RESUMEN
Various previous studies established that the amphiphilic tri-block copolymer known as poloxamer 188 (P188) or Pluronic-F68 can stabilize the plasma membrane following a variety of injuries to multiple mammalian cell types. This characteristic led to proposals for the use of P188 as a therapeutic treatment for various disease states, including muscular dystrophy. Previous studies suggest that P188 increases plasma membrane integrity by resealing plasma membrane disruptions through its affinity for the hydrophobic lipid chains on the lipid bilayer. P188 is one of a large family of copolymers that share the same basic tri-block structure consisting of a middle hydrophobic propylene oxide segment flanked by two hydrophilic ethylene oxide moieties [poly(ethylene oxide)80-poly(propylene oxide)27-poly(ethylene oxide)80]. Despite the similarities of P188 to the other poloxamers in this chemical family, there has been little investigation into the membrane-resealing properties of these other poloxamers. In this study we assessed the resealing properties of poloxamers P181, P124, P182, P234, P108, P407, and P338 on human embryonic kidney 293 (HEK293) cells and isolated muscle from the mdx mouse model of Duchenne muscular dystrophy. Cell membrane injuries from glass bead wounding and multiphoton laser injury show that the majority of poloxamers in our panel improved the plasma membrane resealing of both HEK293 cells and dystrophic muscle fibers. These findings indicate that many tri-block copolymers share characteristics that can increase plasma membrane resealing and that identification of these shared characteristics could help guide design of future therapeutic approaches.
Asunto(s)
Membrana Celular/efectos de los fármacos , Músculos/efectos de los fármacos , Poloxámero/farmacología , Animales , Línea Celular , Células HEK293 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas/efectos de los fármacos , Ratones , Ratones Endogámicos mdx , Distrofia Muscular de Duchenne/tratamiento farmacológicoRESUMEN
OBJECTIVE: The aim of this study was to determine the association between gabapentinoids on the day of surgery and adverse postoperative outcomes in patients undergoing colorectal surgery in the United States. BACKGROUND: Gabapentinoids, gabapentin and pregabalin, are recommended in multimodal analgesia protocols for acute postoperative pain management after colorectal surgery. However, current literature focuses on the efficacy in reducing opioid consumption, but provides limited information about adverse risks. METHODS: This was a retrospective study including 175,787 patients undergoing elective colorectal surgery using the Premier database between 2009 and 2014. Multilevel regression models measured associations of receipt of gabapentinoids with naloxone use after surgery, non-invasive ventilation (NIV), invasive ventilation (IMV), hospital length of stay (LOS), and parental morphine equivalents (PMEs) on the day of surgery and on the day before discharge. RESULTS: Overall, 4677 (2.7%) patients received gabapentinoids on the day of surgery, with use doubling (1.7% in 2009 to 4.3% in 2014). Compared with patients who were unexposed to ganapentinoids, gabapentinoid exposure was associated with lower PMEs on the day of surgery [-2.7âmg; 95% confidence interval (CI), -5.2 to -0.0âmg], and with higher odds of NIV [odds ratio (OR) 1.22, 95% CI, 1.00-1.49] and receipt of naloxone (OR 1.58, 95% CI, 1.11-2.26). There was no difference between the groups with respect to IMV or PMEs on the day before discharge. CONCLUSIONS: Although use of gabapentinoids on the day of surgery was associated with slightly lower PMEs on the day of surgery, it was associated with higher odds of NIV and naloxone use after surgery.
Asunto(s)
Analgésicos/uso terapéutico , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Gabapentina/uso terapéutico , Complicaciones Posoperatorias/etiología , Pregabalina/uso terapéutico , Respiración Artificial , Adulto , Colon/cirugía , Procedimientos Quirúrgicos Electivos , Femenino , Humanos , Tiempo de Internación , Masculino , Morfina , Complicaciones Posoperatorias/tratamiento farmacológico , Recto/cirugía , Estudios RetrospectivosRESUMEN
Injury to lung epithelial cells has a role in multiple lung diseases. We previously identified mitsugumin 53 (MG53) as a component of the cell membrane repair machinery in striated muscle cells. Here we show that MG53 also has a physiological role in the lung and may be used as a treatment in animal models of acute lung injury. Mice lacking MG53 show increased susceptibility to ischaemia-reperfusion and overventilation-induced injury to the lung when compared with wild-type mice. Extracellular application of recombinant human MG53 (rhMG53) protein protects cultured lung epithelial cells against anoxia/reoxygenation-induced injuries. Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema. Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice. Our data indicate a physiological function for MG53 in the lung and suggest that targeting membrane repair may be an effective means for treatment or prevention of lung diseases.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Proteínas Portadoras/metabolismo , Proteínas Portadoras/farmacología , Membrana Celular/efectos de los fármacos , Terapia Molecular Dirigida/métodos , Lesión Pulmonar Aguda/genética , Animales , Proteínas Portadoras/administración & dosificación , Proteínas Portadoras/genética , Hipoxia de la Célula/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Femenino , Humanos , Pulmón/patología , Masculino , Proteínas de la Membrana , Ratones Noqueados , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patología , Respiración Artificial/efectos adversos , Proteínas de Motivos TripartitosRESUMEN
Mitsugumin 53 (MG53), a muscle-specific TRIM family protein, is an essential component of the cell membrane repair machinery. Here, we examined the translational value of targeting MG53 function in tissue repair and regenerative medicine. Although native MG53 protein is principally restricted to skeletal and cardiac muscle tissues, beneficial effects that protect against cellular injuries are present in nonmuscle cells with overexpression of MG53. In addition to the intracellular action of MG53, injury to the cell membrane exposes a signal that can be detected by MG53, allowing recombinant MG53 protein to repair membrane damage when provided in the extracellular space. Recombinant human MG53 (rhMG53) protein purified from Escherichia coli fermentation provided dose-dependent protection against chemical, mechanical, or ultraviolet-induced damage to both muscle and nonmuscle cells. Injection of rhMG53 through multiple routes decreased muscle pathology in the mdx dystrophic mouse model. Our data support the concept of targeted cell membrane repair in regenerative medicine, and present MG53 protein as an attractive biological reagent for restoration of membrane repair defects in human diseases.