RESSALVA Atendendo solicitação do(a) autor(a), o texto completo desta dissertação será disponibilizado somente a partir de 04/11/2023. UNIVERSIDADE ESTADUAL PAULISTA “JÚLIO DE MESQUITA FILHO” FACULDADE DE MEDICINA VETERINÁRIA E ZOOTECNIA PROGRAMA DE PÓS-GRADUAÇÃO EM BIOTECNOLOGIA ANIMAL EFEITO DA PENTOXIFILINA ORAL NA RESPOSTA INFLAMATÓRIA E ACÚMULO DE FLUIDO INTRAUTERINOS APÓS INSEMINAÇÃO ARTIFICIAL E TAXA DE RECUPERAÇÃO EMBRIONÁRIA EM ÉGUAS VELHAS ODILON MARQUEZ DE OLIVEIRA Botucatu - SP Maio, 2022 UNIVERSIDADE ESTADUAL PAULISTA “JÚLIO DE MESQUITA FILHO” FACULDADE DE MEDICINA VETERINÁRIA E ZOOTECNIA PROGRAMA DE PÓS-GRADUAÇÃO EM BIOTECNOLOGIA ANIMAL EFEITO DA PENTOXIFILINA ORAL NA RESPOSTA INFLAMATÓRIA E ACÚMULO DE FLUIDO INTRAUTERINOS APÓS INSEMINAÇÃO ARTIFICIAL E TAXA DE RECUPERAÇÃO EMBRIONÁRIA EM ÉGUAS VELHAS Dissertação apresentada à Faculdade de Medicina Veterinária e Zootecnia, Campus de Botucatu, Unesp, para obtenção do título de Mestre no Programa de Pós- Graduação em Biotecnologia Animal. Odilon Marquez de Oliveira Orientador: Igor Frederico Canisso Botucatu - SP Maio, 2022 ii FICHA CATALOGRÁFICA iii Nome do Autor: Odilon Marquez de Oliveira Título: Efeito Da Pentoxifilina Oral Na Resposta Inflamatória E Acúmulo De Fluido Intrauterinos Após Inseminação Artificial E Taxa De Recuperação Embrionária Em Éguas Velhas Comissão examinadora Prof. Dr. Igor Frederico Canisso Orientador, DVM, MSc, PhD, Dipl. ACT, Dipl. ECAR, Professor Associado Departamento de Cirurgia Veterinária e Reprodução Animal FMVZ – UNESP – Botucatu/SP Profa. Dra. Camila de Paula Freitas Dell Aqua Membro Departamento de Cirurgia Veterinária e Reprodução Animal FMVZ – UNESP – Botucatu/SP Dr. Marcio Teoro do Carmo Membro Mestre e Doutor em Reprodução Animal - Unesp/Botucatu Data da defesa: 03/05/2022 iv AGRADECIMENTOS Primeiramente gostaria de agradecer ao maravilhoso Deus, meu refúgio e minha fortaleza, por permitir a concretização dos meus sonhos. Agradeço pelo amor e apoio incondicional da minha família. Meus queridos pais por toda o suporte, conselhos, dedicação e amor. À minha esposa, minha companheira, Gabrielle Amorim, que tanto me ajuda e me da forças. Aos brilhantes professores pelos ensinamentos, oportunidades e pela amizade: Rodrigo Arruda, Simone Perecmanis, José Dell’Aqua, Camilla Dell’Aqua, Ana Liz, Igor Canisso, Cezinande de Meira, Marco Alvarenga, Lorenzo e Lígia Mota. Agradeço aos meus colegas e amigos que estiveram envolvidos direta ou indiretamente no decorrer desse mestrado, tornando esse período mais ameno. Também agradeço aos animais envolvidos no estudo, pois, sem eles, nada disso seria possível. A instituição “Faculdade Estadual Paulista - UNESP” pela oportunidade de realizar o curso de mestrado. O presente trabalho foi realizado com apoio da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Código de Financiamento 001. v OLIVEIRA, O.M. Efeito da pentoxifilina oral na resposta inflamatória e acúmulo de fluido intrauterinos após inseminação artificial e taxa de recuperação embrionária em éguas velhas. Botucatu, 2022. 65p. Dissertação (Mestrado) – Faculdade de Medicina Veterinária e Zootecnia, Campus de Botucatu, Universidade Estadual Paulista. RESUMO A maioria das éguas doadoras de embrião tem a limpeza uterina prejudicada devido a problemas uterinos e cervicais como resultado de repetidas inseminações e coletas de embrião. Esses problemas levam à suscetibilidade à endometrite persistente pós cobertura (EPPC) que está associada à inflamação persistente, que mostra edema uterino excessivo, acúmulo de líquido intrauterino (FIU), grande número de neutrófilos polimorfonucleares na citologia e cultura positiva. A intensa e prolongada inflamação endometrial cria um ambiente uterino desfavorável ao desenvolvimento embrionário, resultando em queda na fertilidade. A pentoxifilina é um fármaco reolítico, que promove aumento da maleabilidade das hemácias, e apresenta efeitos anti-inflamatórios e antioxidantes. Sendo amplamente utilizado na prática clínica equina e na reprodução por aumentar o fluxo sanguíneo para os diversos tecidos. Este estudo teve como objetivo avaliar a resposta inflamatória uterina pós inseminação artificial e a recuperação embrionária de éguas doadoras velhas e subférteis tratadas com pentoxifilina. Doze éguas (16±3,7 anos) foram classificadas como suscetíveis ou resistentes à EPPC com base no histórico reprodutivo, nos achados ultrassonográficos e na taxa de recuperação embrionária. No início do estudo, uma amostra de biópsia foi coletada para determinar o score de biópsia do padrão Kenney e Doig. Cada égua foi submetida a seis ciclos estrais. Durante os dois primeiros ciclos, todas as éguas receberam, por via oral, 50mL de um suplemento comercial acrescido de 17mg/kg/dia de Pentoxifilina. Os dois ciclos subsequentes foram usados como washout (sem suplemento, sem pentoxifilina). Nos dois últimos ciclos, 50mL de suplemento comercial puro foi administrado por via oral. As coletas de embrião foram realizadas oito ou nove dias após ovulação. A palpação transretal e a ultrassonografia foram realizadas diariamente para avaliar o controle folicular, edema endometrial e acúmulo de fluido intrauterino. A citologia endometrial foi realizada pré e pós (24, 48 e 72h) inseminação artificial, enquanto a cultura uterina foi realizada pré e 72h pós inseminação. As contagens de neutrófilos relacionada aos efeitos do tempo não diferiram entre os grupos, bem como o edema uterino, o acúmulo de fluido intrauterino e a cultura positiva (P>0,05). A recuperação embrionária foi maior no grupo pentoxifilina (P=0,046). Em conclusão, a suplementação com pentoxifilina pode ser uma alternativa para diminuir a resposta inflamatória endometrial pós inseminação artificial e pode melhorar a taxa de recuperação embrionária. Palavras-chave: Éguas, transferência de embriões, endometrite, fertilidade, pentoxifilina. vi OLIVEIRA, O.M. Effects of oral pentoxifylline on intrauterine inflammatory response and fluid accumulation after artificial insemination, and embryo recovery rate in old mares. Botucatu, 2022. 