RESUMEN
PURPOSE: The specific genes or pathways in fibroblasts responsible for the pathogenesis of postoperative abdominal adhesion (PAA) remain to be elucidated. We aim to provide a new insight into disease mechanisms at the transcriptome level. METHODS: Male Sprague-Dawley rats were used to establish a PAA model. Primary fibroblasts were separated from normal peritoneal tissue (NF) and postoperative adhesion tissue (PF). RNA sequencing was used to analyze the transcriptome in NF and PF. RESULTS: One thousand two hundred thirty-five upregulated and 625 downregulated DEGs were identified through RNA-Seq. A pathway enrichment analysis identified distinct enriched biological processes, among which the most prominent was related to immune and inflammatory response and fibrosis. HE staining and Masson's trichrome staining histologically validated the RNA-Seq results. Six hub genes, ITGAM, IL-1ß, TNF, IGF1, CSF1R and EGFR were further verified by RT-PCR. CONCLUSIONS: Our study revealed the roles of the immune and inflammatory responses and fibrosis in the process of PAA. We also found six hub genes that may be potential therapeutic targets for PPA.
Asunto(s)
Fibroblastos , Peritoneo/patología , Complicaciones Posoperatorias/genética , Complicaciones Posoperatorias/patología , Análisis de Secuencia de ARN/métodos , Adherencias Tisulares/genética , Adherencias Tisulares/patología , Transcriptoma/genética , Animales , Antígeno CD11b , Modelos Animales de Enfermedad , Receptores ErbB , Fibroblastos/inmunología , Fibroblastos/patología , Humanos , Factor I del Crecimiento Similar a la Insulina , Interleucina-1beta , Masculino , Terapia Molecular Dirigida , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/terapia , Ratas Sprague-Dawley , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos , Adherencias Tisulares/inmunología , Adherencias Tisulares/terapia , Factor de Necrosis Tumoral alfaRESUMEN
Intrauterine adhesion (IUA) is an endometrial fibrosis disease caused by repeated operations of the uterus and is a common cause of female infertility. In recent years, treatment using mesenchymal stem cells (MSCs) has been proposed by many researchers and is now widely used in clinics because of the low immunogenicity of MSCs. It is believed that allogeneic MSCs can be used to treat IUA because MSCs express only low levels of MHC class I molecules and no MHC class II or co-stimulatory molecules. However, many scholars still believe that the use of allogeneic MSCs to treat IUA may lead to immune rejection. Compared with allogeneic MSCs, autologous MSCs are safer, more ethical, and can better adapt to the body. Here, we review recently published articles on the immunomodulation of allogeneic and autologous MSCs in IUA therapy, with the aim of proving that the use of autologous MSCs can reduce the possibility of immune rejection in the treatment of IUAs.
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Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/inmunología , Enfermedades Uterinas/terapia , Femenino , Enfermedad Injerto contra Huésped/inmunología , Humanos , Tolerancia Inmunológica , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Adherencias Tisulares/inmunología , Adherencias Tisulares/patología , Adherencias Tisulares/terapia , Trasplante Autólogo/métodos , Trasplante Homólogo/métodos , Resultado del Tratamiento , Enfermedades Uterinas/inmunología , Enfermedades Uterinas/patología , Útero/inmunología , Útero/patologíaRESUMEN
OBJECTIVES: Chronic inflammation and pelvic adhesion play a critical role in endometriosis-related infertility. Research studies suggest that TGF-ß superfamily members, such as soluble endoglin (sEng), growth differentiation factor 15 (GDF-15) and tumor growth factor-beta (TGF-ß1) contribute to the regulation of inflammation, angiogenesis and cell adhesion. The objective of this study is to investigate the association between the concentrations of these TGF-ß-related members and the clinical parameters of infertile women with endometriosis. MATERIALS AND METHODS: Sixty-five infertile women who underwent laparoscopy were divided into two groups in this study: those who had endometriosis (n = 33) and control subjects with benign gynecologic disorders (n = 32). The levels of TGF-ß- related members in peritoneal fluid and serum were evaluated by the enzyme-linked immunosorbent assay (ELISA). Clinical and hematological parameters were documented and analyzed. RESULTS: Endometriosis cases had significantly higher levels of sEng, GDF-15 and TGF-ß1 in peritoneal fluid (p<0.0005) compared to control subjects, but not in serum. Moreover, serum GDF-15 level was significantly elevated in the late-stage endometriosis compared to the early-stage group. The levels of three TGF-ß related molecules in peritoneal fluid showed positive correlations with rASRM score. Blood neutrophil counts have correlation with the peritoneal sEng concentration. CONCLUSION: Our novel evidence on the elevated concentration of peritoneal sEng and GDF-15 in endometriosis, specifically in the late-stage, may indicate the essential role of TGF-ß-dependent signaling in endometriosis. Serum GDF-15 might serve as a candidate biomarker for endometriosis severity. Further studies are warranted to investigate the role and regulation of these molecules in endometriosis.
