Impairment of the antifibrotic prostaglandin E2 pathway may influence neutrophil extracellular traps–induced fibrosis in the mare endometrium

Rebordão, Maria Rosa; Amaral, Ana; Łukasik, Karolina; Szóstek‐Mioduchowska, Anna; Pinto‐Bravo, Pedro; Galvão, António; Skarzynski, Dariusz J.; Ferreira‐Dias, Graça

doi:10.1016/j.domaniend.2018.10.004

Cited by 27 publications

(26 citation statements)

References 52 publications

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“…The uteri were immersed in ice-cold Dulbecco's modified Eagle's medium (DMEM) F-12 Ham medium (D/F medium; 1:1 (v/v); D-2960; Sigma, St Louis, MO, USA), supplemented with 100 µg/mL streptomycin (S9137; Sigma), 100 IU/mL penicillin (P3032; Sigma), and 2 µg /mL amphotericin (A2942; Sigma). After collection, uteri and blood were transported on ice to the laboratory, within 1 h. All the collected uteri were confirmed for the absence of endometritis, as previously described [10,27].…”

Section: Animals and Tissue Collectionmentioning

confidence: 99%

The In Vitro Inhibitory Effect of Sivelestat on Elastase Induced Collagen and Metallopeptidase Expression in Equine Endometrium

Amaral

Fernandes

Rebordão

et al. 2020

Animals

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Neutrophil extracellular traps (NETs) fight endometritis, and elastase (ELA), a protease found in NETs, might induce collagen type I (COL1) accumulation in equine endometrium. Metallopeptidases (MMPs) are involved in extracellular matrix balance. The aim was to evaluate the effects of ELA and sivelestat (selective elastase inhibitor) on MMP-2 and MMP-9 expression and gelatinolytic activity, as well as the potential inhibitory effect of sivelestat on ELA-induced COL1 in equine endometrium. Endometrial explants from follicular (FP) and mid-luteal (MLP) phases were treated for 24 or 48 h with ELA, sivelestat, and their combination. Transcripts of COL1A2, MMP2, and MMP9 were evaluated by qPCR; COL1 protein relative abundance by Western blot, and MMP-2 and MMP-9 gelatinolytic activity by zymography. In response to ELA treatment, there was an increase in MMP2 mRNA transcription (24 h) in active MMP-2 (48 h), both in FP, and in MMP9 transcripts in FP (48 h) and MLP (24 h) (p < 0.05). Sivelestat inhibited ELA-induced COL1A2 transcripts in FP (24 h) and MLP (24 h, 48 h) (p < 0.05). The sivelestat inhibitory effect was detected in MMP9 transcripts in FP at 48 h (p < 0.05), but proteases activity was unchanged. Thus, MMP-2 and MMP-9 might be implicated in endometrium fibrotic response to ELA. In mare endometrium, sivelestat may decrease ELA-induced COL1 deposition and hinder endometrosis development.

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Section: Animals and Tissue Collectionmentioning

confidence: 99%

The In Vitro Inhibitory Effect of Sivelestat on Elastase Induced Collagen and Metallopeptidase Expression in Equine Endometrium

Amaral

Fernandes

Rebordão

et al. 2020

Animals

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“…In the physiopathologic mechanisms of mare endometrosis, such as in other inflamed tissues, pro-inflammatory cytokines, growth factors, and chemokines are involved acting on fibroblast and other cells, and influencing extra-cellular matrix deposition and tissue fibrosis (34)(35)(36). The action of the miRNAs, probably, was that of down-regulating the expression of pro-inflammatory molecules, reducing the apoptosis rate, increasing endometrial cell proliferation, and restoring the anti-inflammatory level of some cytokines, such as transforming growth factor-β, as demonstrated in some in vitro studies (17,37).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Use of Amniotic Microvesicles for Regenerative Medicine Treatment of a Mare With Chronic Endometritis