65p. Dissertação (Mestrado) – Faculdade de Medicina Veterinária e Zootecnia, Campus de Botucatu, Universidade Estadual Paulista. ABSTRACT Most embryo donor mares have impaired uterine clearance due to uterine and cervical problems as a result of repeated breeding and embryo flushing. These issues lead to susceptibility to persistent breeding induced endometritis (PBIE) that is associated with persistent inflammation, which shows excessive uterine edema, intrauterine fluid accumulation, large number of polymorphonuclear cells on cytology and positive culture. Intense and prolonged endometrial inflammation creates an unfavorable uterine environment for embryonic development, resulting in a decrease in fertility. Pentoxifylline is a reolytic drug that promotes increased blood cells malleability and has anti-inflammatory and antioxidant effects. Being widely used in equine clinical practice and also in reproduction by increasing blood flow to the various tissues. This study aimed to assess the post-breeding inflammatory response and embryo recovery of sub fertile aged donor mares treated with pentoxifylline. Twelve mares (16±3.7years old) were classified as susceptible or resistant to PBIE based on the reproductive history, ultrasound findings and embryo recovery rate. At the beginning of the study a biopsy sample was taken to determine the Kenney and Doig biopsy score. Each mare was submitted to six estrous cycles. During the first two cycles, all mares received orally, 50mL of a commercial supplement added with 17mg/kg/day of Pentoxifylline. The two subsequent cycles were used as washout (no supplement, no pentoxifylline). The two last cycles, 50mL of plain commercial supplement was orally administered. Embryo flushing was carried out eight or nine days after ovulation. Transrectal palpation and ultrasonography were performed daily to assess follicular control, endometrial edema and intrauterine fluid accumulation. Uterine cytology was performed pre and post (24, 48, and 72h) artificial insemination while uterine culture was performed pre and 72h post insemination. Neutrophil counts related to the effects of time did not differ between groups, as well as uterine edema, intrauterine fluid accumulation and positive culture (P>0.05). Embryo recovery was greater in the pentoxifylline group (P=0.046). In conclusion, supplementation with pentoxifylline may be an alternative to decrease the inflammatory endometrial response after artificial insemination and may enhance embryo recovery rate. Keywords: Mares, embryo transfer, endometritis, fertility, pentoxifylline. SUMARIO Página CAPÍTULO 1........................................................................................................1 1. INTRODUÇÃO..............................................................................................2 2. REVISÃO DE LITERATURA.........................................................................3 2.1. Endometrite................................................................................................3 2.1.1. Endometrite infecciosa....................................................................4 2.1.2. Endometrite não infecciosa.............................................................6 2.1.3. Resposta imune inata......................................................................6 2.1.4. Métodos diagnósticos....................................................................11 2.1.4.1. Ultrassonografia...............................................................11 2.1.4.2. Citologia...........................................................................12 2.1.4.3. Cultura.............................................................................14 2.1.4.4. Biópsia.............................................................................15 2.1.5. Tratamentos..................................................................................16 2.2. Pentoxifilina..............................................................................................19 2.3. Nutracêuticos...........................................................................................22 3. CONCLUSÃO..............................................................................................24 4. REFERÊNCIAS...........................................................................................25 HIPÓTESE E OBJETIVO...................................................................................42 CAPÍTULO 2......................................................................................................43 ARTIGO - Oral supplementation with pentoxifylline in post breeding inflammatory response and embryo recovery rate in old mares.…………….…………………………………………. 44 CAPÍTULO 1 2 1. INTRODUÇÃO Com o intuito de aumentar o número de descendentes de animais de alto valor zootécnico para obtenção de futuros atletas e campeões, a espécie equina vem sendo selecionada geneticamente pela performance atlética e não pelo desempenho reprodutivo. Com o avanço da idade de fêmeas campeãs e produtoras, os índices reprodutivos caem juntamente com a fertilidade, fazendo com que as técnicas de reprodução assistida sejam cada vez mais estudas e utilizadas para minimizar os efeitos do envelhecimento sobre a anatomia e barreiras de proteção naturais do trato reprodutivo da égua, bem como para reduzir os danos causados pela resposta imune uterina exacerbada em éguas susceptíveis (Ignácio et al., 2021). A resposta inflamatória uterina após inseminação é fisiológica e transitória, todavia pode se tornar intensa e prolongada nas éguas susceptíveis (Segabinazzi et al., 2021). A presença de acúmulo de fluido intrauterino 24 a 48 horas após inseminação classifica a égua clinicamente como susceptível à endometrite (Canisso et al., 2016). Éguas susceptíveis a endometrite persistente pós cobertura não são capazes de eliminar o processo inflamatório entre 48 e 72 horas após inseminação e podem apresentar repetição de cio, acúmulo de fluido intra- uterino pré ou pós inseminação, edema uterino exacerbado, grande número de neutrófilos polimorfonucleares, predispondo o útero á infecções (Tongu et al., 2021; Bucca et al., 2008). Após 5.5-6.5 dias da fertilização, o concepto chega ao útero (Betteridge et al., 1982). Todavia, a presença de produtos inflamatórios, fluido e bactérias torna o microambiente uterino incompatível com a sobrevivência embrionária e manutenção da prenhez (Troedsson., 1999). De grande impacto econômico à indústria equina, a endometrite é a terceira enfermidade mais comum que acomete os equinos, a maior causa de redução de fertilidade e está associada a falha na concepção e perda embrionária precoce (Díaz-Bertrana et al., 2021; Segabinazzi et al., 2020). 3 Os nutracêuticos tem sido amplamente utilizados para melhorar os índices reprodutivos e incluem suplementos, vitaminas, minerais, bioprodutos e substâncias farmacêuticas. Porém, o resultado dessa suplementação é variável e sofre influências individuais e ambientais (Freitas et al., 2018). A pentoxifilina promove o aumento do remodelamento das hemácias permitindo aumento na circulação e vascularização de diversos tecidos no organismo (Brisko et al., 2011); possui efeito antioxidante e anti-inflamatório (Pollice et al., 2001) e reduz a resposta inflamatória (Pozor., 2011), podendo facilitar o desempenho uterino frente à inflamação, e desta forma, diminuir a colonização de bactérias (Baumgartner, 2007). O presente trabalho buscou revisar e avaliar os efeitos da pentoxifilina sobre a reação inflamatória após inseminação artificial e taxa de recuperação embrionária em éguas idosas que apresentam endometrite persistente pós cobertura. 