Special Issue "Endometritis and Fibrosis: An Evolving Story"

A special issue of Animals (ISSN 2076-2615). This special issue belongs to the section "Animal Reproduction".

Deadline for manuscript submissions: closed (31 December 2021).

Special Issue Editors

Prof. Dr. Jordi Miró Roig
E-Mail Website
Guest Editor
Equine Reproduction Service, Department of Animal Medicine and Surgery, Faculty of Veterinary Sciences, Autonomous University of Barcelona, E-08193 Bellaterra (Cerdanyola del Vallès), Spain
Interests: reproduction; equine; donkey; endometritis; endometrosis; semen
Dr. Graça Ferreira-Dias
E-Mail Website
Guest Editor
Department of Morphology and Function, CIISA- Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, 1649-004 Lisbon, Portugal
Interests: reproduction; mare; corpus luteum; oviduct; endometrium; endometrosis; endocrinology; cytokines; fibrosis; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Natural breeding and artificial insemination induce a physiological endometrial response, resulting in inflammatory cell migration into the uterus. In many species, innate and adaptive immune mechanisms are essential for the physiological regulation of uterine function. This interplay among inflammatory cells orchestrates endometrial inflammatory response and remodeling events. Pathogenesis of endometritis is very complex, bridging the action of steroid hormones, eicosanoids, cytokines, growth factors, antioxidants, and others. Physiological endometritis differs among species, depending on semen deposition location, reproductive tract anatomy, and other species specificities. In species with vaginal semen deposition, post-breeding endometritis is reduced, while species with intrauterine semen deposition mount an exuberant physiological endometrial reaction. Seminal plasma induces and controls the inflammatory response. Failure of defense mechanisms in the reproductive tract can induce pathological persistent endometritis or metritis. Persistence of endometrial inflammation leads to pro-fibrotic factor release, collagen deposition, and fibrosis, causing uterine failure and infertility. Each species has its own reproductive strategy. As such, knowledge of similar pathways can improve the assisted reproduction outcome by increasing fertility rates in different species. Thus, this Special Issue aims to gather sound knowledge that will help to provide new treatments for pathological endometritis and avoid endometrial degenerative changes.

Prof. Dr. Jordi Miró Roig
Dr. Graça Ferreira Dias
Guest Editors

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Keywords

  • physiological endometritis
  • pathological endometritis
  • endometrosis
  • mammals

Published Papers (10 papers)

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Research

Article
Inflammatory Markers in Uterine Lavage Fluids of Pregnant, Non-Pregnant, and Intrauterine Device Implanted Mares on Days 10 and 15 Post Ovulation
Animals 2021, 11(12), 3493; https://doi.org/10.3390/ani11123493 - 08 Dec 2021
Viewed by 494
Abstract
Intrauterine devices (IUDs) are used in mares to suppress oestrous behaviour, but the underlying mechanism is yet to be elucidated. The presence of an embryo or an IUD prevents cyclooxygenase-2 (COX-2) and, subsequently, prostaglandin (PG) release and luteolysis. However, inflammation may also be [...] Read more.
Intrauterine devices (IUDs) are used in mares to suppress oestrous behaviour, but the underlying mechanism is yet to be elucidated. The presence of an embryo or an IUD prevents cyclooxygenase-2 (COX-2) and, subsequently, prostaglandin (PG) release and luteolysis. However, inflammation may also be involved. Endometrial inflammatory markers in uterine lavage fluid were measured on Day 10 (EXP 1, n = 25) and Day 15 (EXP 2, n = 27) after ovulation in inseminated mares, non-pregnant or pregnant, and in mares in which a small plastic sphere had been inserted into the uterus 4 (EXP 1) or 3 days (EXP 2) after ovulation. Uterine lavage fluid samples were analysed for nitric oxide (NO), prostaglandin E2 (PGE2) (only EXP 1), prostaglandin F (PGF), inhibin A and cytokines, and blood samples for progesterone and oestradiol. On Day 10, the concentration of PGF was lower (p < 0.05) in the IUD group than in pregnant mares. The concentration of the modulatory cytokine IL-10 was significantly higher in the IUD group in comparison to non-pregnant mares, and inhibin A was significantly higher in IUD mares than in the pregnant counterparts on Day 15. The results suggest that the presence of IUD causes endometrial inflammation which is at a resolution stage on Day 15. Full article
(This article belongs to the Special Issue Endometritis and Fibrosis: An Evolving Story)
Article
Equine Endometrosis Pathological Features: Are They Dependent on NF-κB Signaling Pathway?