et al. 2020

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Chronic endometritis is an inflammation in the inner layer of uterine mucosa, with or without an infectious process, which affects the animal's fertility but not its general health. A variety of treatments has been adopted over the years but to date, no effective cures have been able to renew the injured tissue. Since the defects in the fetal-maternal communication are caused by degenerative changes due to chronic endometrial inflammation, our working hypothesis was a new approach to this disease by the regenerative medicine using amniotic derived microvesicles (MVs) for their anti-inflammatory and regenerative effects. The MVs are responsible for horizontal transfer of genetic materials, including microRNA (miRNAs) that are involved in paracrine communication between origin cells and target cells. Thus, intrauterine MV infusion may be beneficial in degenerative chronic endometritis and in the fetal-maternal talk. The selected mare was an 11-year-old Friesian, with a history of failed pregnancies despite numerous insemination attempts. Punctual and evident heats characterized the reproductive history, but no insemination attempts had been made for many years. The first (failed) insemination was when the mare was 9-years-old. In the next two reproductive seasons, other attempts were made at regular intervals but none was successful. After a final insemination attempt using a stallion of proven fertility, the collection of an 8-day old embryo suggested that the mare was affected by implantation failure related to endometritis. The mare was treated with two cycles of intrauterine administration of amniotic-derived MVs. The success of the intrauterine administration of MVs was demonstrated by an improvement in the classification of endometritis and in a successful artificial insemination (AI) with implantation of an embryo, as detected at day 14 and with a pregnancy that is still ongoing. Probably, MVs were able to restore the injured endometrium and re-establish the proper communication for a successful embryo implantation.

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“…Quantification of COL1A2, COL3A1, and IL33 transcripts was accomplished by reverse transcriptase, followed by real-time polymerase chain reaction (qPCR), as previously described ( 15 ). Briefly, after endometrial total RNA extraction with TRI Reagent® (T9424; Sigma) according to the manufacturer's instructions, a NanoDrop system (ND200C; Fisher Scientific, Hampton, PA, USA) was used for RNA quantification.…”

Section: Methodsmentioning

confidence: 99%

Collagen and Eosinophils in Jenny's Endometrium: Do They Differ With Endometrial Classification?

et al. 2020

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Collagen fibers and inflammatory cells are the basis for jenny endometrium Kenney and Doig's classification developed for the mare. The infiltration of a large number of eosinophils in the jenny endometrium is intriguing. Eosinophil and fibroblast produced IL33, which has been related to fibrosis development and chronicity. This work on the endometrium consisted of (i) quantification of collagen type I (COL1A2), type III (COL3A1), and IL33 transcripts; (ii) histological localization and quantification of COL1 and COL3 proteins; and (iii) eosinophil and neutrophil count and correlation with collagen area and IL33 transcripts. Localization of COL protein in the jenny endometrium was also compared to the mare endometrium. As fibrosis increased, eosinophil and neutrophil count decreased ( P < 0.05). A 5-fold increase in IL33 transcripts was noted from categories IIA to III. There was a tendency toward a positive correlation between eosinophil count and IL33 transcripts in category IIA endometrium ( P = 0.055). Neither transcripts of COL1A2 nor COL3A1 nor the areas of COL1 or COL3 differed with endometrial categories. Unlike for the mare, and regardless of the jenny endometrium classification, COL3 was always found to different extents in the stratum compactum, while COL1 was mainly present in deep stroma. As fibrosis progressed in the mare, an extensive increase in COL1 fibers was notorious under the surface epithelium. Correlations between neutrophil count and COL1 and COL3 areas were observed in the jenny endometrium, although no correlation was found for eosinophil count. Neutrophil count positive correlation with the COL1 area and negative correlation with the COL3 area in endometria with mild lesions suggest that neutrophils in the jenny endometrium may be involved in fibrogenesis. In addition, when eosinophilia subsides, the endometrium reacts with fibrosis establishment, which could be stimulated by the pro-fibrotic cytokine IL33, whose release might then be ascribed to fibroblasts. Further studies are needed to analyze the effect of the presence of COL3 next to the surface epithelium in the stratum compactum, or around the endometrial glands on jenny's endometrial function and fertility.

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Impairment of the antifibrotic prostaglandin E2 pathway may influence neutrophil extracellular traps–induced fibrosis in the mare endometrium

Cited by 27 publications

References 52 publications

The In Vitro Inhibitory Effect of Sivelestat on Elastase Induced Collagen and Metallopeptidase Expression in Equine Endometrium

The In Vitro Inhibitory Effect of Sivelestat on Elastase Induced Collagen and Metallopeptidase Expression in Equine Endometrium

Case Report: Use of Amniotic Microvesicles for Regenerative Medicine Treatment of a Mare With Chronic Endometritis

Collagen and Eosinophils in Jenny's Endometrium: Do They Differ With Endometrial Classification?

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