Asunto(s)
Endoglina/metabolismo , Endometriosis/complicaciones , Factor 15 de Diferenciación de Crecimiento/metabolismo , Infertilidad Femenina/inmunología , Enfermedad Inflamatoria Pélvica/inmunología , Adulto , Líquido Ascítico/inmunología , Líquido Ascítico/patología , Biomarcadores/análisis , Biomarcadores/metabolismo , Endoglina/análisis , Endometriosis/sangre , Endometriosis/inmunología , Endometriosis/patología , Femenino , Factor 15 de Diferenciación de Crecimiento/análisis , Humanos , Infertilidad Femenina/sangre , Infertilidad Femenina/diagnóstico , Infertilidad Femenina/patología , Enfermedad Inflamatoria Pélvica/sangre , Enfermedad Inflamatoria Pélvica/diagnóstico , Enfermedad Inflamatoria Pélvica/patología , Adherencias Tisulares/sangre , Adherencias Tisulares/diagnóstico , Adherencias Tisulares/inmunología , Adherencias Tisulares/patologíaRESUMEN
Most multicellular organisms have a major body cavity containing vital organs. This cavity is lined by a mucosa-like serosal surface and filled with serous fluid which suspends many immune cells. Injuries affecting the major body cavity are potentially life-threatening. Here we summarize evidence that unique damage detection and repair mechanisms have evolved to ensure immediate and swift repair of injuries at serosal surfaces. Furthermore, thousands of patients undergo surgery within the abdominal and thoracic cavities each day. While these surgeries are potentially lifesaving, some patients will suffer complications due to inappropriate scar formation when wound healing at serosal surfaces defects. These scars called adhesions cause profound challenges for health care systems and patients. Therefore, reviewing the mechanisms of wound repair at serosal surfaces is of clinical importance. Serosal surfaces will be introduced with a short embryological and microanatomical perspective followed by a discussion of the mechanisms of damage recognition and initiation of sterile inflammation at serosal surfaces. Distinct immune cells populations are free floating within the coelomic (peritoneal) cavity and contribute towards damage recognition and initiation of wound repair. We will highlight the emerging role of resident cavity GATA6+ macrophages in repairing serosal injuries and compare serosal (mesothelial) injuries with injuries to the blood vessel walls. This allows to draw some parallels such as the critical role of the mesothelium in regulating fibrin deposition and how peritoneal macrophages can aggregate in a platelet-like fashion in response to sterile injury. Then, we discuss how serosal wound healing can go wrong, causing adhesions. The current pathogenetic understanding of and potential future therapeutic avenues against adhesions are discussed.
Asunto(s)
Macrófagos Peritoneales/inmunología , Peritoneo/inmunología , Membrana Serosa/inmunología , Heridas y Lesiones/inmunología , Animales , Líquido Ascítico/inmunología , Plaquetas/inmunología , Agregación Celular/inmunología , Factor de Transcripción GATA6/análisis , Humanos , Macrófagos Peritoneales/química , Peritoneo/lesiones , Adherencias Tisulares/inmunologíaRESUMEN
Post-operative adhesions are a leading cause of abdominal surgery-associated morbidity. Exposed fibrin clots on the damaged peritoneum, in which the mesothelial barrier is disrupted, readily adhere to surrounding tissues, resulting in adhesion formation. Here we show that resident F4/80HighCD206- peritoneal macrophages promptly accumulate on the lesion and form a 'macrophage barrier' to shield fibrin clots in place of the lost mesothelium in mice. Depletion of this macrophage subset or blockage of CD11b impairs the macrophage barrier and exacerbates adhesions. The macrophage barrier is usually insufficient to fully preclude the adhesion formation; however, it could be augmented by IL-4-based treatment or adoptive transfer of this macrophage subset, resulting in robust prevention of adhesions. By contrast, monocyte-derived recruited peritoneal macrophages are not involved in the macrophage barrier. These results highlight a previously unidentified cell barrier function of a specific macrophage subset, also proposing an innovative approach to prevent post-operative adhesions.
