FIGURE 1 - uploaded by Aaron B Sullivan
Content may be subject to copyright.
![PGE 2 formation is a key feature of chronic inflammation and neovascularization. Endogenous lipid autacoids were quantified in uninjured corneas and corneas collected after 2, 4, and 7 days of acute (epithelial abrasion) or chronic (suture) injury (n 4 –7; *P 0.05 vs. uninjured ) from female C57Bl/6J mice by MS/MS-based lipidomic analyses using a triple quadrupole linear ion trap LC/MS/MS system and multiple reaction monitoring (MRM) for specific transition ions. (A) Representative images of epithelial abrasion and suture injury models of ocular inflammation . (B) Representative MRM lipidomic profile of prominent eicosanoids (PGE 2 , thromboxane B 2 [TXB 2 ], 12-HETE, 5-HETE, 15-HETE) in uninjured corneas and corneas collected after 4 days of suture injury. (C) Quantification of endogenous PGE 2 formation in corneas with epithelial abrasion or suture injury.](profile/Aaron-Sullivan-3/publication/45101727/figure/fig1/AS:341773449744384@1458496548244/PGE-2-formation-is-a-key-feature-of-chronic-inflammation-and-neovascularization.png)
PGE 2 formation is a key feature of chronic inflammation and neovascularization. Endogenous lipid autacoids were quantified in uninjured corneas and corneas collected after 2, 4, and 7 days of acute (epithelial abrasion) or chronic (suture) injury (n 4 –7; *P 0.05 vs. uninjured ) from female C57Bl/6J mice by MS/MS-based lipidomic analyses using a triple quadrupole linear ion trap LC/MS/MS system and multiple reaction monitoring (MRM) for specific transition ions. (A) Representative images of epithelial abrasion and suture injury models of ocular inflammation . (B) Representative MRM lipidomic profile of prominent eicosanoids (PGE 2 , thromboxane B 2 [TXB 2 ], 12-HETE, 5-HETE, 15-HETE) in uninjured corneas and corneas collected after 4 days of suture injury. (C) Quantification of endogenous PGE 2 formation in corneas with epithelial abrasion or suture injury.
Source publication
Cyclooxygenase (COX)-derived prostaglandin E(2) (PGE(2)) is a prevalent and established mediator of inflammation and pain in numerous tissues and diseases. Distribution and expression of the four PGE(2) receptors (EP1-EP4) can dictate whether PGE(2) exerts an anti-inflammatory or a proinflammatory and/or a proangiogenic effect. The role and mechani...
Citations
... 6 Conversely, other research indicates that ketorolac does not adversely affect wound healing and may, in fact, contribute to a more favourable postoperative course by controlling inflammation effectively. 7 Given these conflicting reports, a systematic examination and synthesis of available data are necessary to provide clarity on the effects of topical ketorolac on wound healing post-cataract surgery. This meta-analysis aims to consolidate existing research, critically evaluate the evidence, and quantify the impact of topical ketorolac on post-cataract surgery wound healing. ...
This meta‐analysis evaluates the impact of topical ketorolac on surgical site wound healing and scar formation after cataract surgery. A thorough literature search, adhering to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines, identified eight relevant studies from 2348 articles. The selected studies were analysed for wound healing efficacy, using the redness, edema, ecchymosis, discharge and approximation (REEDA) scale, and scar formation, assessed by the Manchester scar scale (MSS). Results indicated that ketorolac significantly improved wound healing, with lower REEDA scores 1 week post‐surgery ( I ² = 97%; Random: standardised mean difference (SMD): −10.93, 95% CI: −13.85 to −8.00, p < 0.01), and reduced scar formation, evidenced by lower MSS scores 3 months post‐surgery ( I ² = 74%; Random: SMD: −9.67, 95% CI: −11.03 to −8.30, p < 0.01). The findings suggest that topical ketorolac is beneficial in post‐cataract surgery care, enhancing wound healing and reducing scarring.
... Prostaglandin E 2 is a metabolite of COX-2. However, in the eye, PGE 2 formation may be attributed to both COX-1 and COX-2 [10]. PGE 2 is one of the most studied PGs. ...
