ocular diseases.

What is sPLA2-IIA?

All phospholipase A2 (PLA2) enzymes are capable of hydrolyzing the center (sn-2) ester bond of a natural phospholipid substrate, giving lysophospholipid and free fatty acids, including arachidonic acid [1]. However, due to variable functional and structural features including sequence, molecular weight, disulfide bonding patterns, requirement for Ca2+, as well as catalytic mechanisms (His/Asp, Ser/Asp or Ser/His/Asp hydrolase), evolutionary relationships, and localization [1-8], the superfamily of PLA2 is assigned into at least fifteen separate groups and numerous subgroups [1,2,7-9]. While new groups of PLA2 such as adipose-specific PLA2 (AdPLA2) have been identified, most research has focused on the five main groups: secretory PLA2 (sPLA2), pancreatic or cytosolic PLA2 (cPLA2), Ca2+ independent PLA2 (iPLA2), platelet-activating factor (PAF) acetylhydrolase (PAF-AH), and lysosomal PLA2 [5].

The secretory PLA2 (sPLA2) family, originally purified from patients with rheumatoid arthritis, consists of 10 catalytic active enzymes [5,10,11]. Besides the common characteristics of the PLA2 superfamily mentioned above, members of the sPLA2 family share the unique features of low molecular weight, Ca2+ requirement for catalysis, the presence of a His/Asp dyad and six conserved disulfide bonds [2,8]. High-resolution crystal structure models revealed that two water molecules are bonded to the catalytic histidine and a nearby conserved aspartate is used as a ligand for Ca2+ [12]. Together they help to form a positively charged oxyanion hole that stabilizes the negatively charged sPLA2 enzyme [2-4,12].

Currently, more than 11 sPLA2 isoforms have been identified in mammalian secretions [2,5]. A few sPLA2 isoforms are associated with disease, such as sPLA2-IIB with obesity [13] and sPLA2-III with atherosclerosis and colon cancer [14]. The prototypic member of the group II sPLA2 subfamily, sPLA2-IIa, has been shown to be induced by pro-inflammatory stimuli in a wide variety of cells and tissues of animal species as well as been associated with inflammatory, autoimmune, allergic diseases, such as rheumatoid arthritis, asthma, septic shock, Crohn’s disease, acute respiratory distress syndrome, coronary artery disease, atherosclerosis, sepsis and cancer, earning its nickname “the inflammatory sPLA2” [10,11,15-35].

Pro-inflammatory sPLA2-IIA

The sPLA2-IIA enzyme is best known as a bactericide involved in the degradation of bacterial membrane thus providing a host defense mechanism against microbial infection [36-40]. The enzyme has a high affinity for anionic phospholipids and prefers binding to phosphatidylethanolamine (PE) than phosphatidylcholine (PC), which are found abundantly on bacterial membranes [37]. Due to its highly cationic nature, sPLA2-IIA binds tightly to the anionic phospholipids on Gram-positive bacteria, allowing the enzyme to penetrate the cell wall and hydrolyze membrane phospholipids, causing bacterial death [41].

Under physiological conditions in mammalian membranes, the inner leaflet contains anionic phosphatidylserine (PS) and PE while the exposed outer leaflet contains neutral phospholipids, such as PC, allowing for relatively low levels of sPLA2-IIA enzymatic activity [42-45]. When the phospholipid distribution is perturbed by stress from the oxidation of phospholipids, increased levels of anionic PS and PE are transported to the outer leaflet, which activates sPLA2-IIA leading to indiscriminate hydrolysis of outer leaflet phospholipids and inflammation [46-50].

The activation of its enzymatic function is triggered by environmental stress or diseased conditions, promoting release of arachidonic acid (AA) and the cyclocoxygenase (COX)-mediated production of prostaglandin (PG) (Figure 1) [51-57]. Once AA is released, biosynthesis of a multitude of eicosanoids, including prostaglandins, such as prostaglandin E2 (PGE2), thromboxanes and leukotrienes is initiated through either the external plasma membrane pathway or heparan sulfate proteoglycan (HSPG)-shuttling pathway with the help of cyclooxygenase and lipoxygenase enzymes [52,58-60]. The newly synthesized eicosanoids then bind to specific G-protein coupled receptors, activating multiple signaling transduction pathways that lead to acute or chronic inflammation or even cancers [61-65]. In addition, the lysophospholipids generated by sPLA2-IIA hydrolysis also serve as precursors for lipid mediators, such as platelet activating factor (PAF), which lead to inflammation [66]. Since spontaneous AA release hardly occurs in unstressed human cells, activating sPLA2-IIA is the critical first step of the inflammatory cascade and therefore inhibiting sPLA2-IIA will ultimately prevent the downward formation of additional inflammatory products [67].