Asunto(s)
Macrófagos Peritoneales/inmunología , Peritoneo/inmunología , Complicaciones Posoperatorias/inmunología , Adherencias Tisulares/inmunología , Animales , Antígeno CD11b/genética , Antígeno CD11b/inmunología , Epitelio/inmunología , Epitelio/patología , Humanos , Interleucina-4 , Masculino , Ratones , Ratones Endogámicos C57BL , Peritoneo/patología , Complicaciones Posoperatorias/genética , Complicaciones Posoperatorias/patología , Adherencias Tisulares/genética , Adherencias Tisulares/patologíaRESUMEN
BACKGROUND: Postoperative peritoneal adhesion (PPA) is regarded as fibrous bands connecting both injured abdominal wall and organs or adjacent tissues. It is associated with T helper (Th)1 and Th2 differentiation. However, the critical role of the immunopathogenesis of adhesion formation was precisely unknown. The aim of this study was to investigate the effect of a new agent polylactic acid (PLA) nanoparticles loaded with ligustrazine, that is, ligustrazine nanoparticles (LN) on PPA and identify the potential mechanism. METHODS: Twenty-four Sprague-Dawley rats were randomly divided into the sham, model, LN, and sodium hyaluronate (SH) groups. The structure of LN, including entrapment efficiency (EE) and loading capacity (LC), and in vitro drug release were calculated. Adhesions were scored and the Masson's trichrome staining was used to determine the collagen deposition. The expressions of TLR4, MyD88, and NF-κB were measured by qRT-PCR, immunohistochemistry, and western blot assay. Moreover, Th1-related cytokines (IFN-γ, IL-12), Th2-related cytokines (IL-4, IL-6) in the cecum tissue and serum were conducted by ELISA. RESULTS: LN had good EE, LC, and control-release delivery characters with fairly uniform diameter and spherical morphology. It could effectively prevent adhesion formation after surgery. Besides, it could reduce collagen fibers accumulation, downregulate the expression levels of TLR4, MyD88, and NF-κB, and maintain Th1/Th2 balance. CONCLUSIONS: Ligustrazine nanoparticles had effective effects on Th1/Th2 balance by regulating TLR4/MyD88/NF-κB pathway in PPA rats. It may be served as a promising therapy on postoperative adhesion formation.
Asunto(s)
Nanopartículas , Pirazinas/uso terapéutico , Balance Th1 - Th2 , Adherencias Tisulares/tratamiento farmacológico , Animales , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Adherencias Tisulares/inmunología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
Most multicellular organisms have a major body cavity that harbors immune cells. In primordial species such as purple sea urchins, these cells perform phagocytic functions but are also crucial in repairing injuries. In mammals, the peritoneal cavity contains large numbers of resident GATA6+ macrophages, which may function similarly. However, it is unclear how cavity macrophages suspended in the fluid phase (peritoneal fluid) identify and migrate toward injuries. In this study, we used intravital microscopy to show that cavity macrophages in fluid rapidly form thrombus-like structures in response to injury by means of primordial scavenger receptor cysteine-rich domains. Aggregates of cavity macrophages physically sealed injuries and promoted rapid repair of focal lesions. In iatrogenic surgical situations, these cavity macrophages formed extensive aggregates that promoted the growth of intra-abdominal scar tissue known as peritoneal adhesions.
