Blockage of the P2X7 Receptor Attenuates Harmful Changes Produced by Ischemia and Reperfusion in the Myenteric Plexus

Palombit, Kelly; Mendes, Cristina Eusébio; Tavares-de-Lima, Wothan; Barreto‐Chaves, Maria Luíza Morais; Castelucci, Patrícia

doi:10.1007/s10620-019-05496-8

Cited by 25 publications

(37 citation statements)

References 76 publications

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“…Unexpectedly, BBG increased mP2rx7 expression in the gastrointestinal tract. Given that cellular infiltrates in the duodenum were minimal and similar between groups, this increase in mP2rx7 expression may represent BBG blockade of ATP-mediated death of P2X7-expressing host cells such as intestinal epithelial cells (52) , M cells (53) or myenteric plexus neurons (54) . This notion is indirectly supported by BBG impairing molecular development of gastrointestinal GVHD as evidenced by reduced mReg3g expression in the duodenum.…”

Section: Discussionmentioning

confidence: 91%

P2X7 receptor antagonism increases regulatory T cells and reduces clinical and histological graft-versus-host disease in a humanised mouse model

et al. 2021

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Graft-versus-host disease (GVHD) is a severe inflammatory response arising from allogeneic haematopoietic stem cell transplantation. Previous studies revealed that antagonism of the P2X7 receptor with Brilliant Blue G (BBG) reduced liver GVHD but did not alter clinical GVHD in a humanised mouse model. Therefore, the current study aimed to trial a modified injection regime using more frequent dosing of BBG to improve outcomes in this model of GVHD. NOD-scid IL2Rγnull (NSG) mice were injected intraperitoneal (i.p.) with 10x106 human peripheral blood mononuclear cells (hPBMCs) (day 0), then daily with BBG (50mg/kg) or saline (days 0-10). BBG significantly reduced clinical score, mortality and histological GVHD compared to saline treatment (endpoint). BBG significantly increased proportions of human regulatory T cells (Tregs) and human B cells and reduced serum human interferon-γ compared to saline treatment prior to development of clinical GVHD (day 21). To confirm the therapeutic benefit of P2X7 antagonism, NSG mice were injected i.p. with 10x106 hPBMCs (day 0), then daily with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) (300mg/kg) or saline (days 0-10). PPADS increased human Treg proportions compared to saline treatment (day 21), but potential clinical benefits were confounded by increased weight loss with this antagonist. To investigate the role of P2X7 antagonism on Treg survival, hPBMCs were cultured in reduced serum conditions to promote cell death. BBG increased proportions of Tregs (and B cells) compared to saline under these conditions. In conclusion, P2X7 antagonism reduces clinical and histological GVHD in a humanised mouse model corresponding to an increase in human Tregs.

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Section: Discussionmentioning

confidence: 91%

P2X7 receptor antagonism increases regulatory T cells and reduces clinical and histological graft-versus-host disease in a humanised mouse model

et al. 2021

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“…Apart from its role in the inflammatory process and modulating immune responses, P2X7R has also been shown to have a role in GI malignancies ( Adinolfi et al, 2015 ; Hofman et al, 2015 ; Zhang et al, 2021 ), immune modulation ( Proietti et al, 2014 ; Perruzza et al, 2017 ; Liu and Kim, 2019 ; Perruzza et al, 2019 ; Proietti et al, 2019 ), metabolic regulation ( Bourzac et al, 2013 ; Arguin et al, 2017 ; Perruzza et al, 2017 ; Perruzza et al, 2019 ), ISR injury ( Palombit et al, 2019 ) and intestinal damage due to long-term morphine use ( Bhave et al, 2017 ), chronic binge alcohol feeding ( Su et al, 2019 ) and NSAID use ( Higashimori et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Understanding the Role of Purinergic P2X7 Receptors in the Gastrointestinal System: A Systematic Review

Cheng¹,

Zhang²,

Liu³

2021

Front. Pharmacol.

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Background: The role of purinergic P2X7 receptor (P2X7R) is of interest due to its involvement in inflammation and mediating immune cell responses. P2X7R is particularly implicated in the development of inflammatory bowel disease (IBD). However, the extent of the actions of P2X7R in the gastrointestinal (GI) system under physiological and pathophysiological conditions remains to be elucidated. This systematic review aimed to identify, summarize and evaluate the evidence for a critical role of P2X7R in the GI system.Methods: We searched PubMed, Embase and Scopus with search terms pertained to P2X7R in the GI system in disease or physiological state, including “P2X7 or P2X7 receptor or purinergic signaling” in combination with any of the terms “intestine or colon or gut or gastrointestinal,” “pathology or inflammation or disease or disorder,” and “physiology or expression.” Titles and abstracts were screened for potentially eligible full texts, and animal and human studies published in English were included in this study. Data were extracted from papers meeting inclusion criteria. Meta-analysis was not feasible given the study diversity.Results: There were 48 papers included in this review. We identified 14 experimental colitis models, three sepsis models and one ischemia-reperfusion injury model. Among them, 11 studies examined P2X7R in GI infections, six studies on immune cell regulation, four studies on GI inflammation, two studies on GI malignancies, three studies involving intestinal injury due to various causes, two studies on ATP-activated P2X7R in the GI system and two studies on metabolic regulation.Conclusion: Evidence supports P2X7R mediating inflammation and immune cell responses in GI inflammation, infections and injury due to IBD and other challenges to the intestinal wall. P2X7R inhibition by gene knockout or by application of P2X7R antagonists can reduce tissue damage by suppressing inflammation. P2X7R is also implicated in GI malignancies and glucose and lipid homeostasis. P2X7R blockade, however, did not always lead to beneficial outcomes in the various pathological models of study.