2. REVISÃO DE LITERATURA 2.1. Endometrite A endometrite pode estar associada a infecção por bactérias e fungos ou sêmen após inseminação, tornando-se de natureza multifatorial, o que dificulta o diagnóstico (Canisso et al., 2016). De acordo com Ferris (2017) o útero da égua sadia tem capacidade de limpeza contra bactérias e fungos sem desenvolver infecção, porém, torna-se susceptível quando há alguma falha nos mecanismos de defesa do organismo, como má conformação perineal, esfíncter vestíbulo vaginal danificado, defeito de cérvix, útero penduloso ou com saculação ventral, má condição/score corporal, atividade miometrial prejudicada ou defesa imunológica deficiente (Troedsson et al., 2018). Após 30 minutos da deposição de sêmen no lúmen uterino, o sistema imune responde com quimiotaxia e ativação dos neutrófilos, com o intuito de fagocitar debris, bactérias e células espermáticas não viáveis (Canisso et al., 2016). Todavia, o pico da inflamação endometrial após inseminação ocorre 26 4. REFERÊNCIAS1 Aitken R. A free radical theory of male infertility. Reproduction, Fertility and Development. 1994;6(1):19-24. Al-Maskari MY, Waly MI, Ali A, Al-Shuaibi YS, Ouhtit A. Folate and vitamin B12 deficiency and hyperhomocysteinemia promote oxidative stress in adult type 2 diabetes. Nutrition. 2012 Jul;28(7-8):e23–6. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nature Immunology. 2004 Feb 1;5(3):266–71. Andriguetto JM, Perly L, Minardi I, Gemael A, Flemming JS, Souza GA, Filho AB. As vitaminas na produção animal. In: Nutrição animal. São Paulo: Nobel; 2002;1:135-64. Anwar H, Strap JL, Costerton JW. Establishment of aging biofilms: possible mechanism of bacterial resistance to antimicrobial therapy. Antimicrobial Agents and Chemotherapy. 1992 Jul 1;36(7):1347–51. Arend WP. Biological role of interleukin 1 receptor antagonist isoforms. Annals of the Rheumatic Diseases. 2000 Nov 1;59(90001):60i64. Atreya R, Mudter J, Finotto S, Müllberg J, Jostock T, Wirtz S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo. Nature Medicine [Internet]. 2000 May 1 [citado 2022 Mar 7];6(5):583–8. Disponível em: https://www.nature.com/articles/nm0500_583 Bailey CS, Macpherson ML, Pozor MA, Troedsson MHT, Benson S, Giguere S, et al. Treatment efficacy of trimethoprim sulfamethoxazole, pentoxifylline and altrenogest in experimentally induced equine placentitis. Theriogenology. 2010 Aug;74(3):402–12 Bailey CS, Macpherson ML, Graczyk J, Pozor MA, Troedsson MHT, LeBlanc MM, et al. Treatment efficacy of trimethoprim sulfamethoxazole, pentoxifylline, and altrenogest in equine placentitis. Theriogenology. 2007 Aug; 53:339-40. Barton MH. Treatment of equine endotoxemia. Proc. Am. Assoc. Equine. Pract. 1995;41:112-6. Baskett A, Barton MH, Norton N, Anders B, Moore JN. Effect of pentoxifylline, flunixin meglumine, and their combination on a model of endotoxemia in horses. Am J Vet Res. 1997; 58:1291–9. Baumgartner T. Pentoxifylline. J. Exotic Pet. Med. 2007; 2:118-21. 1 As referências foram formatadas observando-se as normas de Vancouver. 27 Beehan DP, McKinnon AO. How to diagnose common equine reproductive tract bacterial pathogens using chromogenic agar. Proc 55th Ann Conv Am Ass Equine Practitioners. 2009. Betteridge KJ, Eaglesome MD, Mitchell D, Flood PF, Beriault R. Development of horse embryos up to twenty-two days after ovulation: observations on fresh specimens. Journal of Anatomy. 1982; 135:191–209. Bonizzi G, Karin M. The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004; 25:280–8. Boosman R, Nemeth F. Pathogenesis and drug therapy of acute laminitis in horses: A literature review. Tijdschr Diergeneeskd. 1988; 113:1237–46. Borba EVC, Camozzato GC, Malschitzky E, Bustamante-Filho IC, Martins AA, Mattos RC, et al. Is the presence of uterine fluid a reliable indicator of endometrial inflammation? Pferdeheilkunde Equine Medicine. 2012;28(1):27–9 Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science (New York, NY) [Internet. 2004 [citado 2019 Mar 20];303(5663):1532–5. Disponível em: https://www.ncbi.nlm.nih.gov/pubmed/15001782 Brinsko SP, Blanchard TL, Varner DD, Schumacher J, Love CC, Hinrichs K, Hartman D. Manual of Equine Reproduction. 3rd ed. Maryland Heights: Elsevier; 2011. Brinsko SP, Rigby SL, Varner DD, Blanchard TL. A practical method for recognizing mares susceptible to post-breeding endometritis. Proc 49th Ann Conv Am Ass Equine Practitioners. 2003;363-5. Brinsko SP, Varner DD, Blanchard TL. The effect of uterine lavage performed four hours post insemination on pregnancy rate in mares. Theriogenology. 1991; 35:1111-9. Brown K, Arthur J. Selenium, selenoproteins and human health: a review. Public Health Nutrition. 2001 Apr;4(2b):593–9. Bucca S, Carli A, Buckley T, Dolci G, Fogarty U. The use of dexamethasone administered to mares at breeding time in the modulation of persistent mating induced endometritis. Theriogenology. 2008 Oct;70(7):1093–100. Burleson MD, Leblanc MM, Riddle WT, Hendricks. Endometrial microbial isolates are associated with different ultrasonographic and endometrial cytology findings in Thoroughbred mares. Animal Reproduction Science. 2010 Jan;121(1-2):103. Canisso IF, Ball BA, Cray C, Williams NM, Scoggin KE, Davolli GM, et al. Serum Amyloid A and Haptoglobin Concentrations are Increased in Plasma of Mares with Ascending Placentitis in the Absence of Changes in Peripheral Leukocyte Counts or Fibrinogen Concentration. American Journal of Reproductive Immunology. 2014 Jun 11;72(4):376–85. 28 Canisso IF, Silva MAC. Bacterial endometritis. In: Sprayberry KA, Robinson NE, editors. Robinson’s current therapy in equine medicine. St Louis (MO): WB Saunders. 2015;683-8. Canisso IF, Segabinazzi LGTM, Fedorka CE. Persistent Breeding-Induced Endometritis in Mares—A Multifaceted Challenge: From Clinical Aspects to Immunopathogenesis and Pathobiology. International Journal of Molecular Sciences. 2020 Feb 20;21(4):1432. Canisso IF, Stewart J, Silva MAC. Managing Persistent Post-Breeding Endometritis. Vet Clin Equine. 2016; 3:465-80. Card C. Post-breeding inflammation and endometrial cytology in mares. Theriogenology. 2005; 64:580-8. Card CE, Wood MR. Effects of acute administration of clenbuterol on uterine tone and equine fetal and maternal heart rates. Biol Reprod Monogr. 