RESUMO
The intestinal mucosa plays a critical role in the organism, acting as an interface between the lamina propria and the harmful antigens in the lumen. Sepsis is associated with primary injury to the intestinal mucosa, which in turn induces bacterial translocation and hyperpermeability. Cholecystokinin (CCK) is a peptide synthesized by several cell types, whose immunomodulatory activity has been reported in experimental models of inflammation. We hypothesized that the CCK treatment could modulate the inflammatory response and protect the integrity of the intestinal barrier in endotoxemic rats. Ten minutes before the endotoxemia induction by lipopolysaccharide (LPS) administration, rats were pretreated with CCK at two doses (0.4 µg/kg or 40âµg/kg). Mucosal permeability, bacterial translocation, cytokines production, histology injury, and expression of tight junction (TJ) proteins were the parameters assessed. In the early phase of endotoxemia, rats exhibited impaired intestinal barrier function, increased mucosal permeability, bacterial translocation, and also hyperactivation of the inflammatory response. On the other hand, the pretreatment with CCK modulated the mucosal production of pro-inflammatory cytokines and increased the expression of seal-forming TJ proteins (occludin, claudin-1 and junctional adhesion molecule (JAM-A)) only in the colon and also, reduced the bacterial counts in the mesenteric lymph nodes. However, CCK has a site-specific mechanism of action in the colon via CCK-1R, which is upregulated by the CCK treatment. In synergy with previous findings from our research group, the present results demonstrated that CCK preserves the integrity of the intestinal mucosa and might be a promising hormonal adjuvant therapy for the treatment of sepsis.
Assuntos
Colecistocinina/uso terapêutico , Enteropatias/induzido quimicamente , Enteropatias/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/toxicidade , Animais , Enteropatias/metabolismo , Masculino , Ratos , Ratos Wistar , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismoRESUMO
Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 µg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.
Assuntos
Colecistocinina/uso terapêutico , Endotoxemia/tratamento farmacológico , Hipotensão/prevenção & controle , Mediadores da Inflamação/sangue , Choque Séptico/tratamento farmacológico , Animais , Aorta/enzimologia , Pressão Sanguínea/efeitos dos fármacos , Colecistocinina/antagonistas & inibidores , Colecistocinina/sangue , Colecistocinina/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Endotoxemia/sangue , Endotoxemia/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Interleucina-10/sangue , Ácido Láctico/sangue , Lipopolissacarídeos , Fígado/enzimologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/biossíntese , Proglumida/farmacologia , Ratos , Ratos Wistar , Choque Séptico/sangue , Choque Séptico/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Vasopressinas/sangueRESUMO
Colecistoquinina(CCK) y gastrina integran una familia importante de polipéptidos gastroenteropancreáticos. La divesidad de funciones ejercidas por CCK se explica por su distribución en el aparato digestivo y el sistema nervioso tanto central como periférico; más que una hormona clásica es un neurotransmisor peptidérgico. CCK interviene preponderantemente en múltiples funciones digestivas:contracción y vaciamiento de la vesícula biliar, estimulación de la secreción pancreática, de enzimas, detención del vaciamiento gástrico, disminución de la secreción gástrica, regulación de la secreción de insulina, relajación transitoria del esfínter cardial y disminución de la ingestión alimentaria. En todas esta áreas he habido confusión entre los efectos farmacológicos y los fisiológicos. Los procedimientos tecnológicos modernos han producido avances considerables: biotitulación plasmática confiable, entendimiento de la heterogeneidad molecular, identificación y caracterización de los receptorres con sus biotipos, agonistas y antagonistas accesibles para estudios experimentales y clínicos. Los resultados permiten mejorar la perspectiva integradora de la fisiología normal y patológica. La aplicación terapéutica de CCK y sus derivados a algunos problemas específicos, como obesidad y anorexia, es aún incipiente y limitada