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Macrófagos Peritoneales/inmunología , Peritoneo/inmunología , Peritoneo/lesiones , Heridas y Lesiones/inmunología , Animales , Líquido Ascítico/inmunología , Plaquetas/inmunología , Agregación Celular/inmunología , Factor de Transcripción GATA6/análisis , Macrófagos Peritoneales/química , Ratones , Ratones Endogámicos C57BL , Receptores Depuradores de Clase B/inmunología , Trombosis/inmunología , Adherencias Tisulares/inmunologíaRESUMEN
BACKGROUND: Implants used in abdominal wall reconstruction are associated with intra-abdominal inflammation that can cause complications such as adhesions, fistulae, or failure of the implant. This study analyzed the inflammatory response of human peritoneum explants when exposed to different implant materials including synthetic and biological (cross-linked and non-cross-linked). MATERIALS AND METHODS: Human peritoneum explants (parietal and visceral) were incubated in culture with implants used for abdominal wall reconstruction. Implants included Permacol (biological implant with chemical cross-linking); Biodesign and Strattice (biological implants without chemical cross-linking); Prolene (synthetic nonabsorbable); and Vicryl (synthetic absorbable). Control peritoneum samples were incubated without implant. Cytokine concentrations and corresponding gene expression were measured by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. Further evaluation included assessment of tissue viability and implant-cytokine adsorption. RESULTS: Incubation of human peritoneal explants with Biodesign or Strattice was associated with a significant reduction in interleukin-6, interleukin-1ß, and tumour necrosis factor alpha protein and gene expression compared with control. These could not be explained by reduced cell viability or implant-cytokine adsorption. Incubation of explants in Biodesign-conditioned media displayed a similar effect to incubation of explants with Biodesign itself. CONCLUSIONS: Human peritoneal explants cultured with different mesh implant materials show an altered inflammatory cytokine response suggesting a tissue-specific response. Downregulation of key inflammatory cytokines by the peritoneum exposed to non-cross-linked biological implants may be mediated by the release of soluble factors from these implants inhibiting cytokine gene expression. This ex vivo human peritoneal system provides a novel preclinical model to investigate peritoneum-implant interactions.
Asunto(s)
Peritoneo/inmunología , Peritonitis/prevención & control , Procedimientos de Cirugía Plástica/efectos adversos , Prótesis e Implantes/efectos adversos , Mallas Quirúrgicas/efectos adversos , Pared Abdominal/cirugía , Citocinas/inmunología , Citocinas/metabolismo , Perfilación de la Expresión Génica , Humanos , Hernia Incisional/cirugía , Ensayo de Materiales , Peritoneo/patología , Peritonitis/inmunología , Peritonitis/patología , Procedimientos de Cirugía Plástica/instrumentación , Adherencias Tisulares/inmunología , Adherencias Tisulares/patología , Adherencias Tisulares/prevención & control , Técnicas de Cultivo de TejidosRESUMEN
Peritoneal adhesion occurs frequently after gastrointestinal/gynecological surgery. Tissue repair and regeneration are very important during this process. IL-22 is an important cytokine that is secreted from immune cells but functions on mesenchymal cells, such as mesothelial cells. The objective of this study was to investigate the roles of IL-22 and its regulators during adhesion formation. Postsurgical peritoneal drainage fluid from patients and rodent models was examined by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting. It was observed that IL-22 expression in the abdominal cavity was rapidly induced 12 hours after surgery and then slowly decreased to a lower, steady level for up to 7 days after surgery. However, neutralizing IL-22 at the time point at which the highest level of expression was observed failed to reduce adhesion, but neutralizing IL-22 at a later time point, i.e., 3 days after surgery, prevented adhesion significantly. The IL-22 receptor was induced on the mesothelial membrane, and IL-22BP, an inhibitor of IL-22, was reduced 3 days after surgery. Furthermore, IFN-γ was identified to have the ability to induce IL-22R, and IL-18, which was induced by the infiltrating macrophages, was found to inhibit IL-22BP expression both in vivo and in vitro. Together, these data suggest that IL-22 may promote adhesion formation and that the regulation of IL-22, IL-22R, and IL-22BP may have therapeutic potential to prevent adhesion formation after surgery without disturbing the normal immune process.