1995; 1:7– 11. Carnevale EM, Ramirez RJ, Squires EL, Alvarenga MA, Vanderwall DK, McCue PM. Factors affecting pregnancy rates and early embryonic death after equine embryo transfer. Theriogenology. 2000; 54:965–79. Catandi GD, LiPuma L, Obeidat YM, Maclellan LJ, Broeckling CD, Chen T, et al. Oocyte metabolic function, lipid composition, and developmental potential are altered by diet in older mares. Reproduction. 2022 Apr 1;163(4):183–98. Chandrasekharan NV, Simmons DL. The cyclooxygenases. Genome Biol. 2004; 5:241. Chew B, Scenzi T, Wong V, Coelho M. Uptake of B-carotene by plasma, follicular fuid, granulose cells, endometrium in pigs injectable B-carotene. J. Anim. Sci. 1994;72(Supl 1):100. Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F. Toll-like Receptor-4 Mediates Lipopolysaccharide-induced Signal Transduction. Journal of Biological Chemistry. 1999 Apr 16;274(16):10689–92. Christoffersen M, Woodward E, Bojesen AM, Jacobsen S, Petersen MR, Troedsson MH, et al. Inflammatory responses to induced infectious endometritis in mares resistant or susceptible to persistent endometritis. BMC Veterinary Research. 2012;8(1):41. Colenbrander B, Fazeli AR, Van Buiten A, Parlevliet J, Gadella BM. Assessment of sperm cell membrane integrity in the horse. Acta Veterinaria Scandinavica. 1992; 88:49-58. PMid:1283655. Collingridge DR, Rockwell S. Pentoxifylline improves the oxygenation and radiation response of BA1112 rat rhabdomyosarcomas and EMT6 mouse mammary carcinomas. International Journal of Cancer. 2000;90(5):256–64. 29 Contri A, De Amicis I, Molinari A, Faustini M, Gramenzi A, Robbe D, et al. Effect of dietary antioxidant supplementation on fresh semen quality in stallion. Theriogenology. 2011 Apr;75(7):1319–26. Cotran RS, Kumar V, Collins T, Robbins SL. Pathologic Basis of Disease. 6th ed. Philadelphia: W.B. Saunders; 1999. Couper KN, Blount DG, Riley EM. IL-10: The Master Regulator of Immunity to Infection. The Journal of Immunology [Internet]. 2008 Apr 18;180(9):5771– 7. Disponível em: https://www.jimmunol.org/content/180/9/5771 Crisman MV, Wilcke JR, Correll LS, Irby MH. Pharmacokinetic disposition of intravenous and oral pentoxifylline in horses. Journal of Veterinary Pharmacology and Therapeutics. 1993 Mar;16(1):23–31. Cronin JG, Turner ML, Goetze L, Bryant CE, Sheldon IM. Toll-Like Receptor 4 and MYD88-Dependent Signaling Mechanisms of the Innate Immune System Are Essential for the Response to Lipopolysaccharide by Epithelial and Stromal Cells of the Bovine Endometrium1. Biology of Reproduction. 2012 Feb 1;86(2):51. Cuervo-Arango J, Newcombre JR. Effect of changes in endometrial edema score following mating on pregnancy rate in mare. Anim Reprod Sci. 2010; 121S:S115-7. Cuervo-Arango J, Newcombe J. Risk Factors for the Development of Haemorrhagic Anovulatory Follicles in the Mare. Reproduction in Domestic Animals. 2008 Oct 16;45(3):473–80. Cyktor JC, Turner J. Interleukin-10 and Immunity against Prokaryotic and Eukaryotic Intracellular Pathogens. Maurelli AT, editor. Infection and Immunity. 2011 Aug;79(8):2964–73. Deichsel K, Palm F, Koblischke P, Budik S, Aurich C. Effect of a dietary antioxidant supplementation on semen quality in pony stallions. Theriogenology. 2008 May;69(8):940–5. Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R. Insights into the regulation of TNF-a production in human mononuclear cells: the effects of non- specific phosphodiesterase inhibition. Clinics. 2008;63(3):321–8. Diao H, Kohanawa M. Endogenous Interleukin-6 Plays a Crucial Protective Role in Streptococcal Toxic Shock Syndrome via Suppression of Tumor Necrosis Factor Alpha Production. Infection and Immunity. 2005 May 19;73(6):3745–8. Díaz-Bertrana ML, Deleuze S, Pitti Rios L, Yeste M, Morales Fariña I, Rivera del Alamo MM. Microbial Prevalence and Antimicrobial Sensitivity in Equine Endometritis in Field Conditions. Animals [Internet]. 2021 May 1 [citado 2022 Apr 8];11(5):1476. Disponível em: https://www.mdpi.com/2076- 2615/11/5/1476/htm 30 Doré M, Sirois J. Regulation of P-Selectin Expression by Inflammatory Mediators in Canine Jugular Endothelial Cells. Veterinary Pathology. 1996 Nov;33(6):662–71. El-Shahat KH, Abo-El maaty AM. The effect of dietary supplementation with calcium salts of long chain fatty acids and/or l-carnitine on ovarian activity of Rahmani ewes. Animal Reproduction Science. 2010 Jan;117(1-2):78–82. Fedorka CE, Loux SL, Scoggin KE, Adams AA, Troedsson MHT, Ball BA. Alterations in T cell-related transcripts at the feto-maternal interface throughout equine gestation. Placenta. 2020 Jan; 89:78–87. Ferris RA. Bacterial endometritis: A focus on biofilms. Clin. Theriogenol. 2014; 6:315–19. Ferris RA. Current understanding of bacterial biofilms and latent infections: A clinical perspective. Rev. Bras. Reprod. Anim. 2017; 41:74–80. Ferris RA. Diagnostic Tools for Infectious Endometritis. Vet. CLin. Equine. 2016; 32:481-98. Ferris RA. Therapeutics for Infectious Endometritis: A Clinical Perspective. Rev. Bras. Reprod. Animal. 2017;41(1):175-9. Ferris RA, Bohn A, McCue PM. Equine endometrial cytology: Collection techniques and interpretation. Equine Veterinary Education. 2015 Feb 3;27(6):316–22. Ferris RA, McCue PM, Borlee GI, Loncar KD, Hennet ML, Borlee BR. In Vitro Efficacy of Nonantibiotic Treatments on Biofilm Disruption of Gram- Negative Pathogens and an In Vivo Model of Infectious Endometritis Utilizing Isolates from the Equine Uterus. Fenwick BW, editor. Journal of Clinical Microbiology. 2016 Mar;54(3):631–9. Finno CJ, Valberg SJ. A Comparative Review of Vitamin E and Associated Equine Disorders. Journal of Veterinary Internal Medicine. 2012 Aug 27;26(6):1251–66. Fioratti EG, Villaverde AISB, Melo CM, Tsunemi MH, Papa FO, Alvarenga MA. Influence of Steroidal Anti-Inflammatory Drugs on Viability and Fertility of Equine Semen. Journal of Equine Veterinary Science. 2012 Dec;32(12):771–5. Franchi L, Warner N, Viani K, Nuñez G. Function of Nod-like receptors in microbial recognition and host defense. Immunological Reviews. 2009 Jan;227(1):106–28. Freeman DA, Weber JA, Geary RT, Woods GL. Time of embryo transport through the mare oviduct. Theriogenology. 1991 Nov;36(5):823–30. Freitas ML, Bouéres CS, Pignataro TA, Gonçalves de Oliveira FJ, de Oliveira Viu MA, de Oliveira RA. Quality of Fresh, Cooled, and Frozen Semen from Stallions Supplemented with Antioxidants and Fatty Acids. Journal of Equine Veterinary Science. 2016 Nov; 46:1–6. 31 Freitas ML, Oliveira RA de. Nutraceutical in male reproduction. Brazilian Journal of Veterinary Medicine. 2018;40. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. The Journal of Cell Biology [Internet]. 