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“…Quanto à densidade neuronal, foi observado nos neurônios NOS-ir uma diminuição no grupo Colite 24h e houve um aumento significante de 28% de neurônios NOS-ir no grupo BBG 24 h. No grupo de 7 dias, houve aumento significante de 8% no grupo Colite 7 dias quando comparado ao grupo Colite 24 h e uma diminuição significante de 12% no grupo BBG 7 dias quando comparado ao grupo BBG 24 h. Resultados semelhantes foram observados em modelo de isquemia e reperfusão intestinal tratados com BBG (Palombit et al, 2018). No entanto, um estudo feito em cobaias, demonstrou aumento no número de neurônios NOS-ir após indução de colite, nos períodos de 24 horas e 72 horas, assim como em estudos experimentais de colite e estudos da Doença de Chron em humanos (GEOBEOS et al, 1998;GULBRANSEN et al, 2012).…”

Section: Considerações Sobre a Densidade Neuronalunclassified

>b<Estudo do antagonista do receptor P2X7, >i<Brilliant Blue G>/i<, sobre os neurônios entéricos do colo distal de ratos submetidos à colite ulcerativa experimental>b/<

Evangelinellis¹

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Seria impossível listar todas as pessoas que fizeram parte dessa jornada e que direta ou indiretamente contribuíram para esta tese. Á Universidade de São Paulo, por possibilitar a realização deste trabalho. Ao CNPq, Capes e FAPESP pelo apoio financeiro. À minha mãe, Maria Ivete Munhoz, mãe, melhor amiga, terapeuta, incentivadora, patrocinadora oficial do evento. Obrigada por acreditar em mim. Por mais uma vez fazer do meu sonho o seu sonho. A minha luta, a sua luta. Por enxugar minhas lágrimas, me reerguer e me ensinar todos os dias como ser um ser humano melhor. Nós conseguimos! Ao meu pai, Joannis Evangelos Evangelinellis (in memorian), que mesmo na ausência física sempre esteve presente na minha vida. Que vibrou com a primeira palavra lida. De quem eu herdei a curiosidade e o desejo de aprender sempre. Que de onde estiver, me guia, me protege, me orienta. Aos membros da banca, por aceitarem avaliar esta tese e compartilharem seus conhecimentos. À minha orientadora, Patrícia Castelucci, por abrir as portas do Laboratório de Neurogastroenterologia e aceitar me orientar. Obrigada pelo apoio e conhecimentos compartilhados. À minha vó, Josefa Pelayo Munhoz (in memoriam). Eterna luz da minha vida, exemplo de vida, amor eterno. Quem dera Deus cometesse um descuido e te devolvesse pra nós. À minha vó de coração, Maria Geralda Pereira, minha calanga amada, pela paciência, amor, carinho. Que acompanha minha vida acadêmica desde os tempos de aulas de jazz e piano. Aos meus irmãos Vinsent Munhoz Evangelinellis, Joannis Evangelos Soares Evangelinellis, Ricardo Kutney Evangelinellis e Pedro Kutney Evangelinellis pelo carinho, amor e palavras de incentivo. À amiga e mentora Beatriz Freitas, pelo apoio, confiança, carinho. Sem você esse doutorado jamais teria existido! À Prof. Dra. Patrícia Baleeiro Beltrão Braga, por abrir as portas da Universidade de São Paulo e me receber em seu laboratório. Aos pais e pacientes do Projeto A Fada do Dente. Obrigada por me permitirem fazer parte desse mundo azul, por me receberem em suas casas, acreditarem no meu trabalho e tantos aprendizados. Ao Prof. Dr. José Roberto Kfoury, que cedeu os equipamentos de seu laboratório na primeira etapa deste doutorado. Obrigada pela confiança e suporte na transição de projetos. Aos professores do Departamento de Anatomia Veterinária dos Animais Domésticos e Silvestres, pelos ensinamentos e conhecimento compartilhado. Obrigada pela confiança ao cederem seus equipamentos e espaços. Aos amigos e funcionários do departamento, pelo apoio e suporte durante meu doutorado. Aos amigos queridos da Universidade Federal de São Paulo, que também tiveram participação na primeira etapa deste doutorado. Em especial à Prof. Dra. Janete Cerutti e ao Prof. Dr. Rui Monteiro Maciel por autorizarem o uso de equipamentos e me receberem em seus laboratórios.

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Blockage of the P2X7 Receptor Attenuates Harmful Changes Produced by Ischemia and Reperfusion in the Myenteric Plexus

Cited by 25 publications

References 76 publications

P2X7 receptor antagonism increases regulatory T cells and reduces clinical and histological graft-versus-host disease in a humanised mouse model

P2X7 receptor antagonism increases regulatory T cells and reduces clinical and histological graft-versus-host disease in a humanised mouse model

Understanding the Role of Purinergic P2X7 Receptors in the Gastrointestinal System: A Systematic Review

>b<Estudo do antagonista do receptor P2X7, >i<Brilliant Blue G>/i<, sobre os neurônios entéricos do colo distal de ratos submetidos à colite ulcerativa experimental>b/<

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