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Células Epiteliales/inmunología , Interleucinas/inmunología , Macrófagos Peritoneales/inmunología , Enfermedades Peritoneales/inmunología , Receptores de Interleucina/inmunología , Animales , Líquido Ascítico , Ensayo de Inmunoadsorción Enzimática , Epitelio/inmunología , Citometría de Flujo , Humanos , Interleucinas/antagonistas & inhibidores , Ratones , Periodo Posoperatorio , Linfocitos T Citotóxicos/inmunología , Adherencias Tisulares/inmunología , Interleucina-22RESUMEN
Peripheral nerve fibrosis and painful adhesions are common, recurring pathological sequelae following injury. In this study, vital human amnion (hAM), an increasingly interesting biomaterial for regenerative medicine, was investigated as a novel therapy. hAM was first analyzed in vitro regarding its anti-adhesive characteristics. Then, the reflected region of hAM which was identified as more suitable, was transplanted into female Sprague Dawley rats with recurring sciatic nerve scarring (nâ¯=â¯24) and compared with untreated controls (nâ¯=â¯30) at one, four and twelve weeks. Immune response and fibrosis were investigated by (immuno)histochemical analysis. Nerve structure was examined and function determined using electrophysiology and gait analysis. Here we identified strongly reduced adhesions in the hAM-treated rats, displaying a significant difference at four weeks post transplantation compared to untreated controls (pâ¯=â¯.0052). This correlated with the in vitro cell attachment test on hAM explants, which demonstrated a distinctly limited ability of fibroblasts to adhere to amniotic epithelial cells. Upon hAM transplantation, significantly less intraneural fibrosis was identified at the later time points. Moreover, hAM-treated rats exhibited a significantly higher sciatic functional index (SFI) after four weeks compared to controls (pâ¯<â¯.05), which indicated a potentially pro-regenerative effect of hAM. As a possible explanation, an impact of hAM on the endogenous immune response, including T cell and macrophage subsets, was indicated. We conclude that hAM is strongly effective against recurring nerve scarring and induces an anti-fibrotic and pro-regenerative effect, making it highly promising for treating adhesion-related disorders. STATEMENT OF SIGNIFICANCE: Abnormal fibrotic bonding of tissues, frequently involving peripheral nerves, affects millions of people worldwide. These so-called adhesions usually cause severe pain and drastically reduce quality of life. To date, no adequate treatment exists and none is routinely used in the clinical practice. In this study, vital human amnion, the innermost of the fetal membranes, was transplanted in a rat model of peripheral nerve scarring and recurring adhesions as novel therapeutic approach. Amniotic cells have already demonstrated to feature stem-cell like properties and produce pro-regenerative factors, which makes the amnion an increasingly promising biomaterial for regenerative medicine. We identified that its transplantation was very effective against peripheral nerve scarring and distinctly reduced recurring adhesions. Moreover, we identified a pro-regenerative effect. This study showed that the amnion is a highly promising novel therapeutic approach for adhesion-related disorders.
Asunto(s)
Amnios/trasplante , Cicatriz/patología , Nervio Ciático/patología , Adherencias Tisulares/prevención & control , Adherencias Tisulares/terapia , Animales , Adhesión Celular , Cicatriz/fisiopatología , Modelos Animales de Enfermedad , Femenino , Fibrosis , Humanos , Ratones , Células 3T3 NIH , Regeneración Nerviosa , Ratas Sprague-Dawley , Recuperación de la Función , Nervio Ciático/fisiopatología , Adherencias Tisulares/inmunología , Adherencias Tisulares/fisiopatologíaRESUMEN
OBJECTIVE: Spinal epidural fibrosis is a clinical condition that develops after laminectomy and can compress the spine. Many agents have been tried for the treatment, but none has entered clinical use at present. Pegaptanib sodium is an antiangiogenetic drug that prevents the development of new vessels and thus adhesion by inhibiting the effect of VEGF. MATERIAL AND METHOD: 20 Wistar rats were used in this study. The rats were divided into 2 different groups as the control and pegaptanib sodium group. Three levels of laminectomy were performed. Only laminectomy was performed in the control group. A cotton ball soaked with 3 mg/kg Pegaptanib sodium diluted 1: 10 with 0.9 % NaCl was topically applied to the dura in the surgical field for 5 minutes in the pegaptanib sodium group. The rats were sacrificed 3 weeks later and histopathologically examined. The epidural fibrosis was graded. RESULTS: The epidural fibrosis grade in the pegaptanib sodium was significantly lower than in the control group c2 = 11,65; (p = 0.004)CONCLUSION: Pegaptanib sodium blocked the VEGF through its anti-VEGF effect and decreased spinal epidural fibrosis in rats that had undergone laminectomy (Tab. 2, Fig. 3, Ref. 53).