Animals 2021, 11(11), 3151; https://doi.org/10.3390/ani11113151 - 04 Nov 2021
Viewed by 324
Abstract
Endometrosis is an important mares’ disease which considerably decreases their fertility. As classic endometrial classification methods might be insufficient for tissue pathological evaluation, further categorization into active/inactive and destructive/non-destructive types was developed by Hoffmann and others. This study aimed to compare NF-κB pathway [...] Read more.
Endometrosis is an important mares’ disease which considerably decreases their fertility. As classic endometrial classification methods might be insufficient for tissue pathological evaluation, further categorization into active/inactive and destructive/non-destructive types was developed by Hoffmann and others. This study aimed to compare NF-κB pathway genes transcription among histopathological types of endometrosis, following Hoffmann and co-authors’ classification. Endometrial samples, collected postmortem from cyclic mares (n = 100) in estrus or diestrus, were classified histologically and used for gene transcription assessment. Gene transcription of NF-κB subunits (RelA, NF-κB1, NF-κB2), pro-inflammatory molecules (MCP-1, IL-6), and hyaluronan synthases (HAS 1, HAS 2, HAS 3) was compared among endometrosis types (active, non-active, destructive, non-destructive). Most individual mRNA samples showed high expression of RelA, NF-κB1, and MCP-1 gene transcripts and the destructive type of endometrosis, simultaneously. The expression of RelA and NF-κB1 genes was higher in active destructive group than in the other groups only in the follicular phase, as well as being higher in the inactive destructive group than in the others, only in the mid-luteal phase. The increase in gene transcription of the NF-κB canonical activation pathway in destructive endometrosis may suggest the highest changes in extracellular matrix deposition. Moreover, the estrous cycle phase might influence fibrosis pathogenesis. Full article
(This article belongs to the Special Issue Endometritis and Fibrosis: An Evolving Story)
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Article
Simple Tube Centrifugation Method for Platelet-Rich Plasma (PRP) Preparation in Catalonian Donkeys as a Treatment of Endometritis-Endometrosis
Animals 2021, 11(10), 2918; https://doi.org/10.3390/ani11102918 - 09 Oct 2021
Viewed by 405
Abstract
The aim of this study was to standardize a simple, manual platelet-rich plasma (PRP) protocol in Catalonian donkeys using single-spin tube centrifugation as a treatment for jenny endometritis. The objective was to obtain a blood product with a moderate concentration of platelets (2 [...] Read more.