2007 Jan 8 [citado 2019 Feb 28];176(2):231–41. Disponível em: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063942/ Fumuso E, Giguère S, Wade J, Rogan D, Videla-Dorna I, Bowden RA. Endometrial IL-1β, IL-6 and TNF-α, mRNA expression in mares resistant or susceptible to post-breeding endometritis. Veterinary Immunology and Immunopathology. 2003 Nov;96(1-2):31–41. Fumuso E, Aguilar J, Gigu S. Interleukin-8 (IL-8) and 10 (IL-10) mRNA transcriptions in the endometrium of normal mares and mares susceptible to persistent post-breeding endometritis. Animal Reproduction Science. 2006 Aug;94(1-4):282–5. Fumuso EA, Aguilar J, Giguère S, Rivulgo M, Wade J, Rogan D. Immune parameters in mares resistant and susceptible to persistent post-breeding endometritis: Effects of immunomodulation. Veterinary Immunology and Immunopathology. 2007 Jul;118(1-2):30–9. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, et al. Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus Erythematosus. Science Translational Medicine. 2011 Mar 9;3(73). Gerard N, Caillaud M, Martoriati A, Goudet G, Lalmanach A. The interleukin-1 system and female reproduction. Journal of Endocrinology. 2004 Feb 1;180(2):203–12. Ginther OJ, Pierson RA. Ultrasonic anatomy and pathology of the equine uterus. Theriogenology. 1984 Mar;21(3):505–16. Girling JE, Hedger MP. Toll‐like receptors in the gonads and reproductive tract: emerging roles in reproductive physiology and pathology. Immunology & Cell Biology. 2007 Jun 26;85(6):481–9. Gliozzi TM, Zaniboni L, Maldjian A, Luzi F, Maertens L, Cerolini S. Quality and lipid composition of spermatozoa in rabbits fed DHA and vitamin E rich diets. Theriogenology. 2009 Apr;71(6):910–9. Gomes GM, Ramos DDS, Jacob JCF, Crespilho AM, Cortes PP, De Macedo LP, et al. Influencia da administração do promater® sobre a produção de embriões e perfil hematológico de doadoras de embrião equino. Revista de Saúde. 2014 Dec 1;5(1.2):11-21. Gores-Lindholm AR, LeBlanc MM, Causey R, Hitchborn A, Fayrer-Hosken RA, Kruger M, et al. Relationships between intrauterine infusion of N-acetylcysteine, equine endometrial pathology, neutrophil function, post-breeding therapy, and reproductive performance. Theriogenology. 2013 Aug;80(3):218–27. 32 Goulart H de M, Silva AEDF, McManus C, Papa FO. Efeitos da pentoxifilina sobre a viabilidade in vitro dos espermatozóides de eqüinos, após o resfriamento a 5oC. Revista Brasileira de Zootecnia. 2004 Feb;33(1):112–22. Graczyk J, Macpherson ML, Pozor MA, Troedsson MHT, Eichelberger AC, Leblanc MM, et al. Treatment efficacy of trimethoprim sulfamethoxazole and pentoxifylline in equine placentitis. Animal Reproduction Science. 2006 Aug;94(1-4):434–5. Griscavage JM, Wilk S, Ignarro LJ. Inhibitors of the proteasome pathway interfere with induction of nitric oxide synthase in macrophages by blocking activation of transcription factor NF-kappa B. Proceedings of the National Academy of Sciences. 1996 Apr 16;93(8):3308–12. Grossman TR, Hettrick LA, Johnson RB, Hung G, Peralta R, Watt A, et al. Inhibition of the alternative complement pathway by antisense oligonucleotides targeting complement factor B improves lupus nephritis in mice. Immunobiology. 2016 Jun;221(6):701–8. Hackett T-L, Holloway R, Holgate ST, Warner JA. Dynamics of pro- inflammatory and anti-inflammatory cytokine release during acute inflammation in chronic obstructive pulmonary disease: an ex vivo study. Respiratory Research. 2008 May 29;9(1). Hȧkansson A, Albihn A, Magnusson U. The contribution of complement to opsonic activity in the uterine secretions of mares free of endometritis. Theriogenology. 1993 Mar;39(3):601–9. Hendry JM, Lester GD, Hansen PJ, O’Donnell LJ. Patterns of uterine myoelectrical activity in reproductively normal mares in late gestation and in mares with experimentally induced ascending placentitis. Theriogenology. 2002 Aug;58(2-4):853–5. Hunt LD. The effects of dietary protein on reproduction in pony mares. 1983;29 p. IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp Ignácio FS, Meira C. Subfertility in mares: how to diagnose the cause? Rev Bras Reprod Anim. 2021;45(4):533-41. Jacoby D, Mohler ER. Drug Treatment of Intermittent Claudication. Drugs. 2004;64(15):1657–70. Janeway CA, Medzhitov R. Innate immune recognition. Ann. Rev. Immunol. 2002; 20:197–216. Jones SA. Directing Transition from Innate to Acquired Immunity: Defining a Role for IL-6. The Journal of Immunology. 2005 Sep 7;175(6):3463–8. Jørgensen N, Persson G, Hviid TVF. The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer. Frontiers in Immunology. 2019 May 8;10:911. 33 Katila T. Evaluation of diagnostic methods in equine endometritis. Reproductive Biology. 2016 Sep;16(3):189–96. Katila T. Onset and Duration of Uterine Inflammatory Response of Mares after Insemination with Fresh Semen. Biology of Reproduction. 1995 Jan 1;52(monograph_series1):515–7. Kelley DE, Warren LK, Mortensen CJ. L-Arginine supplementation reduces uterine fluid accumulation post foaling in the mare. Journal of Equine Veterinary Science. 2011 May;31(5-6):315–6. Kenney RM. Cyclic and pathologic changes of the mare’s endometrium as detected by biopsy, with a note on early embryonic death. J Am Vet Med Assoc.1978; 172:241-62. Kenney RM, Doig PA. Equine endometrial biopsy: Current therapy in Theriogenology. Philadelphia: WB Saunders. 1986;723-9. Kirschvink N, Moffarts B de, Lekeux P. The oxidant/antioxidant equilibrium in horses. The Veterinary Journal. 2008 Aug;177(2):178–91. Kitaya K, Yamada H. Pathophysiological Roles of Chemokines in Human Reproduction: An Overview. American Journal of Reproductive Immunology. 2010 Nov 19;65(5):449–59 Knutti B, Pycock JF, Weijden GC, Küpfer U. The influence of early postbreeding uterine lavage on pregnancy rate in mares with intrauterine fluid accumulations after breeding. Equine Veterinary Education. 2010 Jan 5;12(5):267–70. Kornreich B, Enyeart M, Jesty SA, Nydam DV, Divers T. The Effects of Pentoxifylline on Equine Platelet Aggregation. Journal of Veterinary Internal Medicine. 2010 Aug 12;24(5):1196–202. Kozdrowski R, Sikora M, Buczkowska J, Nowak M, Raś A, Dzięcioł M. Effects of cycle stage and sampling procedure on interpretation of endometrial cytology in mares. Animal Reproduction Science. 2015 Mar;154:56–62. Kuchma SL, Connolly JP, O’Toole GA. A Three-Component Regulatory System Regulates Biofilm Maturation and Type III Secretion in Pseudomonas aeruginosa. Journal of Bacteriology [Internet]. 2005 Feb 1;187(4):1441–54. Disponível em: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545632/ Kumar V. The complement system, toll-like receptors and inflammasomes in host defense: three musketeers’ one target. International Reviews of Immunology. 