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Aptámeros de Nucleótidos , Espacio Epidural/efectos de los fármacos , Fibrosis/tratamiento farmacológico , Animales , Duramadre/patología , Duramadre/cirugía , Espacio Epidural/patología , Espacio Epidural/cirugía , Laminectomía/efectos adversos , Complicaciones Posoperatorias , Ratas , Ratas Wistar , Adherencias Tisulares/tratamiento farmacológico , Adherencias Tisulares/inmunología , Adherencias Tisulares/prevención & controlRESUMEN
Intraperitoneal adhesions are frequently encountered and present significant challenges to the practicing surgeon, including increased operating time, bowel obstruction, pelvic pain, and infertility. Until recently, however, our knowledge of the biology of adhesion formation within the peritoneal cavity has been limited, which in turn limits prevention and treatment strategies for surgical patients. Extensive research has now led to an increased understanding of adhesion formation, with hypoxia playing a central role. Hypoxia stimulates a cascade that leads to oxidative stress, anaerobic metabolism, formation of free radicals, and ultimately the adhesion phenotype. By understanding the precipitants to adhesion development, we may begin to develop prevention and treatment therapies that will provide clinically significant improvement over the currently available approaches to limit postoperative adhesions.
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Cavidad Peritoneal/patología , Enfermedades Peritoneales , Adherencias Tisulares , Humanos , Enfermedades Peritoneales/etiología , Enfermedades Peritoneales/inmunología , Enfermedades Peritoneales/metabolismo , Enfermedades Peritoneales/patología , Adherencias Tisulares/etiología , Adherencias Tisulares/inmunología , Adherencias Tisulares/metabolismoRESUMEN
Peritoneal adhesions are fibrous tissues formed after surgery. Both cytokines and transforming growth factors (TGFs) are involved in this process. The objective of this study was to investigate the cross talk between these entities. Peritoneal drainage fluid after surgery from patients and rodent models was examined by enzyme-linked immunosorbent assay and fluorescence-activated cell sorter. Data showed that the concentrations of interferon (IFN)-γ and interleukin (IL)-17 reached their peaks 6-12 hours after surgery, whereas TGF-ß1 concentrations showed two postoperative peak time points at 2 and 72-96 hours. By neutralizing IFN-γ, IL-17 6-12 hours, and TGF-ß1 72-96 hours after surgery, the degree of adhesion reduced significantly. However, neutralizing TGF-ß1 2 hours after surgery did not affect adhesion formation. Furthermore, in vitro studies showed that compared with the fibroblasts that were directly stimulated with TGF-ß1, the prestimulation of IL-17 promoted plasminogen activator inhibitor-1 production while inhibiting tissue-type plasminogen activator production. Moreover, additional stimulation with IFN-γ enhanced this effect. Together, these data indicate that IL-17 may promote adhesion formation by increasing the reaction of fibroblasts against TGF-ß1. Blocking IL-17 might have a therapeutic potential in preventing adhesion formation after surgery.
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Interferón gamma/inmunología , Interleucina-17/inmunología , Enfermedades Peritoneales/inmunología , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta1/inmunología , Adulto , Anciano , Animales , Colectomía/efectos adversos , Femenino , Fibroblastos/metabolismo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Células 3T3 NIH , Enfermedades Peritoneales/etiología , Serpina E2/metabolismo , Transducción de Señal/inmunología , Adherencias Tisulares/etiología , Adherencias Tisulares/inmunología , Activador de Tejido Plasminógeno/metabolismoRESUMEN
Intestinal adhesion, characterized by connection of the loops of the intestine with other abdominal organs by fibrous tissue bands, remains an inevitable event of abdominal operations and can cause a number of complications. Berberine hydrochloride (berberine), a natural plant alkaloid derived from Chinese herbal medicine, is characterized by diverse pharmacological effects, such as anticancer and lower elevated blood glucose. This study is designed to investigate the effects of berberine on adhesion and inflammation after abdominal surgeries and the underlying molecular mechanisms. Adhesion severity grades and collagen deposition were assessed 14 days after surgery. We evaluated the levels of intercellular adhesion molecule-1 (ICAM-1) and inflammatory cytokines interleukin-1ß (IL-1ß), IL-6, transforming growth factor ß (TGF-ß), tumor necrosis factor-α (TNF-α), and examined transforming growth factor-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK) and TAK1/nuclear factor κB (NF-κB) signaling. The surgery group experienced the most severe adhesions, and berberine strikingly reduced the density and severity of adhesion. Results showed significant lower expression of IL-1ß, IL-6, TGF-ß, TNF-α, and ICAM-1, in berberine groups compared with the operation group. Activities of phosphorylated JNK and phosphorylated NF-κB were inhibited in the berberine groups compared with the surgery group. Our novel findings identified berberine hydrochloride as a promising strategy to prevent adhesion by downregulating ICAM-1 and reduce inflammation by inhibiting the TAK1/JNK and TAK1/NF-κB signaling after abdominal surgery, which brought out a good therapeutic approach for the development of clinical application for postoperative abdominal adhesion and inflammation.