Previous studies have shown that Acanthamoeba spp. may invade the eyes by migrating along the optic nerve to the eyes from the brain. This study aimed to confirm the presence of inflammation in the eyes of mice with disseminated acanthamoebiasis by examining prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) concentrations in the eyes of immunocompetent and immunocompromised mice intranasally inoculated with Acanthamoeba spp. The PGE2 concentration was statistically significantly lower in the immunocompromised amoebae-infected mice on 8 dpi compared with the noninfected group of animals, and it was higher in the eyes of immunosuppressed amoebae-infected mice on 16 dpi than in the control group of animals. There was a statistically significant lower TXB2 concentration in the eyes of immunocompetent infected mice compared with the noninfected group on 8 dpi. However, on 24 dpi, we noted statistically significant higher TXB2 levels in the immunocompetent infected mice than in the control group. In immunocompromised mice, there was a lower TXB2 level on 8 dpi than in control mice. This study confirmed the existence of an inflammatory process in the eyes of immunocompetent and immunocompromised mice infected with Acanthamoeba spp. without damaged corneas.
... Previous studies have reported that inflammation is an important factor in the development of CNV [38], and CNV can aggravate corneal scar formation and reduce vision [39]. CD31 marks the vascular endothelial cells and reflects the level of angiogenesis [40]. ...
Background:
Vitamin C (Vc) has been found to promote corneal wound healing after alkali burns. However, the specific mechanism and functional modes are still unclear. The present study sought to assess the mechanisms of Vc function on corneal alkali burns.
Methods:
Eighty BALB/c mice were divided into four groups: a normal group without alkali injury (n = 10), an alkali injury group without any treatment (1-day group, n = 10), a Vc group treated with topical 10% Vc (Vc group, n = 30), and a control group treated with topical sterile water (control group, n = 30). Except in the blank control group, the alkali injuries were induced in one eye of each mouse. The mice in the treatment group were given Vc by topical application (q 1 h for 6 days), while those in the control group were given topical sterile water. The clinical evaluations, including corneal fluorescent staining, corneal opacity, and neovascularization, were assessed on days 1, 4, 7, and 10 using slit-lamp microscopy. Ten mice at each time point were sacrificed. The protein expressions in the corneas of p63, PCNA, CK3, MPO, CD31, and α-SMA were detected by immunohistochemistry to examine the corneal epithelial stem cells, corneal epithelium wound healing, corneal stroma inflammation, neovascularization, and fibrosis.
Results:
The scores of the corneal epithelium defects, corneal neovascularization, and corneal opacities in the Vc group were significantly decreased compared to the control group on day 10. We found that Vc promoted the activation of the corneal epithelial stem cells as shown by a higher number of p63-positive and PCNA-positive cells and an increased CK3 expression when compared with the control group (p < 0.001). The central corneal re-epithelialization was completed by day 10. Moreover, Vc inhibited MPO, CD31, and α-SMA expressions. These results first indicated that the frequent use of topical Vc in the first 6 days of corneal alkali burns alleviated corneal inflammatory cell infiltration, activated corneal epithelial stem cell activity, and reduced corneal neovascularization and fibrosis within 10 days.
Conclusions:
The study, therefore, showed the therapeutic benefits of Vc on corneal alkali burns and provided new insight into the mechanisms of Vc regulation on corneal wound healing.
... High concentrations of PGF2α can cause uterine smooth muscle contraction, and the consequent reduction of blood flow may cause uterine ischemia and anoxia, which may lead to the accumulation of acidic metabolites, causing dysmenorrhea (28). Also, abnormally high levels of prostaglandins can cause pain by inducing aseptic inflammation, increasing vascular permeability and enhancing the pain effect of pain molecules such as BK (29). BK is considered a mediator of inflammatory pain; its elevated levels after tissue injury and inflammation occur via the activation of two types of GPCRs, termed BKB1R and BKB2R (30). ...
Endometriosis (EM), a benign aseptic inflammatory disease, is associated with the presence of endometrial foci. Pain, one of its typical symptoms, has been reported as a constant stressor, but the etiology and pathogenesis of EM-associated pain are unclear. In the present study, eutopic and ectopic endometrium samples from women with EM (n=50) and normal endometrium samples from control subjects (n=20) were collected. Serum levels of prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α) and bradykinin (BK) were measured using commercial ELISA kits. The expression of the BKB1 receptor (BKB1R) protein was evaluated by immunohistochemical staining and western blot assay. The mRNA expression of BKB1R was measured by reverse transcription-quantitative PCR. The results revealed that there was a substantial increase in the protein and mRNA expression of BKB1R, as well as the release of PGE2, PGF2α and BK in the blood, in the EM group compared with that in the control group. Moreover, PGE2, PGF2α and BK levels were significantly correlated with each other, as well as with the pain intensity of EM. The increased expression levels of BKB1R protein and mRNA were positively correlated with the pain degree of EM. Thus, these data indicated that BK and BKB1R were involved in the pathological onset of EM-associated pain and that they may play an important role in EM-related pain by inducing PGE2 and PGF2α. The data indicate a potential new therapeutic target for EM-related pain.