2019 May 8;38(4):131–56. Lauterbach R, Pawlik D, Zembala M, Szymura-Oleksiak J, Lisowska-Miszczyk I, Kowalczyk D, et al. Pentoxyfylline in and prevention and treatment of chronic lung disease. Acta Paediatrica. 2007 Jan 2; 93:20–2. Lauterbach R, Zembala M. Pentoxifylline reduces plasma tumour necrosis factor-alpha concentration in premature infants with sepsis. Eur J Pediatr 1996;155(5):404–9. 34 Lawrence T. The Nuclear Factor NF- B Pathway in Inflammation. Cold Spring Harbor Perspectives in Biology [Internet]. 2009 Oct 7;1(6):a001651–1. Disponível em: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882124/ Leal L, Nogueira EWC. Tratamento conservativo de avulsão no casco de um equino- relato de caso. Anais do Salão Internacional de Ensino, Pesquisa e Extensão. 2020 Feb 14; 8(1). LeBlanc M. Advances in the Diagnosis and Treatment of Chronic Infectious and Post-Mating-Induced Endometritis in the Mare. Reproduction in Domestic Animals. 2010 May 17; 45:21–7. LeBlanc M, Causey R. Clinical and Subclinical Endometritis in the Mare: Both Threats to Fertility. Reproduction in Domestic Animals. 2009 Sep; 44:10–22. LeBlanc MM, Neuwirth L, Asbury AC, Trant T, Mauragis D, Klapstein E. Scintigraphic measurement of uterine clearance in normal mares and mares with recurrent endometritis. Equine Veterinary Journal. 1994 Mar;26(2):109–13. Lee T. Differential lipogenic effects of cilostazol and pentoxifylline in patients with intermittent claudication: potential role for interleukin-6. Atherosclerosis. 2001 Oct;158(2):471–6. Liu I, Rakestraw P, Coit C, Harmon F, Snyder J. An in vitro investigation of the mechanism of neuromuscular regulation in myometrial contractility. Pferdeheilkunde. 1997; 13:557. Lögters T, Margraf S, Altrichter J, Cinatl J, Mitzner S, Windolf J, et al. The clinical value of neutrophil extracellular traps. Medical Microbiology and Immunology. 2009 Aug 4;198(4):211–9. Ma L, Jackson KD, Landry RM, Parsek MR, Wozniak DJ. Analysis of Pseudomonas aeruginosa Conditional Psl Variants Reveals Roles for the Psl Polysaccharide in Adhesion and Maintaining Biofilm Structure Postattachment. Journal of Bacteriology. 2006 Sep 15;188(23):8213–21. Macpherson ML. Diagnosis and Treatment of Equine Placentitis. Veterinary Clinics of North America: Equine Practice. 2006 Dec;22(3):763–76. Mah TFC, O’Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001:9:34–9. Marques A, Arruda RP, Celeghini ECC, Gobesso AAO, Neto JRN. Effects of ascorbic acid and pentoxifylline on equine cryopreserved semen submitted to in vitro incubation. Theriogenology. 2002 Aug;58(2-4):257–60. Marth CD, Firestone SM, Hanlon D, Glenton LY, Browning GF, Young ND, et al. Innate immune genes in persistent mating-induced endometritis in horses. Reproduction, Fertility and Development. 2018;30(3):533. Martoriati A, Duchamp G, GérardN. In Vivo Effect of Epidermal Growth Factor, Interleukin-1β, and Interleukin-1RA on Equine Preovulatory Follicles1. Biology of Reproduction. 2003 May 1;68(5):1748–54. 35 Medzhitov R, Janeway Jr CA. Innate immune recognition and control of adaptive immune responses. Seminars in Immunology. 1998 Oct;10(5):351–3. Meri S. Self-nonself discrimination by the complement system. FEBS Letters. 2016 Jul 19;590(15):2418–34. Merighi M, Lee VT, Hyodo M, Hayakawa Y, Lory S. The second messenger bis- (3’-5’)-cyclic-GMP and its PilZ domain-containing receptor Alg44 are required for alginate biosynthesis in Pseudomonas aeruginosa. Molecular Microbiology. 2007 Aug;65(4):876–95. Meru VA, Mittra S, Thyagarajan B, Chugh A. Intermittent claudication: Na overview. Atherosclerosis. 2006;187(2):221-37. Mesa AM, Warren LK, Sheehan JM, Kelley DE, Mortensen CJ. l-Arginine supplementation 0.5% of diet during the last 90 days of gestation and 14 days postpartum reduced uterine fluid accumulation in the broodmare. Animal Reproduction Science. 2015 Aug; 159:46–51. Metcalf ES. The effect of Platelet-Rich Plasma (PRP) on intraluminal fluid and pregnancy rates in mares susceptible to Persistent Mating-Induced Endometritis (PMIE). Journal of Equine Veterinary Science. 2014 Jan;34(1):128. Mitchell G, Liu IK, Perryman LE, Stabenfeldt GH, Hughes JP. Preferential production and secretion of immunoglobulins by the equine endometrium—A mucosal immune system. J. Reprod. Fertil. Suppl. 1982; 32:161–8. Moldenhauer LM, Diener KR, Thring DM, Brown MP, Hayball JD, Robertson SA. Cross-Presentation of Male Seminal Fluid Antigens Elicits T Cell Activation to Initiate the Female Immune Response to Pregnancy. The Journal of Immunology. 2009 Jun 3;182(12):8080–93. Mustoe T. Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy. The American Journal of Surgery [Internet]. 2004 May;187(5): S65–70. Disponível em: https://www.sciencedirect.com/science/article/pii/S0002961003003064 Nash DM, Sheldon IM, Herath S, Lane EA. Markers of the uterine innate immune response of the mare. Animal Reproduction Science. 2010 May;119(1- 2):31–9. Nielsen JM. Endometritis in the mare: A diagnostic study comparing cultures from swab and biopsy. Theriogenology. 2005 Aug;64(3):510–8. Nielsen JM, Nielsen FH, Petersen MR. Diagnosis of equine endometritis- microbiology, cytology and histology of endometrial biopsies and the correlation to fertility, Pferdeheilkunde. 2012; 28:8-13. Nocera FP, Ambrosio M, Conte A, Palma TD, Castaldo S, Pasolini MP, Fiorito F, Martino LD. Importance of broth-enrichment culture in equine endometritis diagnosis. New Microbiologica. 2021;44(1):19-23. 36 Nonaka M. Evolution of the complement system. Subcell. Biochem. 2014; 80:31–43. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest. 2000; 117:1162–72. Otani S, Kuinose M, Murakami T, Saito S, Iwagaki H, Tanaka N, et al. Preoperative oral administration of pentoxifylline ameliorates respiratory index after cardiopulmonary bypass through decreased production of IL-6. Acta Med Okayama 2008 Apr;62(2):69–74. Ott E, Lechner H, Fazekas F. Hemorheological Effects of Pentoxifylline on Disturbed Flow Behavior of Blood in Patients with Cerebrovascular Insufficiency. European Neurology. 1983;22(1):105–7. Overbeck W, Witte TS, Heuwieser W. Comparison of three diagnostic methods to identify subclinical endometritis in mares. Theriogenology. 2011 Apr;75(7):1311–8. Palm F, Walter I, Budik S, Kolodziejek J, Nowotny N, Aurich C. Influence of different semen extenders and seminal plasma on PMN migration and on expression of IL-1β, IL-6, TNF-α and COX-2 mRNA in the equine endometrium. Theriogenology. 2008 Sep;70(5):843–51. Palmer E, Chavette-Palmer P, Duchamp G, Levy L. Lack of effect of clenbuterol for delaying parturition in late pregnant mares. Theriogenology. 2002 Aug;58(2- 4):797–9 Parham P. The Immune System. 4th Edition. New York: Garland Science. 