The aim of this study was to standardize a simple, manual platelet-rich plasma (PRP) protocol in Catalonian donkeys using single-spin tube centrifugation as a treatment for jenny endometritis. The objective was to obtain a blood product with a moderate concentration of platelets (2 or 3 times baseline physiologic values) and a low WBC (White Blood Cells) concentration. Blood was drawn from six Catalonian donkeys using acid citrate dextrose (ACD) as an anticoagulant, and then processed by single centrifugation at 133× g for two different centrifugation times (10 and 15 min). The PRP samples were evaluated by flow cytometry, and TGF-β1 (Transforming Growth Factor-Beta1) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). The 10 min centrifugation protocol resulted in a slightly greater release of TGF-β1 (6044.79 ng/mL), a 2.06-fold increase in platelet concentration, and a 15-fold reduction in leukocyte concentration when compared to the initial values. The 15 min centrifugation time resulted in a 2.44-fold increase in baseline platelet concentration, a reduction in WBC count by a factor of 20, and slightly lower TGF levels (5206 ng/mL). We conclude that both protocols are adequate for the obtention of PRP, and both may have an acceptable therapeutic potential for use in this species, although this needs to be further validated. Full article
(This article belongs to the Special Issue Endometritis and Fibrosis: An Evolving Story)
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Article
Enzymes Present in Neutrophil Extracellular Traps May Stimulate the Fibrogenic PGF Pathway in the Mare Endometrium
Animals 2021, 11(9), 2615; https://doi.org/10.3390/ani11092615 - 06 Sep 2021
Cited by 2 | Viewed by 722
Abstract
Endometrosis, a fibrotic disease of mare endometrium, impairs uterine function. Prostaglandins (PG), despite modulating reproductive physiological functions, may also cause local pathological collagen deposition (fibrogenesis). We have previously shown that neutrophil extracellular traps (NETs) may also favor mare endometrosis. The aim of this [...] Read more.
Endometrosis, a fibrotic disease of mare endometrium, impairs uterine function. Prostaglandins (PG), despite modulating reproductive physiological functions, may also cause local pathological collagen deposition (fibrogenesis). We have previously shown that neutrophil extracellular traps (NETs) may also favor mare endometrosis. The aim of this study was to investigate the effect of enzymes present in NETs on PGF-pathway activation. Kenney and Doig’s type I/IIA and IIB/III mare endometria, from follicular phase (FLP) and mid-luteal (MLP) phase, were cultured in vitro in the presence of NETs enzymes (elastase, cathepsin-G or myeloperoxidase). Production of PGF (EIA) and transcription (qPCR) of its synthases (PTGS2, AKR1C3) and receptor (PTGFR) genes were evaluated. PGF and PTGFR were influenced by endometrial category and estrous cycle phase. In FLP endometrium, NETs enzymes induced both high PGF production and/or PTGFR transcription. In MLP type I/IIA tissues, down-regulation of PTGFR transcripts occurred. However, in MLP type IIB/III endometrium, high levels of PTGFR transcripts were induced by NETs enzymes. As PGF2α-pathway activation facilitates fibrogenesis in other tissues, PGF2α may be involved in endometrosis pathogenesis. In the mare, the endocrine microenvironment of healthy and pathological endometrium might modulate the PGF pathway, as well as fibrosis outcome on endometrium challenged by NETs enzymes. Full article
(This article belongs to the Special Issue Endometritis and Fibrosis: An Evolving Story)
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Article
Characterization of an Ex Vivo Equine Endometrial Tissue Culture Model Using Next-Generation RNA-Sequencing Technology
Animals 2021, 11(7), 1995; https://doi.org/10.3390/ani11071995 - 03 Jul 2021
Viewed by 1539
Abstract
Persistent mating-induced endometritis is a major cause of poor fertility rates in the mare. Endometritis can be investigated using an ex vivo equine endometrial explant system which measures uterine inflammation using prostaglandin F as a biomarker. However, this model has yet to [...] Read more.