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Antiinflamatorios/uso terapéutico , Berberina/uso terapéutico , Enfermedades Intestinales/prevención & control , Complicaciones Posoperatorias/prevención & control , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Berberina/administración & dosificación , Berberina/química , Modelos Animales de Enfermedad , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-1beta/inmunología , Interleucina-6/inmunología , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/metabolismo , Masculino , Estructura Molecular , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/metabolismo , Ratas , Ratas Sprague-Dawley , Adherencias Tisulares/inmunología , Adherencias Tisulares/metabolismo , Adherencias Tisulares/prevención & control , Factor de Crecimiento Transformador beta/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The reaction of various tissues of rats to implantation of polyhydroxyalkanoate films and ultrafine fibers was studied by optic microscopy. Implantation of polyhydroxyalkanoate films into the abdominal cavity caused a peritoneal reaction, leading after 1 month to the formation of fibrous adhesions between polyhydroxyalkanoate and intestinal loops. Under the skin and in the muscle tissue polyhydroxyalkanoate films were encapsulated in a thick fibrous capsule. Implantation of polyhydroxyalkanoate ultrathin fibers led to formation of foreign body granulomas in all tissues with perifocal inflammation and sclerosis of the adjacent tissues. The polymer was fragmented in these granulomas and phagocytosed by macrophages with the formation of giant foreign body cells. Hence, polyhydroxyalkanoate materials implanted in vivo caused chronic granulomatous inflammatory reaction and were very slowly destroyed by macrophages.
Asunto(s)
Cuerpos Extraños/inmunología , Reacción a Cuerpo Extraño/inmunología , Granuloma de Cuerpo Extraño/inmunología , Peritoneo/inmunología , Polihidroxialcanoatos/inmunología , Cavidad Abdominal , Animales , Reacción a Cuerpo Extraño/patología , Granuloma/inducido químicamente , Granuloma/inmunología , Inflamación/inducido químicamente , Inflamación/inmunología , Macrófagos/inmunología , Masculino , Microscopía , Peritoneo/efectos de los fármacos , Polihidroxialcanoatos/administración & dosificación , Polihidroxialcanoatos/farmacología , Ratas , Ratas Wistar , Esclerosis/inducido químicamente , Esclerosis/inmunología , Adherencias Tisulares/inducido químicamente , Adherencias Tisulares/inmunologíaRESUMEN
OBJECTIVE: To investigate, in an experimental animal study, the effects of letrozole and tamoxifen in the reduction of adhesion formation following abdominopelvic surgery. STUDY DESIGN: Thirty female Wistar albino rats were included and divided into three groups. One group received 500 µg/d tamoxifen and a second group received 1 mg/kg/d letrozole through an enteric tube. A third group did not receive any drugs and served as the control group. On the fifth day, a laparotomy was performed and the right uterine horn was injured by monopolar cautery. The left uterine horn was incised with a scalpel and sutured. The preventive therapy protocols were continued for 7 days after surgery. On the 14th day after first surgery the animals were sacrificed, and the intraperitoneal macroscopic adhesion formation and microscopic adhesion features were evaluated. The Kruskal-Wallis test was used to compare the scores of the macroscopic adhesion scores and histologic features among the three groups, followed by a post hoc Mann-Whitney test. The total histological score was analyzed with a one-way ANOVA, followed by post hoc Bonferroni correction tests. p values ≤0.05 were considered statistically significant. The level of significance was set at p≤0.016 for the post hoc tests. RESULTS: The letrozole and tamoxifen groups had significantly lower adhesion scores for the right uterine horn than the control group (p=0.005 and p=0.013, respectively). For the left horn, however, only the letrozole group had a lower macroscopic adhesion score than the controls (p=0.011). The total histological score was significantly lower in the letrozole group than in the control group (p=0.014), but no differences were found between the tamoxifen group and the control group (p=0.954). Inflammation, fibroblastic activity, collagen formation and vascular proliferation were significantly lower in the letrozole group compared with the control group (p<0.05). The foreign body reactions were similar among the three groups (p>0.05). Tamoxifen administration did not result in any significant effects on the histological scores (p>0.05). CONCLUSION: Letrozole resulted in a significant decrease in postoperative macroscopic adhesion formation and the total histological scores, but tamoxifen did not demonstrate a similar effect on the histological scores.