Figure 1. sPLA2-IIA activation promotes inflammation. The oxidation of phospholipids produces stress causing anionic phospholipids (phosphatidylserine (PS) and phosphatidylethanolamine (PE)) to be transported to the outer leaflet, activating cationic sPLA2-IIA. Higher sPLA2-IIA activity promotes the hydrolysis of outer leaflet phospholipids into arachidonic acid and lysophospholipids. Through cyclooxygenase and 5-lipoxygenase enzymes, arachidonic acid is converted into prostaglandins, leukotrienes, and other eicosanoids. Lysophospholipids is converted into platelet-activating factors (PAFs). All four products have been linked to inflammation. Many inflammatory treatments target the arachidonic acid pathway and its enzymes, but targeting sPLA2-IIA may offer direct inhibition to the formation of all downstream inflammatory products

sPLA2-IIA in tears and inflammatory ocular diseases

High levels of sPLA2-IIA activity have been found in the progression of non-ocular inflammatory diseases and cancers, such as atherosclerosis [26,27], astrocytoma [28], colorectal cancer [29], lung cancer [30-32], prostate cancer [33], rheumatoid arthritis [34] and acute respiratory distress syndrome (ARDS; [35]) as well as many inflammatory ocular diseases. Since phospholipids serve as surfactants between the aqueous and oil layers of the tear film, higher levels of sPLA2-IIA disrupt the phospholipid layer causing the production of eicosanoids in tears and potentially chronic blepharitis, a condition characterized by the inflammation of the eyelid margins [1,68,69]. In addition, an increase in the number of free fatty acid and sPLA2-IIA have been found on contact lenses of patients with contact lens intolerance, emphasizing sPLA2-IIA’s ability to damage the ocular surface, which leads to discomfort and dryness [70,71].

In allergic conjunctivitis (AC), an eye inflammation caused by an allergic reaction to substances, such as pollen, sPLA2-IIA acts as a chemoattractant for eosinophils, which have been activated by allergens irritating the conjunctiva [72]. Higher levels of sPLA2-IIA create tear film instability, leading to the further progression of allergic conjunctivitis [73, 74]. In patients with dry eye disease (DED) or keratoconjunctivitis sicca, a disease noted by aqueous tear deficiency, high levels of sPLA2-IIA activity and protein concentration stimulate PGE2 production in compromised ocular surface epithelial cells, resulting in the excess production of cytokines in tears and inflammatory cell infiltration [75-78].

Importance of sPLA2-IIA inhibition

The most commonly prescribed drugs for treatment of ocular inflammatory conditions are non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase, thereby suppressing arachidonic acid metabolism and the synthesis of prostaglandins as seen in Figure 1 [79,80]. However, previous studies have shown the possibility of corneal melting and perforation following the use of NSAIDS after ocular surgery in patients with or without systemic diseases, such as rheumatoid arthritis, Sjögren Syndrome, and rosacea [81-83]. Since NSAIDs only inhibit COX-1 and COX-2, having no effect on leukotrienes or PAF [84], inhibiting sPLA2-IIA offers a better solution in blocking the production of additional inflammatory substances.

Figure 1. sPLA2-IIA activation promotes inflammation. The oxidation of phospholipids produces stress causing anionic phospholipids (phosphatidylserine (PS) and phosphatidylethanolamine (PE)) to be transported to the outer leaflet, activating cationic sPLA2-IIA. Higher sPLA2-IIA activity promotes the hydrolysis of outer leaflet phospholipids into arachidonic acid and lysophospholipids. Through cyclooxygenase and 5-lipoxygenase enzymes, arachidonic acid is converted into prostaglandins, leukotrienes, and other eicosanoids. Lysophospholipids is converted into platelet-activating factors (PAFs). All four products have been linked to inflammation. Many inflammatory treatments target the arachidonic acid pathway and its enzymes, but targeting sPLA2-IIA may offer direct inhibition to the formation of all downstream inflammatory products

Furthermore, a natural inhibitor of sPLA2-IIA, ochnaflavone has been shown to strongly inhibit sPLA2-IIA activity by preventing the progression of calcium-tetrachloride (CCl4)-induced PE hydrolysis [85]. Since several ocular inflammatory diseases, such as chronic blepharitis [68] involve the degradation of the tear film, implicated by sPLA2-IIA-initiated PS hydrolysis, inhibiting sPLA2-IIA may be a promising alternative to prevent the formation of inflammatory mediators and the progression of inflammatory ocular diseases.