Persistent mating-induced endometritis is a major cause of poor fertility rates in the mare. Endometritis can be investigated using an ex vivo equine endometrial explant system which measures uterine inflammation using prostaglandin F as a biomarker. However, this model has yet to undergo a wide-ranging assessment through transcriptomics. In this study, we assessed the transcriptomes of cultured endometrial explants and the optimal temporal window for their use. Endometrium harvested immediately post-mortem from native pony mares (n = 8) were sampled (0 h) and tissue explants were cultured for 24, 48 and 72 h. Tissues were stored in RNALater, total RNA was extracted and sequenced. Differentially expressed genes (DEGs) were defined using DESeq2 (R/Bioconductor). Principal component analysis indicated that the greatest changes in expression occurred in the first 24 h of culture when compared to autologous biopsies at 0 h. Fewer DEGs were seen between 24 and 48 h of culture suggesting the system was more stable than during the first 24 h. No genes were differentially expressed between 48 and 72 h but the low number of background gene expression suggested that explant viability was compromised after 48 h. ESR1, MMP9, PTGS2, PMAIP1, TNF, GADD45B and SELE genes were used as biomarkers of endometrial function, cell death and inflammation across tissue culture timepoints. STRING assessments of gene ontology suggested that DEGs between 24 and 48 h were linked to inflammation, immune system, cellular processes, environmental information processing and signal transduction, with an upregulation of most biomarker genes at 24 h. Taken together our observations indicated that 24–48 h is the optimal temporal window when the explant model can be used, as explants restore microcirculation, perform wound healing and tackle inflammation during this period. This key observation will facilitate the appropriate use of this as a model for further research into the equine endometrium and potentially the progression of mating-induced endometritis to persistent inflammation between 24 and 48 h. Full article
(This article belongs to the Special Issue Endometritis and Fibrosis: An Evolving Story)
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Article
Specific Seminal Plasma Fractions Are Responsible for the Modulation of Sperm–PMN Binding in the Donkey
Animals 2021, 11(5), 1388; https://doi.org/10.3390/ani11051388 - 13 May 2021
Cited by 2 | Viewed by 579
Abstract
While artificial insemination (AI) with frozen-thawed sperm results in low fertility rates in donkeys, the addition of seminal plasma, removed during cryopreservation, partially counteracts that reduction. Related to this, an apparent inflammatory reaction in jennies is induced following AI with frozen-thawed sperm, as [...] Read more.
While artificial insemination (AI) with frozen-thawed sperm results in low fertility rates in donkeys, the addition of seminal plasma, removed during cryopreservation, partially counteracts that reduction. Related to this, an apparent inflammatory reaction in jennies is induced following AI with frozen-thawed sperm, as a high amount of polymorphonuclear neutrophils (PMN) are observed within the donkey uterus six hours after AI. While PMN appear to select the sperm that ultimately reach the oviduct, two mechanisms, phagocytosis and NETosis, have been purported to be involved in that clearance. Remarkably, sperm interacts with PMN, but the presence of seminal plasma reduces that binding. As seminal plasma is a complex fluid made up of different molecules, including proteins, this study aimed to evaluate how different seminal plasma fractions, separated by molecular weight (<3, 3–10, 10–30, 30–50, 50–100, and >100 kDa), affect sperm–PMN binding. Sperm motility, viability, and sperm–PMN binding were evaluated after 0 h, 1 h, 2 h, 3 h, and 4 h of co-incubation at 38 °C. Two seminal plasma fractions, including 30–50 kDa or 50–100 kDa proteins, showed the highest sperm motility and viability. As viability of sperm not bound to PMN after 3 h of incubation was the highest in the presence of 30–50 and 50–100 kDa proteins, we suggest that both fractions are involved in the control of the jenny’s post-breeding inflammatory response. In conclusion, this study has shown for the first time that specific fractions rather than the entire seminal plasma modulate sperm–PMN binding within the donkey uterus. As several proteins suggested to be involved in the control of post-AI endometritis have a molecular weight between 30 and 100 kDa, further studies aimed at determining the identity of these molecules and evaluating their potential effect in vivo are much warranted. Full article
(This article belongs to the Special Issue Endometritis and Fibrosis: An Evolving Story)
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Article
Effect of Intrauterine Infusion of Equine Fresh Platelets-Rich Plasma (PRP) or Lyophilized PRP (L-GFequina) on Ovarian Activity and Pregnancy Rate in Repeat Breeder Purebred Arabian Mares
Animals 2021, 11(4), 1123; https://doi.org/10.3390/ani11041123 - 14 Apr 2021
Cited by 2 | Viewed by 677
Abstract
This study was designed to examine the effect of the intrauterine infusion of platelet-rich plasma (PRP) or equine lyophilized growth factor (L-GFequina) on the follicular growth, endometrial thickness, estrus cycle length, and pregnancy rate in purebred Arabian mares. A total of [...] Read more.