... The importance of PGE 2 in corneal neovascularization has also been reported. PGE 2 levels were elevated in a corneal suture-injury mouse model; PGE 2 exacerbated corneal neovascularization by promoting chronic inflammatory neovascularization [159]. It is worthy to note that COX2 inhibitors suppressed ocular pathological neovascularization in retina, choroid, and cornea [160][161][162], implicating COX2 is also involved in the pathogenesis of ocular neovascularization as well as PGE 2 . ...
Vasculogenesis and angiogenesis play a crucial role in embryonic development. Pathological neovascularization in ocular tissues can lead to vision-threatening vascular diseases, including proliferative diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, choroidal neovascularization, and corneal neovascularization. Neovascularization involves various cellular processes and signaling pathways and is regulated by angiogenic factors such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF). Modulating these circuits may represent a promising strategy to treat ocular neovascular diseases. Lipid mediators derived from membrane lipids are abundantly present in most tissues and exert a wide range of biological functions by regulating various signaling pathways. In particular, glycerophospholipids, sphingolipids, and polyunsaturated fatty acids exert potent pro-angiogenic or anti-angiogenic effects, according to the findings of numerous preclinical and clinical studies. In this review, we summarize the current knowledge regarding the regulation of ocular neovascularization by lipid mediators and their metabolites. A better understanding of the effects of lipid signaling in neovascularization may provide novel therapeutic strategies to treat ocular neovascular diseases and other human disorders.
... Surprisingly, despite the fact that topical NSAIDS and PGF 2 α analogs are effective and standard treatments for ocular surface diseases such as trauma and glaucoma, little is known about the endogenous formation, cell specific expression of receptors and role of prostanoids in the ocular surface. In vitro studies, human corneal epithelial cells (HCEs) can upregulate many of the enzymes needed to generate a wide variety of lipid mediators including leukotrienes, prostanoids and SPMs [63][64][65]. Following UVB induced oxidative stress, HCEs upregulate or induce mRNA expression of COX-2, prostaglandin and thromboxane synthases (mPGES-2, PGDS, PGFS and TXAS) and lipoxygenases (5-LOX, 15-LOX-2, 12-LOX) [63]. ...
... Following UVB induced oxidative stress, HCEs upregulate or induce mRNA expression of COX-2, prostaglandin and thromboxane synthases (mPGES-2, PGDS, PGFS and TXAS) and lipoxygenases (5-LOX, 15-LOX-2, 12-LOX) [63]. Receptors for AA-derived prostaglandin E 2 (PGE 2 ) are expressed in the cornea (EP1-4) but acute inflammation such as abrasion injury does not lead to robust formation of PGE 2 in the mouse cornea nor does PGE 2 effect corneal wound healing [64]. The corneal PGE 2 circuit appears to be activated selectively during chronic inflammation where it promotes corneal neovascularization [64]. ...
... Receptors for AA-derived prostaglandin E 2 (PGE 2 ) are expressed in the cornea (EP1-4) but acute inflammation such as abrasion injury does not lead to robust formation of PGE 2 in the mouse cornea nor does PGE 2 effect corneal wound healing [64]. The corneal PGE 2 circuit appears to be activated selectively during chronic inflammation where it promotes corneal neovascularization [64]. It is of interest that BLT2 a receptor for the COX pathway metabolite 12-HHT is expressed in corneal epithelial cells and the conjunctiva [65]. ...
In the last twenty years an impressive body of evidence in diverse inflammatory animal disease models and human tissues, has established polyunsaturated fatty acids (PUFA) derived specialized-pro-resolving mediators (SPM), as essential mediators for controlling acute inflammation, immune responses and wound healing and for resolving acute inflammation in many non-ocular tissues. SPM pathways and receptors are highly expressed in the ocular surface where they regulate wound healing, nerve regeneration, innate immunity and sex-specific regulation of auto-immune responses. Recent evidence indicates that in the eye these resident SPM networks are important for maintaining ocular surface health and immune homeostasis. Here, we will review and discuss evidence for SPMs and other PUFA-derived mediators as important endogenous regulators and biomarkers of ocular surface health and disease and their therapeutic potential.
... Effect of MGS on LPS-induced production of proinflammatory mediators. The biosynthesis of PGE 2 , which is tightly regulated by COX-2, is significantly increased in inflamed tissue, contributing to the development of the cardinal signs of acute inflammation (23). Therefore, the inhibitory effects of MGS on the mRNA and protein expression of COX-2 were investigated. ...