The search for effective inhibitors with high specificity to sPLA2-IIA

One of the first small-molecule inhibitors specific for human sPLA2-IIA, LY311727, was designed to fit the active site of human non-pancreatic sPLA2 enzyme through tight binding interactions, in contrast to the weak or lack of inhibition of previously used snake venom and pancreatic enzyme derivatives [86-88]. While LY311727 has a high affinity for group II sPLA2 at an enzyme concentration that is 20,000 times less than the phospholipid substrate concentration, studies have found that the inhibitor can also inhibit group V sPLA2 with an IC50 of 36 nanomolar (nM) [79,89], stressing one of the main obstacles in sPLA2-IIA inhibition research, sufficient sPLA2-IIA selectivity.

The most heavily researched sPLA2 inhibitor, Varespladib sodium (also known as LY315920 and S-5920) was optimized to be five to ten-folds less active against sPLA2 group V and 40-fold less active against group IB, with negligible activity against groups IV, VI and cytosolic phospholipases [90-92]. The small-molecule indole-based sPLA2 inhibitor has IC50 as low as 9-14 nM for human sPLA2-IIA [93] and was found to mechanistically inhibit surfactant degradation [94]. Having wide existing pharmacological data, Varespladib has already undertaken phase II and III clinical studies in adults (both orally and intravenously) for a variety of clinical symptoms, such as sepsis, acute coronary syndrome, and sickle cell disease-induced acute chest syndrome (IMPACTS trial, NCT00434473) [9,95-100]. However, the oral pro-drug of Varespladib sodium, Varespladib-methyl (LY333013) has been found to have varying efficacies in the treatment of coronary artery disease (CAD) [96-98] as well as been ineffective in treatment of rheumatoid arthritis, leading researchers to believe that Varespladib has limited efficacy in clinical studies [101].

One reason for this failure may be due to the incomplete inactivation of sPLA2 influenced by an inadequate inhibitor concentration in the trial, which the authors fail to report [102]. In some diseases, Varespladib was found to bind non-specifically to high levels of proteins before reaching the sPLA2 catalytic site for effective inhibition [91,100]. Increasing Varespladib dosage has also been noted as a solution to overcoming incomplete inactivation of sPLA2 [100]. Furthermore, an alternative small molecule sPLA2 inhibitor (PIP-18) was proposed to have a stronger suppressive effect on sPLA2 transcription and translation than Varespladib which offers another solution to the limited efficacy found in Varespladib clinical studies [103,104]. This 18-residue peptide contains two presumed pharmacophores. Each pharmacophore binds to more than one molecule of sPLA2 through the hydrophobic binding pocket near the N-terminal helix of sPLA2, inhibiting more than 70% of sPLA2 secreted and lowering PGE2 production [103-106].

On the other hand, a naturally produced triterpene, Celastrol, has shown multiple inhibitory effects on sPLA2-IIA and other enzymes along the AA pathway including COX-2 and 5-LOX, in an apparent concentration-dependent manner [107]. The inhibitor demonstrates positive pharmacological effects and use as a therapeutic molecule in inflammatory diseases, such as arthritis and cancer [108], suggesting that targeting both sPLA2-IIA and inflammatory mediators may serve as a useful and potentially powerful strategy.

Human integrins αvβ3 and α4β1 on leukocytes have also recently been implicated as two sPLA2-IIA human receptors and targets for chronic inflammatory diseases [109-111]. Using docking simulation, Takada et al. designed a peptide, named compound 21, which was able to inhibit nearly 93% of sPLA2-IIA-integrin αvβ3 interactions in water soluble conditions thus suppressing αvβ3-mediated cell adhesion, migration and inflammation [112]. In addition, other inhibitors with heterocycle-peptide conjugate structures have been identified, such as compound 4, compound 8 and compound 16, which binds to integrins and blocks the ligand function of sPLA2-IIA [110]. This type of inhibitor may provide a different and effective strategy to suppressing sPLA2-IIA-induced inflammation.

sPLA2-IIA inhibitors for symptom relief in ocular inflammatory diseases

There is an increasing body of evidence demonstrating the beneficial use of sPLA2-IIA inhibitors in ocular inflammatory diseases. Oleanolic acid was found to effectively reduce production of sPLA2-IIA and other pro-inflammatory mediators by eosinophils and mast cells in the conjunctiva of allergic mice [74]. Varespladib and a recently studied sPLA2-IIA inhibitor, S-3319, have also shown to decrease symptoms of corneal superficial punctate keratitis (SPK), a disorder noted by the death of small group of cells in DED mice [113]. S-3319 was shown to selectively bind to sPLA2-IIA in vivo in mice with an IC50 as high as 29 nM [114-116] as well as in mouse conjunctiva [77,117]. S-3319 also has a significant inhibitory role on PGE2 production in the conjunctiva of BALB/c mouse models, used for their functional sPLA2-IIA gene [77,118]. Like Varespladib, increasing dosage (0.08μM to 10μM) reduced PGE2 production by 29% [77], indicating that current sPLA2-IIA inhibition may have low potency. All three inhibitors decrease symptoms in conjunctival or corneal epithelia, suggesting their involvement with sPLA2-IIA activity and/or production. However, the current basic research on sPLA2-IIA in ocular inflammatory diseases is limited to only a few inhibitors (Table 1) and future research will need to experiment with inhibitors used in other inflammatory diseases to possibly combat issues of potency and high IC50.

