Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia: A New Target for Sepsis
Само за регистроване кориснике
2019
Аутори
Gatica, SebastianEltit, Felipe
Santibanez, Juan F.
Varela, Diego
Cabello-Verrugio, Claudio
Simon, Felipe
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Background: Main pathological features detected during sepsis and endotoxemia include over-secretion of pro-inflammatory cytokines and multiorgan dysfunction syndrome (MODS). Unfortunately, current clinical efforts to treat sepsis are unsatisfactory, and mortality remains high. Interestingly, transient receptor potential (TRP) melastatin 7 (TRPM7) ion channel controlling Ca2+ and Mg2+ permeability is involved in cytokine production and inflammatory response. Furthermore, TRPM7 downregulation has been shown to alleviate local symptoms in some models of sepsis, but its effects at a systemic level remain to be explored. Objective: To test whether TRPM7 mediates cytokine production and MODS during endotoxemia. Methods: Endotoxemic and sham-endotoxemic rats were subjected to pharmacological inhibition of TRPM7 using carvacrol, or to expression suppression by adenovirus delivery of shRNA (AdV(shTRPM7)). Then, cytokine and MODS levels in the blood were measured. Results: Inhibition of TRPM7 w...ith carvacrol and suppression with AdV(shTRPM7 )were both efficient in inhibiting the over-secretion of pro-inflammatory cytokines TNF-alpha, IL-1 beta, IL-6, and IL-12 in endotoxemic rats, without inducing downregulation in blood levels of anti-inflammatory cytokines IL-10 and IL-4. Additionally, the use of carvacrol and AdV(shTRPM7) significantly prevented liver and pancreas dysfunction, altered metabolic function, and hypoglycemia, induced by endotoxemia. Furthermore, muscle mass wasting and cardiac muscle damage were also significantly reduced by the use of carvacrol and AdV(shTRPM7) in endotoxemic rats. Conclusion: Our results indicate TRPM7 ion channel as a key protein regulating inflammatory responses and MODS during sepsis. Moreover, TRPM7 appears as a novel molecular target for the management of sepsis.
Кључне речи:
Endotoxemia / TRPM7 / cytokine / sepsis / organ dysfunction / MODSИзвор:
Current Molecular Medicine, 2019, 19, 8, 547-559Издавач:
- Bentham Science Publ Ltd, Sharjah
Финансирање / пројекти:
- Fondo Nacional de Desarrollo Científico y Tecnológico – FONDECYT [1161288, 1160900, 1161646]
- Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) [21171566]
- Millennium Institute on Immunology and Immunotherapy [P09-016-F]
- Iniciativa Científica Milenio of the Ministry of Economy, Development and Tourism (Chile), UNAB DI-741-15/N
- Programa de Cooperación Científica ECOS-CONICYT [C16S02]
- BASAL Grant CEDENNA FB0807
- Биолошки механизми, нутритивни унос и статус полинезасићених масних киселина и фолата: Унапређење исхране у Србији (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41030)
- Испитивање патогенезе хематолошких малигнитета (RS-MESTD-Basic Research (BR or ON)-175053)
DOI: 10.2174/1566524019666190709181726
ISSN: 1566-5240
PubMed: 31288723
WoS: 000484548900002
Scopus: 2-s2.0-85072546272
Институција/група
Institut za medicinska istraživanjaTY - JOUR AU - Gatica, Sebastian AU - Eltit, Felipe AU - Santibanez, Juan F. AU - Varela, Diego AU - Cabello-Verrugio, Claudio AU - Simon, Felipe PY - 2019 UR - http://rimi.imi.bg.ac.rs/handle/123456789/905 AB - Background: Main pathological features detected during sepsis and endotoxemia include over-secretion of pro-inflammatory cytokines and multiorgan dysfunction syndrome (MODS). Unfortunately, current clinical efforts to treat sepsis are unsatisfactory, and mortality remains high. Interestingly, transient receptor potential (TRP) melastatin 7 (TRPM7) ion channel controlling Ca2+ and Mg2+ permeability is involved in cytokine production and inflammatory response. Furthermore, TRPM7 downregulation has been shown to alleviate local symptoms in some models of sepsis, but its effects at a systemic level remain to be explored. Objective: To test whether TRPM7 mediates cytokine production and MODS during endotoxemia. Methods: Endotoxemic and sham-endotoxemic rats were subjected to pharmacological inhibition of TRPM7 using carvacrol, or to expression suppression by adenovirus delivery of shRNA (AdV(shTRPM7)). Then, cytokine and MODS levels in the blood were measured. Results: Inhibition of TRPM7 with carvacrol and suppression with AdV(shTRPM7 )were both efficient in inhibiting the over-secretion of pro-inflammatory cytokines TNF-alpha, IL-1 beta, IL-6, and IL-12 in endotoxemic rats, without inducing downregulation in blood levels of anti-inflammatory cytokines IL-10 and IL-4. Additionally, the use of carvacrol and AdV(shTRPM7) significantly prevented liver and pancreas dysfunction, altered metabolic function, and hypoglycemia, induced by endotoxemia. Furthermore, muscle mass wasting and cardiac muscle damage were also significantly reduced by the use of carvacrol and AdV(shTRPM7) in endotoxemic rats. Conclusion: Our results indicate TRPM7 ion channel as a key protein regulating inflammatory responses and MODS during sepsis. Moreover, TRPM7 appears as a novel molecular target for the management of sepsis. PB - Bentham Science Publ Ltd, Sharjah T2 - Current Molecular Medicine T1 - Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia: A New Target for Sepsis EP - 559 IS - 8 SP - 547 VL - 19 DO - 10.2174/1566524019666190709181726 ER -
@article{ author = "Gatica, Sebastian and Eltit, Felipe and Santibanez, Juan F. and Varela, Diego and Cabello-Verrugio, Claudio and Simon, Felipe", year = "2019", abstract = "Background: Main pathological features detected during sepsis and endotoxemia include over-secretion of pro-inflammatory cytokines and multiorgan dysfunction syndrome (MODS). Unfortunately, current clinical efforts to treat sepsis are unsatisfactory, and mortality remains high. Interestingly, transient receptor potential (TRP) melastatin 7 (TRPM7) ion channel controlling Ca2+ and Mg2+ permeability is involved in cytokine production and inflammatory response. Furthermore, TRPM7 downregulation has been shown to alleviate local symptoms in some models of sepsis, but its effects at a systemic level remain to be explored. Objective: To test whether TRPM7 mediates cytokine production and MODS during endotoxemia. Methods: Endotoxemic and sham-endotoxemic rats were subjected to pharmacological inhibition of TRPM7 using carvacrol, or to expression suppression by adenovirus delivery of shRNA (AdV(shTRPM7)). Then, cytokine and MODS levels in the blood were measured. Results: Inhibition of TRPM7 with carvacrol and suppression with AdV(shTRPM7 )were both efficient in inhibiting the over-secretion of pro-inflammatory cytokines TNF-alpha, IL-1 beta, IL-6, and IL-12 in endotoxemic rats, without inducing downregulation in blood levels of anti-inflammatory cytokines IL-10 and IL-4. Additionally, the use of carvacrol and AdV(shTRPM7) significantly prevented liver and pancreas dysfunction, altered metabolic function, and hypoglycemia, induced by endotoxemia. Furthermore, muscle mass wasting and cardiac muscle damage were also significantly reduced by the use of carvacrol and AdV(shTRPM7) in endotoxemic rats. Conclusion: Our results indicate TRPM7 ion channel as a key protein regulating inflammatory responses and MODS during sepsis. Moreover, TRPM7 appears as a novel molecular target for the management of sepsis.", publisher = "Bentham Science Publ Ltd, Sharjah", journal = "Current Molecular Medicine", title = "Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia: A New Target for Sepsis", pages = "559-547", number = "8", volume = "19", doi = "10.2174/1566524019666190709181726" }
Gatica, S., Eltit, F., Santibanez, J. F., Varela, D., Cabello-Verrugio, C.,& Simon, F.. (2019). Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia: A New Target for Sepsis. in Current Molecular Medicine Bentham Science Publ Ltd, Sharjah., 19(8), 547-559. https://doi.org/10.2174/1566524019666190709181726
Gatica S, Eltit F, Santibanez JF, Varela D, Cabello-Verrugio C, Simon F. Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia: A New Target for Sepsis. in Current Molecular Medicine. 2019;19(8):547-559. doi:10.2174/1566524019666190709181726 .
Gatica, Sebastian, Eltit, Felipe, Santibanez, Juan F., Varela, Diego, Cabello-Verrugio, Claudio, Simon, Felipe, "Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia: A New Target for Sepsis" in Current Molecular Medicine, 19, no. 8 (2019):547-559, https://doi.org/10.2174/1566524019666190709181726 . .