Guettarda speciosa Linn. (G. speciosa, Rubiaceae) has been used as a traditional medicinal plant in Asia for the treatment of various inflammatory conditions, including cough, fever and maternal postpartum infection. However, the mechanisms underlying the anti‑inflammatory action of G. speciosa extracts have remained elusive. In the present study, the anti‑inflammatory effects of the methanol extract of G. speciosa (MGS) were investigated in murine macrophages by measuring the production of inflammatory mediators and the underlying mechanisms of action by performing immunoblotting analysis of proteins that are potentially involved. MGS reduced nitric oxide (NO) production through regulation of the expression of inducible NO synthase (iNOS) in lipopolysaccharide‑activated RAW 264.7 cells; however, cyclooxygenase‑2, the enzyme responsible for prostaglandin E2 production, was not affected at the mRNA or protein level. MGS reduced interleukin‑6 (IL‑6) production, but had no effect on tumor necrosis factor (TNF)‑α production. In addition, MGS suppressed the transcription of IL‑6, but not that of IL‑1β and TNF‑α. The effect of MGS on proinflammatory mediators resulted from the inhibition of the activation of spleen tyrosine kinase and c‑Jun N‑terminal kinase. In conclusion, the present study suggested that MGS may be a potential candidate for development as a therapeutic for alleviating inflammation.
... ciated with pathological angiogenic processes [9][10][11][12] . CCR3 has been related to injury-induced corneal angiogenesis [9,10] and to laser-induced choroidal neovascularization in a mouse experimental model [11][12][13] . ...
... ciated with pathological angiogenic processes [9][10][11][12] . CCR3 has been related to injury-induced corneal angiogenesis [9,10] and to laser-induced choroidal neovascularization in a mouse experimental model [11][12][13] . To our knowledge, there is no previous report of an association between CCR3 and retinal neovascularization. ...
... In this study, we found that CCR3-eotaxin pathways are involved in retinal angiogenesis, and we demonstrated that intravitreous anti-CCR3 Ab treatment could reduce retinal neovascularization. Although the CCR3-eotaxin pathway has been shown to be involved in ocular pathological angiogenesis in choroidal neovascularization (CNV) [11][12][13][22][23][24] and in corneal angiogenesis [9,10] , to our knowledge, this is the first report to dem- onstrate a role for CCR3-eotaxin pathways in retinal neovascularization. Historically, the CCR3-eotaxin pathway has been known to contribute to eosinophil migration in allergic reactions [25] . ...
Purpose:
To investigate the association between retinal neovascularization and the CC chemokine receptor-3 (CCR3) in a mouse model of oxygen-induced retinopathy (OIR).
Methods:
An OIR model in C57BL/6J mice was used as a retinal neovascularization model. An enzyme-linked immunosorbent assay was performed to evaluate the chronological change in vascular endothelial growth factor A (VEGF-A) and eotaxin expressions. CCR3 and VEGF subtype expression in the retina was examined using real-time RT-PCR, and CCR3, eotaxin, VEGF-A, and CD31 expression was examined immunohistochemically. A CCR3 neutralizing antibody (Ab) was injected into the vitreous humor on both postnatal days 12 (P12) and 14 (P14). Retinal neovascularizations were quantified by measurement of the percentages of neovascular area.
Results:
The mean eotaxin and VEGF-A protein level was significantly downregulated at P10 and P12 and was significantly upregulated at P14 and P17 (p < 0.05). CCR3 mRNA expression was significantly upregulated at P12 (p < 0.05). VEGF164 mRNA expression was significantly upregulated at P14 (p < 0.05). The areas of vaso-obliteration and neovascularization were significantly suppressed in anti-CCR3 Ab-treated eyes (p < 0.05). Anti-CCR3 Ab treatment suppressed VEGF and eotaxin but not monocyte chemoattractant protein-1. And VEGF 164 mRNA but not VEGF120 mRNA was suppressed by anti-CCR3 Ab treatment.
Conclusions:
The present data suggest that anti-CCR3 treatment can suppress retinal neovascularization. Anti-CCR3 treatment may have potential as a new therapy for retinopathies with retinal neovascularization such as diabetic retinopathy and retinopathy of prematurity.
