Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia: a New Target for Sepsis

Sebastian Gatica, Felipe Eltit, Juan F. Santibanez, Diego Varela, Claudio Cabello-Verrugio, Felipe Simon

Resultado de la investigación: Article

Resumen

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 (AdVshTRPM7). Then, cytokine and MODS levels in the blood were measured. RESULTS: Inhibition of TRPM7 with carvacrol and suppression with AdVshTRPM7 were both efficient in inhibiting the over-secretion of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-12, in endotoxemic rats, without inducing downregulation in blood levels of antiinflammatory cytokines IL-10 and IL-4. Additionally, the use of carvacrol and AdVshTRPM7 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 AdVshTRPM7 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.

Idioma originalEnglish
Páginas (desde-hasta)547-559
Número de páginas13
PublicaciónCurrent Molecular Medicine
Volumen19
N.º8
DOI
EstadoPublished - 1 ene 2019

Huella dactilar

Endotoxemia
Multiple Organ Failure
Sepsis
Cytokines
Rats
Ion Channels
Muscle
Blood
Down-Regulation
Systemic Inflammatory Response Syndrome
Interleukin-12
Interleukin-1
Hypoglycemia
Adenoviridae
Interleukin-4
Liver
Interleukin-10
Small Interfering RNA
Liver Diseases
Pancreas

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology

Citar esto

@article{b59de05121cd4bf4b93d636c0e906081,
title = "Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia: a New Target for Sepsis",
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 (AdVshTRPM7). Then, cytokine and MODS levels in the blood were measured. RESULTS: Inhibition of TRPM7 with carvacrol and suppression with AdVshTRPM7 were both efficient in inhibiting the over-secretion of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-12, in endotoxemic rats, without inducing downregulation in blood levels of antiinflammatory cytokines IL-10 and IL-4. Additionally, the use of carvacrol and AdVshTRPM7 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 AdVshTRPM7 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.",
keywords = "cytokine, Endotoxemia, MODS, organ dysfunction, sepsis., TRPM7",
author = "Sebastian Gatica and Felipe Eltit and Santibanez, {Juan F.} and Diego Varela and Claudio Cabello-Verrugio and Felipe Simon",
year = "2019",
month = "1",
day = "1",
doi = "10.2174/1566524019666190709181726",
language = "English",
volume = "19",
pages = "547--559",
journal = "Current Molecular Medicine",
issn = "1566-5240",
publisher = "Bentham Science Publishers B.V.",
number = "8",

}

TY - JOUR

T1 - Expression Suppression and Activity Inhibition of TRPM7 Regulate Cytokine Production and Multiple Organ Dysfunction Syndrome During Endotoxemia

T2 - a New Target for Sepsis

AU - Gatica, Sebastian

AU - Eltit, Felipe

AU - Santibanez, Juan F.

AU - Varela, Diego

AU - Cabello-Verrugio, Claudio

AU - Simon, Felipe

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 (AdVshTRPM7). Then, cytokine and MODS levels in the blood were measured. RESULTS: Inhibition of TRPM7 with carvacrol and suppression with AdVshTRPM7 were both efficient in inhibiting the over-secretion of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-12, in endotoxemic rats, without inducing downregulation in blood levels of antiinflammatory cytokines IL-10 and IL-4. Additionally, the use of carvacrol and AdVshTRPM7 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 AdVshTRPM7 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.

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 (AdVshTRPM7). Then, cytokine and MODS levels in the blood were measured. RESULTS: Inhibition of TRPM7 with carvacrol and suppression with AdVshTRPM7 were both efficient in inhibiting the over-secretion of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-12, in endotoxemic rats, without inducing downregulation in blood levels of antiinflammatory cytokines IL-10 and IL-4. Additionally, the use of carvacrol and AdVshTRPM7 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 AdVshTRPM7 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.

KW - cytokine

KW - Endotoxemia

KW - MODS

KW - organ dysfunction

KW - sepsis.

KW - TRPM7

UR - http://www.scopus.com/inward/record.url?scp=85072546272&partnerID=8YFLogxK

U2 - 10.2174/1566524019666190709181726

DO - 10.2174/1566524019666190709181726

M3 - Article

C2 - 31288723

AN - SCOPUS:85072546272

VL - 19

SP - 547

EP - 559

JO - Current Molecular Medicine

JF - Current Molecular Medicine

SN - 1566-5240

IS - 8

ER -