This study was designed to examine the effect of the intrauterine infusion of platelet-rich plasma (PRP) or equine lyophilized growth factor (L-GFequina) on the follicular growth, endometrial thickness, estrus cycle length, and pregnancy rate in purebred Arabian mares. A total of 73 purebred Arabian mares who experienced repeat breeding for three successive cycles were randomly divided into the following three groups: control group, without treatment; second Group (PRP group), in which mares were intrauterine infused with 20 mL of fresh PRP on the second day after the end of physic estrus phase; and the third group (L-GFequina Group), consisting of mares that were intrauterine infused with 20 mL of reconstituted lyophilized horse platelets growth factors (L-GFequina) on the second day after the estrus phase. The results showed no significant difference between control and treated groups in the diameter of the preovulatory follicles during the post treatment cycle. The endometrium thickness increased significantly in the L-GFequina and PRP groups ahead of the non-treated group. Intrauterine L-GFequina or PRP administration shortened the estrus cycle length. A higher pregnancy rate was recorded in the L-GFequina and PRP treated mares. In conclusion, the intrauterine infusion of L-GFequina or PRP increased the endometrial thickness and pregnancy rate and could be used to improve fertility in Arabian purebred mares who experienced from repeat breeding. Full article
(This article belongs to the Special Issue Endometritis and Fibrosis: An Evolving Story)
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Article
Myeloperoxidase Inhibition Decreases the Expression of Collagen and Metallopeptidase in Mare Endometria under In Vitro Conditions
Animals 2021, 11(1), 208; https://doi.org/10.3390/ani11010208 - 16 Jan 2021
Cited by 3 | Viewed by 692
Abstract
Neutrophils can originate neutrophil extracellular traps (NETs). Myeloperoxidase (MPO) is a peroxidase found in NETs associated to equine endometrosis and can be inhibited by 4-aminobenzoic acid hydrazide (ABAH). Metallopeptidases (MMPs) participate in extracellular matrix stability and fibrosis development. The objectives of this in [...] Read more.
Neutrophils can originate neutrophil extracellular traps (NETs). Myeloperoxidase (MPO) is a peroxidase found in NETs associated to equine endometrosis and can be inhibited by 4-aminobenzoic acid hydrazide (ABAH). Metallopeptidases (MMPs) participate in extracellular matrix stability and fibrosis development. The objectives of this in vitro work were to investigate, in explants of mare’s endometrium, (i) the ABAH capacity to inhibit MPO-induced collagen type I (COL1) expression; and (ii) the action of MPO and ABAH on the expression and gelatinolytic activity of MMP-2/-9. Explants retrieved from the endometrium of mares in follicular or mid-luteal phases were treated with MPO, ABAH, or their combination, for 24 or 48 h. The qPCR analysis measured the transcription of COL1A2, MMP2, and MMP9. Western blot and zymography were performed to evaluate COL1 protein relative abundance and gelatinolytic activity of MMP-2/-9, respectively. Myeloperoxidase elevated COL1 relative protein abundance at both treatment times in follicular phase (p < 0.05). The capacity of ABAH to inhibit MPO-induced COL1 was detected in follicular phase at 48 h (p < 0.05). The gelatinolytic activity of activated MMP-2 augmented in mid-luteal phase at 24 h after MPO treatment, but it was reduced with MPO+ABAH treatment. The activity of MMP-9 active form augmented in MPO-treated explants. However, this effect was inhibited by ABAH in the follicular phase at 48 h (p < 0.05). By inhibiting the pro-fibrotic effects of MPO, it might be possible to reduce the development of endometrosis. Metallopeptidase-2 might be involved in an acute response to MPO in the mid-luteal phase, while MMP-9 might be implicated in a prolonged exposition to MPO in the follicular phase. Full article
(This article belongs to the Special Issue Endometritis and Fibrosis: An Evolving Story)
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Article
Effects of Intrauterine Infusion of a Chitosan Solution on Recovery and Subsequent Reproductive Performance of Early Postpartum Dairy Cows with Endometritis: A Pilot Field Trial
Animals 2021, 11(1), 197; https://doi.org/10.3390/ani11010197 - 15 Jan 2021
Cited by 1 | Viewed by 751
Abstract
This study investigated the efficacy of intrauterine infusion of a chitosan solution (CHT) on uterine recovery in early postpartum dairy cows with or without endometritis, and their subsequent reproductive performance. In Experiment 1, cows with endometritis at 3 weeks postpartum were administered CHT [...] Read more.