Table 1. List of inhibitors of sPLA2-IIA used in inflammation studies.

Number

Inhibitor

IC50

Used in ocular inflammatory studies

Reference

1

Oleanolic Acid

-

Yes

[74]

2

Ochnaflavone

3.45 μM

No

[85]

3

LY311727

36 nM

No

[79,89]

4

LY315920/LY333013

9 – 14 nM

Yes

[93,113]

5

PIP-18

1.19 μM

No

[103-106]

6

Celastrol

-

No

[107]

7

Compound 4

85 μM

No

[110]

8

Compound 8

20 μM

No

[110]

9

Compound 16

-

No

[110]

10

Compound 21

71 μM

No

[112]

11

S-3319

29 nM

Yes

[114-116]

12

Fucoidan

-

No

[119]

13

KH064

29 nM

No

[120]

14

PX-18

-

No

[121]

15

Ursolic Acid

12 – 18 μM

No

[122]

Concluding remarks

sPLA2-IIA is confirmed to be higher in concentration and activity in ocular inflammatory diseases, such as DED, allergic conjunctivitis, and chronic blepharitis, which demonstrates a need for sPLA2-IIA inhibition in treatment of inflammation on the human ocular surface. However, due to the multiple mechanisms of action of sPLA2-IIA enzymes as well as the limited efficacy of inhibitors in clinical trials, the usefulness of inhibiting sPLA2-IIA has not yet been realized. Basic research in sPLA2-IIA inhibition with tissue culture and the ocular surface of animal models will continue to be effective tools leading to potential effective inhibitors and clinical studies in human diseases. Future research will need to focus on identifying novel or existing sPLA2-IIA inhibitors with higher affinity for sPLA2-IIA, as well as determining the mechanism of sPLA2-IIA in ocular inflammatory diseases. Only then will designing new inhibitors, with methods such as docking simulation, as well as specific humanized and sPLA2-IIA neutralizing antibodies for the study of inhibition be effective. Consideration must also focus on sPLA2-IIA inhibitors with high water solubility to allow for dissolution on the ocular surface with high potency. Identifying effective and selective sPLA2-IIA inhibitors will provide the key to future approaches in the treatment of ocular surface inflammation.

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Editorial Information

Editor-in-Chief

Article Type

Review Article

Publication history

Received date: August 30, 2018
Accepted date: September 21, 2018
Published date: October 05, 2018

Copyright

© 2018 Liu MX. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Citation

Liu MX, Chao LV, Feng JS, Asbell PA, Wei Y (2018) The need for Group IIA secretory phospholipase A2 (sPLA2-IIA) inhibitors in inflammatory ocular disease treatment, Med Dent Res. 1: DOI: 10.15761/MDR.1000106

Corresponding author

Yi Wei

Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Figure 1. sPLA2-IIA activation promotes inflammation. The oxidation of phospholipids produces stress causing anionic phospholipids (phosphatidylserine (PS) and phosphatidylethanolamine (PE)) to be transported to the outer leaflet, activating cationic sPLA2-IIA. Higher sPLA2-IIA activity promotes the hydrolysis of outer leaflet phospholipids into arachidonic acid and lysophospholipids. Through cyclooxygenase and 5-lipoxygenase enzymes, arachidonic acid is converted into prostaglandins, leukotrienes, and other eicosanoids. Lysophospholipids is converted into platelet-activating factors (PAFs). All four products have been linked to inflammation. Many inflammatory treatments target the arachidonic acid pathway and its enzymes, but targeting sPLA2-IIA may offer direct inhibition to the formation of all downstream inflammatory products

Table 1. List of inhibitors of sPLA2-IIA used in inflammation studies.

Number

Inhibitor

IC50

Used in ocular inflammatory studies

Reference

1

Oleanolic Acid

-

Yes

[74]

2

Ochnaflavone

3.45 μM

No

[85]

3

LY311727

36 nM

No

[79,89]

4

LY315920/LY333013

9 – 14 nM

Yes

[93,113]

5

PIP-18

1.19 μM

No

[103-106]

6

Celastrol

-

No

[107]

7

Compound 4

85 μM

No

[110]

8

Compound 8

20 μM

No

[110]

9

Compound 16

-

No

[110]

10

Compound 21

71 μM

No

[112]

11

S-3319

29 nM

Yes

[114-116]

12

Fucoidan

-

No

[119]

13

KH064

29 nM

No

[120]

14

PX-18

-

No

[121]

15

Ursolic Acid

12 – 18 μM

No

[122]