... 25,26 The ocular surface highly expresses lipoxygenase (LOX) and cyclooxygenase (COX) enzymes that metabolize PUFAs into lipid mediators, which regulate inflammatory, immune, and wound-healing responses. 17,23,[27][28][29][30][31] Experimental evidence from cell culture and animal models of DE suggests that DHA-derived neuroprotectin D 1 (NPD 1 ), resolvin D 1 (RvD 1 ), and EPA-derived resolvin E 1 (RvE 1 ) are proresolving lipid mediators that are particularly relevant in maintaining ocular surface health and tear film function. 14,15,17,18,32 Here, for the first time, we evaluate whether x-3 and x-6 lipid profiles can be detected in human tears and whether these measures correlate with DE disease severity in human subjects. ...
... Tandem MS/MS analyses were performed in negative ion mode, and prominent fatty acid metabolites were quantified in multiple reaction monitoring mode using established and specific transitions as previously described. 30,31,[38][39][40][41] Calibration curves (1-1000 pg) and specific LC retention times for each compound were established with synthetic standards (Cayman Chemical, Ann Arbor, MI, USA). Structures were confirmed for selected autacoids by MS/MS analyses using enhanced product ion mode with appropriate selection of the parent ion in quadrupole 1. ...
Purpose:
ω-3 and ω-6 polyunsaturated fatty acids modulate inflammatory processes throughout the body through distinct classes of lipid mediators that possess both proinflammatory and proresolving properties. The purpose of this cross-sectional study was to explore the relationship between lipid profiles in human tears and dry eye (DE) symptoms and signs.
Methods:
Forty-one patients with normal eyelid and corneal anatomy were prospectively recruited from a Veterans Administration Hospital over 18 months. Symptoms and signs of DE were assessed, and tear samples was analyzed by mass spectrometry-based lipidomics. Statistical analyses comparing the relationship between tear film lipids and DE included Pearson/Spearman correlations and t-tests.
Results:
Arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) were present in more than 90% of tear film samples. The ratio of ω-6 (AA) to ω-3 (DHA+EPA) fatty acids was correlated with multiple measures of tear film dysfunction (tear breakup time, Schirmer 2 scores, and corneal staining; all P < 0.05). Arachidonic acid-derived prostaglandin E2 was detected in the majority of samples and correlated with low tear osmolarity, meibomian gland plugging, and corneal staining.
Conclusions:
Both ω-3 and ω-6 lipid circuits are activated in the human tear film. The ratio of ω-6:ω-3 tear lipids is elevated in DE patients in proportion to the degree of tear film dysfunction and corneal staining. Metabolic deficiency of ω-3 tear film lipids may be a driver of chronic ocular surface inflammation in DE.
... Commonly used manual techniques include grading scales, where a score is arbitrarily given depending on the number, density, and tortuosity of vessels [5][6][7][8] ; and quantitative methods, where vessel arcades are connected on the inner side and the region from this line and the limbal arcade, normalized for the corneal area, is calculated. [9][10][11][12] Bock et al. 13 described a semiautomatic quantitative method to calculate CNV in corneal flat mounts. This technique resulted in more precision, accuracy, and reproducibility and saved time compared to a manual quantitative method. ...
Purpose:
To quantify blood and lymph angiogenesis in mouse corneal flat mounts by means of a novel plug-in for ImageJ, called VesselJ, based on a dynamic threshold algorithm.
Methods:
Corneal neovascularization (CNV) was induced in the right corneas of 20 C57BL6/N mice by means of alkali burn (n = 10) or intrastromal sutures (n = 10). All corneal flat mounts were stained for blood vessels with CD31 and for lymphatics with LYVE1. Three independent operators measured blood and lymphatic CNV with both a published manual method (mCNV) and VesselJ (automatic method; aCNV).
Results:
Both methods showed a strong reliability, defined as intraclass correlation coefficient (ICC) > 0.90, in quantifying hemangiogenesis for sutures and alkali burn. However, reliability of lymphatic mCNV varied from moderate in alkali burn (ICC: 0.700) to poor in sutures (ICC: 0.415), whereas it remained high in aCNV (alkali ICC: 0.996; sutures ICC: 0.959). Among sutures, a significant correlation between mCNV and aCNV was found among all the three operators for blood vessels and just for one operator for lymphatic vessels (P < 0.001). In the alkali burn model, correlation between blood mCNV and aCNV was significant for all operators after excluding three noisy flat mounts (P < 0.001), whereas no significant correlation was seen for lymphatic vessels.
Conclusions:
VesselJ is a semiautomatic, reliable, and fast method to quantify corneal hem- and lymphangiogenesis in corneal flat mounts. VesselJ can be easily used in the sutures model; it should be applied to other models (e.g., alkali burn) only after checking for background hyperfluorescence.