This study investigated the efficacy of intrauterine infusion of a chitosan solution (CHT) on uterine recovery in early postpartum dairy cows with or without endometritis, and their subsequent reproductive performance. In Experiment 1, cows with endometritis at 3 weeks postpartum were administered CHT (n = 5) and prostaglandin F (PGF) (n = 4). Untreated cows (n = 7) served as the control group. In Experiment 2, 18 cows with a normally recovered uterus at the fresh cow check (mean, 35 days postpartum) were assigned to the CHT (n = 10) and control (n = 8) groups, and intrauterine infusion was conducted in the CHT group. Overall, in Experiment 1, the percentage of polymorphonuclear leukocytes significantly declined in the CHT group (32.3 ± 10.2 to 5.5 ± 2.4, p < 0.05) from week 3 to week 5, but no decline occurred in the PGF and control groups. In Experiment 2, the CHT and control groups showed no significant differences in reproductive parameters, suggesting the absence of adverse effects of CHT on fertility. These results suggest that intrauterine infusion of CHT in the early postpartum period effectively accelerates uterine recovery from endometritis and might be a suitable replacement for PGF administration. Full article
(This article belongs to the Special Issue Endometritis and Fibrosis: An Evolving Story)
Article
Endometrial Status in Queens Evaluated by Histopathology Findings and Two Cytological Techniques: Low-Volume Uterine Lavage and Uterine Swabbing
Animals 2021, 11(1), 88; https://doi.org/10.3390/ani11010088 - 05 Jan 2021
Viewed by 651
Abstract
Endometritis is associated with fertility problems in many species, with endometrial biopsy being the main diagnostic tool. In feline queens, the reduced size of the uterus may make it difficult to obtain representative diagnostic samples. Endometrial cytology may represent a valuable diagnostic tool [...] Read more.
Endometritis is associated with fertility problems in many species, with endometrial biopsy being the main diagnostic tool. In feline queens, the reduced size of the uterus may make it difficult to obtain representative diagnostic samples. Endometrial cytology may represent a valuable diagnostic tool for evaluating the health status of the endometrium in queens. Fifty domestic shorthair queens were included and divided into two cytological diagnostic technique groups, the uterine lavage (UL; n = 28) and uterine swabbing (US; n = 22) groups. Cytological results were compared with histopathological and bacteriological information. Changes in the histopathological patterns were also evaluated and compared with progesterone levels to confirm previous published data. Furthermore, the results from both cytological sampling methods were compared to evaluate the utility of each method. Endometritis was ruled out in all queens by means of histology and microbiology. Leukocyte counts and red blood cell/endometrial cell ratios were significantly higher in US than UL samples. Additionally, UL sampling is less affected by blood contamination and cells are better preserved. The combination of endometrial cytology and uterine culture might be useful for evaluating the endometrial characteristics in queens. The UL evaluation method is more representative of the actual endometrial status than the US technique. Full article
(This article belongs to the Special Issue Endometritis and Fibrosis: An Evolving Story)
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