2015 Pekmezci D. Vitamin E and immunity. Vitam Horm. 2011; 86:179-215. Perelló M, González-Foruria I, Castillo P, Martínez-Florensa M, Lozano F, Balasch J, et al. Oral Administration of Pentoxifylline Reduces Endometriosis- Like Lesions in a Nude Mouse Model. Reproductive Sciences. 2016 Oct 12;24(6):911–8. Petersen MR, Skive B, Christoffersen M, Lu K, Nielsen JM, Troedsson MHT, et al. Activation of persistent Streptococcus equi subspecies zooepidemicus in mares with subclinical endometritis. Veterinary Microbiology. 2015 Aug;179(1- 2):119–25. Politis I, Hidiroglou M, Batra TR, Gilmore JA, Gorewit RC, Scherf H. Effects of vitamin E on immune function of dairy cows. Am J Vet Res. 1995 Feb;56(2):179-84. Pollice PF, Rosier RN, Looney RJ, Puzas JE, Schwarz EM, O’Keefe RJ. Oral Pentoxifylline Inhibits Release of Tumor Necrosis Factor-Alpha from Human Peripheral Blood Monocytes. The Journal of Bone and Joint Surgery-American Volume. 2001 Jul;83(7):1057–61. Pozor MA, Muehlhaus J, King A, Macpherson ML, Troedsson MH, Bailey CS. Effect of pentoxifylline treatment on testicular perfusion and semen quality in Miniature horse stallions. Theriogenology. 2011 Oct;76(6):1027–35. 37 Prasad K, Lee P. Suppression of hypercholesterolemic atherosclerosis by pentoxifylline and its mechanism. Atherosclerosis. 2007 Jun;192(2):313–22. Pycock JF, Allen WE. Inflammatory components in uterine fluid from mares with experimentally induced bacterial endometritis. Equine Veterinary Journal. 1990 Nov;22(6):422–5. Pycock JF, Paccamonti D, Jonker H, Newcombe J, van der Weijden G, Taverne M. Can mares be classified as resistant or susceptible to recurrent endometritis. Pferdeheilkunde Equine Medicine. 1997;13(5):431–6. Ramírez‐Agámez L, Hernández‐Avilés C, Makloski‐Cohorn C. Cytology of the Endometrium. In: Wiley Blackwell. Equine Hematology, Cytology, and Clinical Chemistry. 2020 Nov;243-255. Rasmussen CD, Petersen MR, Bojesen AM, Pedersen HG, Lehn-Jensen H, Christoffersen M. Equine Infectious Endometritis—Clinical and Subclinical Cases. Journal of Equine Veterinary Science. 2015 Feb;35(2):95– 104. Rebello SA, Macpherson ML, Murchie TA, et al. The detection of placental drug transfer in equine allantoic fluid. Theriogenology 2005;64(3):776–7. Rebello SA, Macpherson ML, Murchie TA, Leblanc MM, Vickroy TW. Placental transfer of trimethoprim sulfamethoxazole and pentoxifylline in pony mares. Animal Reproduction Science. 2006 Aug;94(1-4):432–3. Rebordão MR, Carneiro C, Alexandre-Pires G, Brito P, Pereira C, Nunes T, et al. Neutrophil extracellular traps formation by bacteria causing endometritis in the mare. Journal of Reproductive Immunology. 2014 Dec; 106:41–9. Reilas T, Katila T, Mäkelä O, Huhtinen M, Koskinen E. Intrauterine Fluid Accumulation in Oestrous Mares. Acta Veterinaria Scandinavica. 1997 Mar;38(1):69–78. Riddle WT, LeBlanc MM, Stromberg AJ. Relationships between uterine culture, cytology and pregnancy rates in a Thoroughbred practice. Theriogenology. 2007 Aug;68(3):395–402. Ricketts SW, Mackintosh ME. Role of anaerobic bacteria in equine endometritis. J Reprod Fertil Suppl. 1987;(35):343-51. Robertson SA, Chin P-Y, Femia JG, Brown HM. Embryotoxic cytokines— Potential roles in embryo loss and fetal programming. Journal of Reproductive Immunology. 2018 Feb; 125:80–8. Rus H, Cudrici C, Niculescu F. The Role of the Complement System in Innate Immunity. Immunologic Research. 2005;33(2):103–12. Sakaguchi S, Sakaguchi N. Regulatory T Cells in Immunologic Self-Tolerance and Autoimmune Disease. International Reviews of Immunology. 2005 Jan;24(3-4):211–26. 38 Samardzic T, Jankovic V, Stosic-Grujicic S, Popadic D, Trajkovic V. Pentoxifylline inhibits the synthesis and IFN-γ-inducing activity of IL-18. Clinical and Experimental Immunology. 2001 May;124(2):274–81. Santos MS, Meydani SN, Leka L, Wu D, Fotouhi N, Meydani M, et al. Natural killer cell activity in elderly men is enhanced by beta-carotene supplementation. The American Journal of Clinical Nutrition [Internet]. 1996 Nov 1 [citado 2020 Jun 28];64(5):772–7. Disponível em: https://academic.oup.com/ajcn/article/64/5/772/4655325 Schillo KK. Effects of dietary energy on control of luteinizing hormone secretion in cattle and sheep. Journal of Animal Science. 1992 Apr 1;70(4):1271–82. Schjenken JE, Robertson SA. Seminal fluid signaling in the female reproductive tract: Implications for reproductive outcome and offspring health. Adv. Exp. Med. Biol. 2015; 868:127-58. Schmid-Lausigk Y, Aurich C. Influences of a diet supplemented with linseed oil and antioxidants on quality of equine semen after cooling and cryopreservation during winter. Theriogenology [Internet]. 2014 Apr 15;81(7):966–73. Disponível em: https://www.sciencedirect.com/science/article/abs/pii/S0093691X1400054 Scott MA, Liu IKM, Overstreet JW. Sperm transport to the oviducts: Abnormalities and their clinical implications. Proc Am Assoc Equine Pratt. 1995; 41:1-2. Scott MA. A glimpse at sperm function in vivo: sperm transport and epithelial interaction in the female reproductive tract. Animal Reproduction Science. 2000 Jul;60-61:337–48. Segabinazzi LGTM, Canisso IF, Podico G, Cunha LL, Novello G, Rosser MF, et al. Intrauterine Blood Plasma Platelet-Therapy Mitigates Persistent Breeding- Induced Endometritis, Reduces Uterine Infections, and Improves Embryo Recovery in Mares. Antibiotics. 2021 Apr 23;10(5):490. Segabinazzi LG, Friso AM, Correal SB, Crespilho AM, Dell’Aqua JA, Miró J, et al. Uterine clinical 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 Dec; 104:120–6. Semeco E, Falcon J, Pivat IV, Fernández M, Rodriguez M, Basalo A, et al. Efficacy os pentoxifylline in the treatment of Exercise-Induced pulmonary hemorrhage in Thouroughbred racehorses. Revista Científica de Veterinaria. 2006 Sep;16(5):481-91. Shah D, Zhang Z, Khodursky A, Kaldalu N, Kurg K, Lewis K. A distinct physiological state of E. coli. BMC Microbiology. 2006;6(1):53. Sheldon IM, Cronin J, Goetze L, Donofrio G, Schuberth H-J. Defining Postpartum Uterine Disease and the Mechanisms of Infection and Immunity in the Female Reproductive Tract in Cattle1. Biology of Reproduction. 2009 Dec 1;81(6):1025–32. 39 Shevach EM. CD4+CD25+ suppressor T cells: more questions than answers. Nature Reviews Immunology. 2002 Jun;2(6):389–400. Smith OB, Akinbamijo OO. Micronutrients and reproduction in farm animals. Animal Reproduction Science. 2000 Jul;60-61:549–60. Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology. 2004 May;112(1):38–43. Soria J, Giovannangeli ML, Jolchine IE, Chassoux G. Pentoxifylline, fibrinogen and leukocytes. Blood Coagul Fibrinolysis. 1990 Oct;1(4– 5):485–7. Souza-Fonseca-Guimaraes F, Adib-Conquy M, Cavaillon J-M. Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils? Molecular Medicine. 2011 Nov 10;18(2):270–85. Steckler D, Naidoo V, Gerber D, Kähn W. Ex vivo influence of carbetocin on equine myometrial muscles and comparison with oxytocin. Theriogenology. 2012 Aug;78(3):502–9. Takeda K, Akira S. TLR signaling pathways. Seminars in Immunology. 2004 Feb;16(1):3–9. Thomas PGA, Ball BA, Brinsko SP. Interaction of Equine Spermatozoa with Oviduct Epithelial Cell Explants is Affected by Estrous Cycle and Anatomic Origin of Explant1. Biology of Reproduction. 1994 Aug 1;51(2):222–8. Tizard IR. Innate immunity: The recognition of invaders. In Veterinary Immunology. 9th ed. St. Louis: Elsevier Saunders. 2009; 1:11–20. Tongu EA de O, Segabinazzi LGTM, Alvarenga ML, Monteiro A, Papa FO, Alvarenga MA. Allogenic mesenchymal stem cell-conditioned medium does not affect sperm parameters and mitigates early endometrial inflammatory responses in mares. Theriogenology. 2021 Jul; 169:1–8. Troedsson MHT, Ababneh MM, Ohlgren AF, Madill S, Vetscher N, Gregas M. Effect of periovulatory prostaglandin F2α on pregnancy rates and luteal function in the mare. Theriogenology. 2001 Jun;55(9):1891–9. Troedsson MHT, Liu IKM, Ing M, Pascoe J, Thurmond M. Multiple site electromyography recordings of uterine activity following an intrauterine bacterial challenge in mares susceptible and resistant to chronic uterine infection. Reproduction. 1993 Nov 1;99(2):307–13. Troedsson MHT, Liu IKM, Ing M, Pascoe J. Smooth Muscle Electrical Activity in the Oviduct, and the Effect of Oxytocin, Prostaglandin F2α, and Prostaglandin E2 on the Myometrium and the Oviduct of the Cycling Mare1. Biology of Reproduction. 1995 Jan 1;52(monograph_series1):475–88. Troedsson MHT, Møller Nielsen J. Non-antibiotic treatment of equine endometritis. Pferdeheilkunde Equine Medicine. 2018;34(1):17–22. 40 Troedsson MHT. Uterine clearance and resistance to persistent endometritis in the mare. Theriogenology. 1999 Aug;52(3):461–71. Tsunoda RH, Celeghini ECC, Arruda RP, Recalde ECS, Oliveira BMM, Nichi M, et al. The effect of semen extender supplemented with pentoxifylline on post- breeding inflammation response assessed by endometrial cytology. Journal of Equine Veterinary Science. 2014 Jan;34(1):156. Túnon AM, Rodriguez-Martinez H, Haglund A, Albihn A, Magnusson U, Einarsson S. Ultrastructure of the secretory endometrium during oestrus in young maiden and foaled mares. Equine Veterinary Journal. 1995 Sep;27(5):382–8. Turner M, Healey G, Sheldon I. Immunity and Inflammation in the Uterus. Reproduction in Domestic Animals [Internet]. 2012 Jul 25 [citado 2019 Sep 11]; 47:402–9. Disponível em: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1439- 0531.2012.02104.x Van de Craen M, Declercq W, Van den brande I, Fiers W, Vandenabeele P. The proteolytic procaspase activation network: an in vitro analysis. Cell Death & Differentiation. 1999 Nov;6(11):1117–24. Van der Hoek KH, Woodhouse CM, Brännström M, Norman RJ. Effects of Interleukin (IL)-6 on Luteinizing Hormone- and IL-1β-lnduced Ovulation and Steroidogenesis in the Rat Ovary1. Biology of Reproduction. 1998 May 1;58(5):1266–71. Van Der Holst M. Experiences with oral administration of beta-carotene to pony mares in early spring. Proc. 35th Annu. Meet. Eur. Assoc. Anim. Prod. 1984. Van Niekerk FE, Van Niekerk CH. The effect of dietary protein on reproduction in the mare. IV. Serum progestagen, FSH, LH and melatonin concentrations during the anovulatory, transitional and ovulatory periods in the non-pregnant mare. Journal of the South African Veterinary Association. 1997 Jul 13;68(4). Vanderwall DK, Woods GL. Effect on fertility of uterine lavage performed immediately prior to insemination in mares. Journal of the American Veterinary Medical Association [Internet]. 2003 Apr 15 [citado 2021 May 4];222(8):1108– 10. Disponível em: https://pubmed.ncbi.nlm.nih.gov/12710775/ Vasseur P. The pel genes of the Pseudomonas aeruginosa PAK strain are involved at early and late stages of biofilm formation. Microbiology. 2005 Mar 1;151(3):985–97. von Reitzenstein M, Callahan MA, Hansen PJ, LeBlanc MM. Aberrations in uterine contractile patterns in mares with delayed uterine clearance after administration of detomidine and oxytocin. Theriogenology. 2002 Sep;58(5):887–98. Walport MJ. Complement. N. Engl. J. Med. 2001; 344:1058–66. Ward A, Clissold SP. Pentoxifylline. Drugs. 1987 Jul;34(1):50–97. 41 Watson ED, Stokes CR, Bourne FJ. Cellular and humoral defence mechanisms in mares susceptible and resistant to persistent endometritis. Veterinary Immunology and Immunopathology. 1987 Sep;16(1-2):107–21 Watson ED, Stokes CR, Bourne FJ. Influence of arachidonic acid metabolites in vitro and in uterine washings on migration of equine neutrophils under agarose. Research in Veterinary Science. 1987 Sep;43(2):203–7. Watson ED. Opsonins in uterine washings influencing in vitro activity of equine neutrophils. Equine Veterinary Journal. 1988 Nov;20(6):435–7. Weiler JM, Daha MR, Austen KF, Fearon DT. Control of the amplification convertase of complement by the plasma protein beta1H. Proc. Nati. Acad. of Sci. 1976 Sep;73(9):3268–72. Wolfsdorf KE. How to utilize endometrial culture, cytology, and biopsy to manage the sub-fertile mare. American Association of Equine Pratitioners (AAEP), Lexington. 2016;164-8. Woodward E, Christoffersen M, Campos J, Horohov D, Scoggin K, Squires E, et al. An Investigation of Uterine Nitric Oxide Production in Mares Susceptible and Resistant to Persistent Breeding-Induced Endometritis and the Effects of Immunomodulation. Reproduction in Domestic Animals. 2012 Dec 10;48(4):554–61. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. Journal of Clinical Investigation. 1998 Jan 15;101(2):311–20. Yovich JL. Pentoxifylline: actions and applications in assisted reproduction. Human Reproduction. 1993 Nov;8(11):1786–91. Zarezadeh R, Mehdizadeh A, Leroy JLMR, Nouri M, Fayezi S, Darabi M. Action mechanisms of n-3 polyunsaturated fatty acids on the oocyte maturation and developmental competence: Potential advantages and disadvantages. Journal of Cellular Physiology. 2018 Aug 2;234(2):1016–29. Zent W, Troedsson M, Xue JL. Postbreeding uterine fluid accumulation in a normal population of Thoroughbred mares: a field study. Proceedings of the American Association of Equine Practitioners. 1998; 44:64–5. Zerbe H, Schuberth HJ, Engelke F, Frank J, Klug E, Leibold W. Development and comparison of in vivo and in vitro models for endometritis in cows and mares. Theriogenology. 2003 Jul;60(2):209–23. Zeyner A, Harmeyer J. Metabolic functions of L‐Carnitine and its effects as feed additive in horses. A review. Archiv für Tierernaehrung. 1999 Jan;52(2):115–38.