Papel de los quimioreceptores carotídeos en la progresión de la sepsis hacia falla orgánica múltiple en ratas endotoxemicas
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Fecha
2012
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Profesor/a Guía
Facultad/escuela
Idioma
es
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Universidad Andrés Bello
Nombre de Curso
Licencia CC
Licencia CC
Resumen
Los síndromes sépticos, sepsis y shock séptico, son la principal causa de morbimortalidad
en pacientes críticos. Involucran una serie de procesos fisiopatológicos como
inflamación sistémica y falla orgánica múltiple (FOM). Esta última se caracteriza por la
pérdida progresiva de la función de distintos órganos, de tal manera que la homeostasis
no puede ser mantenida sin intervención. La FOM como consecuencia de la sepsis por
bacterias Gram-negativo, se inicia por el lipopolisacárido (LPS), que induce una respuesta
inflamatoria sistémica descontrolada, estimulando la síntesis y secreción de citoquinas
pro-inflamatorias, como el TNF-a, que daña los órganos parenquimatosos y provocan la
pérdida de su funcionalidad.
El cuerpo carotídeo, principal quimiorreceptor arterial, juega un papel importante
durante la sepsis, ya que ratas endotoxémicas sometidas a neurotomía carotídea bilateral
(BCN) tienen un tiempo de sobrevida menor al que presentan ratas endotoxémicas con su
inervación carotídea intacta. Adicionalmente, durante una inflamación sistémica
provocada por LPS, el cuerpo carotídeo activaría al SNC, por lo cual podría actuar como
un sensor de la inflamación. Asi, la hipótesis de este trabajo es que los quimiorreceptores
carotídeo juegan un rol protector durante la progresión de la sepsis hacia falla orgánica
múltiple, para lo cual el objetivo es determinar su participación durante esta progresión.
La administración de LPS (15 mg/kg, IP) a ratas Sprague-Dawley sometidas a
BCN, provocó una caída en la frecuencia respiratoria y en la ventilación total, mientras
que el volumen corriente no cambia, lo que indica una supresión de la respuesta
hiperventilatoria vista en ratas endotoxémicas con su inervación carotídea intacta, además
de un mayor aumento en la frecuencia cardiaca y una caída más abrupta en la presión
sistólica. Asimismo, se observa una disminución en el tiempo de sobrevida de estas ratas,
debido, presumiblemente, a que los niveles plasmáticos de TNF-a están aumentados,
consecuencia de que los niveles plasmáticos de cortisol están disminuidos, y los niveles
de adrenalina están aumentados. Adicionalmente, encontramos una aparición temprana
de la falla orgánica múltiple, detectada por un aumento en los niveles plasmáticos de
Creatina Kinasa, Lactato Deshidrogenasa, Fosfatasa Alcalina, Amilasa, Creatinina,
Bilirrubina total y Alanina Aminotransferasa, además de la caída de la glicemia.
Estos resultados sugieren que el cuerpo carotideo juega un papel protector en la
progresión de la sepsis hacia la falla orgánica múltiple.
Sepsis syndromes, sepsis and septic shock are the leading cause of morbidity and mortality in critically ill patients. They involve a series of pathophysiological processes such as systemic inflammation and multiple organ dysfunctions (MOD). The latter is characterized by progressive loss of function of various organs, so that homeostasis cannot be maintained without intervention. Gram-negative-induced sepsis and MOD are initiated by lipopolysaccharide (LPS), through an uncontrolled systemic inflammatory response, stimulating the synthesis and secretion of pro-inflammatory cytokines such as TNF-a, which damages the parenchymatous organs causing loss of functionality. The carotid body, the main arterial chemoreceptor, plays an important role during sepsis, based on evidence sowhing that endotoxemic rats subjected to bilateral carotid neurotomy (BCN) have a lower survival time than rats with intact carotid nerves. Additionally, during LPS-induced systemic inflammation, the carotid body could activate the CNS; which may act as a sensor of inflammation. Thus, the hypothesis of this work is the carotid chemoreceptors play a protective role during the progression of sepsis to multiple organ dysfunction, for which the objective is determine their participation during this progression. Sprague-Dawley rats were treated intraperitoneally with 15 mg/kg LPS after BCN. Endotoxin treatment evoked a fall in respiratory frequency and in total ventilation, while tidal volume was unchanged, indicating a suppression of the hiperventilatory response seen in endotoxemic rats with intact carotid innervation. Additionally, a greater increase in heart frequency and an abrupt fall in systolic blood pressure. A decrease in survival time of these rats was also observed. TNF-a plasma levels were increased correlated to a lack of increased cortisol plasma levels, and increased levels of epinephrine, a negative and positive regulator of TNF-a expression, respectively. The increased TNF-a plasma levels, induced early onset of MOD, was detected by increased plasma levels of Creatine Kinase, Lactate Dehydrogenase, Alkaline Phosphatase, Amylase, Creatinine, total Bilirrubin and Alanine Aminotransferase, in addition to the hypoglycemia. These results suggest that the carotid body plays a protective role in the sepsis progression to multiple organ dysfunction.
Sepsis syndromes, sepsis and septic shock are the leading cause of morbidity and mortality in critically ill patients. They involve a series of pathophysiological processes such as systemic inflammation and multiple organ dysfunctions (MOD). The latter is characterized by progressive loss of function of various organs, so that homeostasis cannot be maintained without intervention. Gram-negative-induced sepsis and MOD are initiated by lipopolysaccharide (LPS), through an uncontrolled systemic inflammatory response, stimulating the synthesis and secretion of pro-inflammatory cytokines such as TNF-a, which damages the parenchymatous organs causing loss of functionality. The carotid body, the main arterial chemoreceptor, plays an important role during sepsis, based on evidence sowhing that endotoxemic rats subjected to bilateral carotid neurotomy (BCN) have a lower survival time than rats with intact carotid nerves. Additionally, during LPS-induced systemic inflammation, the carotid body could activate the CNS; which may act as a sensor of inflammation. Thus, the hypothesis of this work is the carotid chemoreceptors play a protective role during the progression of sepsis to multiple organ dysfunction, for which the objective is determine their participation during this progression. Sprague-Dawley rats were treated intraperitoneally with 15 mg/kg LPS after BCN. Endotoxin treatment evoked a fall in respiratory frequency and in total ventilation, while tidal volume was unchanged, indicating a suppression of the hiperventilatory response seen in endotoxemic rats with intact carotid innervation. Additionally, a greater increase in heart frequency and an abrupt fall in systolic blood pressure. A decrease in survival time of these rats was also observed. TNF-a plasma levels were increased correlated to a lack of increased cortisol plasma levels, and increased levels of epinephrine, a negative and positive regulator of TNF-a expression, respectively. The increased TNF-a plasma levels, induced early onset of MOD, was detected by increased plasma levels of Creatine Kinase, Lactate Dehydrogenase, Alkaline Phosphatase, Amylase, Creatinine, total Bilirrubin and Alanine Aminotransferase, in addition to the hypoglycemia. These results suggest that the carotid body plays a protective role in the sepsis progression to multiple organ dysfunction.
Notas
Tesis (Bioquímico, Magíster en Bioquímica)
Palabras clave
Quimioreceptores