(e.g., cytokeratin, vimentin, a-smooth muscle actin, and laminin) associated with the development of pathological fibrosis in the horse endometrium.45,46 Preliminary results of the authors’ group demonstrate thatMSCsmay improve the endometrial score ofmares suffering from CDE.68 Moreover, in rats as an experi- mental model, MSCs regulated endometrial inflamma- tory cytokines, regenerated endometrial cells, and up- regulated markers for endometrial receptivity (integrin agb3 and leukemia inhibitory factor).47 It is well known that mares with a higher grade of endometrial fibrosis aremore prone to develop endometritis and have fewer chances to carry a pregnancy to term.48 Therefore, MSCsmight have a potential application inmares with CDE and must be further explored. Of interest, the MSC-CM has shown potential to mitigate post-inflam- matory response in mares susceptible to endometritis.8 In this study, the intrauterine infusion of MSC-CM, before breeding ormixed with semen, increased intrau- terine expression of IL10, and reduced post-breeding intrauterine fluid accumulation, endometrial PMNs counts, and uterine expression of IL6 inmares suscepti- ble to endometritis. Although fertility rates were not changed in the study, a positive numerical difference (2-fold) could be observed after MSC-CM therapy. In addition, it was interesting that MSC-CM was not harmful to the sperm when semen was supple- mented with MSC-CM, which opens an alternative for the time of treatment using this therapy. Another important benefit of MSC-CM is that it is not a cell suspension; therefore, it does not require tests to determine compatibility with possible recipients.58,61 Moreover, MSC-CM can be frozen or manufactured, lyophilized, packaged, and transported, which makes this therapy available more quickly than others (e.g., PRP,MSCs, ACS) for immediate application. In summary, biologic therapies provide an excel-
lent treatment for alleviating post-breeding inflam- mation in mares. The regulation of the inflammatory factors and the inflammatory process create a better uterine environment both for the sperm and the embryo entering the uterus. Although much more must be explored in biological therapies to treat uter- ine problems in mares, the evidence so far is en- couraging.
Acknowledgments
The Authors would like to thank FAPESP (São Paulo Research Foundation, SP, Brazil) and USDA Animal Health Hatch funds for funding some of the key studies described in this manuscript.
Declaration of Ethics
The Authors have adhered to the Principles of Veteri- naryMedical Ethics of theAVMA.
Conflict of Interest The Authors have no conflicts of interest.
INFLAMMATION, INFECTION, OR BOTH? ROOT CAUSES OF ENDOMETRITIS References and Footnotes
1. TroedssonMHT.Uterine clearance and resistance to persistent endometritis in themare. Theriogenology 1999;52:461–471.
2. Troedsson MH, Liu IK, Crabo B. Sperm transport and sur- vival in the mare. Theriogenology 1998;49:905–915.
3. Canisso IF, Segabinazzi LGTM, Fedorka CE. Persistent breeding-induced endometritis in mares — A multifaceted challenge: from clinical aspects to immunopathogenesis and pathobiology. IJMS 2020;21:1432.
4. Riddle WT, LeBlanc MM, Stromberg AJ. Relationships between uterine culture, cytology and pregnancy rates in a Thoroughbred practice. Theriogenology 2007;68:395–402.
5. Carnevale EM, Ramirez RJ, Squires EL, et al. Factors affecting pregnancy rates and early embryonic death after equine embryo transfer. Theriogenology 2000;54:965–979.
6. Troedsson MHT. Therapeutic considerations for mating- induced endometritis. Pferdeheilkd. Equine Med 1997;13: 516–520.
7. Troedsson MH, Liu IK. Uterine clearance of non-antigenic markers (51Cr) in response to a bacterial challenge in mares potentially susceptible and resistant to chronic uterine infections. J Reprod Fertil Suppl 1991;44:283–288.
8. Tongu EAdO, Segabinazzi LGTM, Alvarenga ML, et al. Allogenic mesenchymal stemcell-conditionedmediumdoes not affect sperm parameters and mitigates early endometrial inflammatory responses in mares. Theriogenology 2021;169: 1–8.
9. Segabinazzi LGTM, Canisso IF, Podico G, et al. Intrauterine blood plasma platelet-therapy mitigates persistent breed- ing-induced endometritis, reduces uterine infections, and improves embryo recovery in mares. Antibiotics 2021; 10:490.
10. Ferris RA, Frisbie DD, McCue PM. Use of mesenchymal stem cells or autologous conditioned serum to modulate the inflammatory response to spermatozoa in mares. Theriogenology 2014;82:36–42.
11. Segabinazzi LG, Friso AM, Correal SB, et al. Uterine clini- cal findings, fertility rate, leucocyte migration, and COX-2 protein levels in the endometrial tissue of susceptible mares treated with platelet-rich plasma before and after AI. Theriogenology 2017;104:120–126.
12. Reghini MFS, Ramires Neto C, Segabinazzi LG, et al. Inflammatory response in chronic degenerative endometritis mares treated with platelet-rich plasma. Theriogenology 2016;86:516–522.
13. Metcalf ES, Scoggin K, Troedsson MHT. The effect of plate- let-rich plasma on endometrial pro-inflammatory cytokines in susceptible mares following semen deposition. J. Equine Vet. Sci 2012;32:498.
14. Metcalf ES. The effect of Platelet-Rich Plasma (PRP) on in- traluminal fluid and pregnancy rates in mares susceptible to persistent mating-induced endometritis (PMIE). J. Equine Vet. Sci 2014;34:128.
15. Pasch L, Schmidt A, King W. Clinical observations after pre breeding intrauterine plasma infusion in 18 mares insemi- nated with thawed frozen semen. J Equine Vet Sci 2021; 99:103389.
16. Kim H-J, Yeom JS, Koh Y-G, et al. Anti-inflammatory effect of platelet-rich plasma on nucleus pulposus cells with response of TNF-aand IL-1. J Orthop Res 2014;32:551–556.
18. Wu C-C, Chen W-H, Zao B, et al. Regenerative potentials of platelet-rich plasma enhanced by collagen in retrieving pro- inflammatory cytokine-inhibited chondrogenesis. Biomaterials 2011;32:5847–5854.
19. Anitua E, Alonso R, Girbau C, et al. Antibacterial effect of plasma rich in growth factors (PRGF®-Endoret®) against Staphylococcus aureus and Staphylococcus epidermidis strains. Clin Exp Dermatol 2012;37:652–657.
20. Álvarez M, López C, Giraldo C, et al. In vitro bactericidal ac- tivity of equine platelet concentrates, platelet poor plasma,
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