Asunto(s)
Inhibidores de la Aromatasa/uso terapéutico , Nitrilos/uso terapéutico , Peritoneo/efectos de los fármacos , Adherencias Tisulares/prevención & control , Triazoles/uso terapéutico , Útero/efectos de los fármacos , Animales , Femenino , Reacción a Cuerpo Extraño/inmunología , Reacción a Cuerpo Extraño/patología , Reacción a Cuerpo Extraño/prevención & control , Letrozol , Cavidad Peritoneal/patología , Cavidad Peritoneal/cirugía , Peritoneo/inmunología , Peritoneo/patología , Peritoneo/cirugía , Periodo Posoperatorio , Periodo Preoperatorio , Distribución Aleatoria , Ratas , Ratas Wistar , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/uso terapéutico , Adherencias Tisulares/inmunología , Adherencias Tisulares/patología , Útero/cirugíaRESUMEN
AIM: Spinal epidural fibrosis is an inherent result of surgical trauma after laminectomy. The conditions in which epidural fibrosis is excessive are in the etiology of failed back syndrome. There have been many attempts to prevent formation of epidural fibrosis. Bevacizumab which is an anti-angiogenic medication, inhibits the effect of VEGF and thereby decreases the new blood vessel formation and as a result prevents adhesions. This study shows the effect of bevacizumab on spinal epidural fibrosis developing after laminectomy in rats. MATERIAL AND METHODS: In this study, 20 Wistar rats were used. Rats were divided into two groups; a control group, and a bevacizumab group. Three-level laminectomy was performed on the rats. Rats in the control group only had the laminectomy. In the bevacizumab group, 2.5 mg/kg bevacizumab diluted in 0.9% NaCl with a factor of 1:10 impregnated on cotton was applied on the dura topically for 5 minutes. Three weeks later, rats were sacrificed for histopathologic examination. Epidural fibrosis tissue was graded following sacrifice. RESULTS: Statistically, it was found that the bevacizumab group had significantly less epidural fibrosis compared to the control group (p < 0.05). CONCLUSION: Bevacizumab reduced the spinal epidural fibrosis significantly that developed in rats after laminectomy via its anti-VEGF effect by blocking VEGF receptors.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Espacio Epidural/efectos de los fármacos , Fibrosis/tratamiento farmacológico , Complicaciones Posoperatorias/prevención & control , Animales , Bevacizumab , Duramadre/patología , Duramadre/cirugía , Espacio Epidural/patología , Espacio Epidural/cirugía , Laminectomía/efectos adversos , Masculino , Complicaciones Posoperatorias/patología , Ratas , Ratas Wistar , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/inmunología , Adherencias Tisulares/tratamiento farmacológico , Adherencias Tisulares/inmunologíaRESUMEN
OBJECTIVE: To evaluate inflammatory/angiogenic cytokines-interleukin-1ß (IL-1ß), IL-6, IL-8, IL-12, interferon-γ (IFN-γ), tumor necrosis factor (TNF), and vascular endothelial growth factor A (VEGF-A)-in the peritoneal fluid of patients with endometriosis in relation to the occurrence and severity of pelvic adhesions and in control women without pelvic pathology. DESIGN: Case-control study. SETTING: University research institution and hospital. PATIENT(S): Sixty-five women with laparoscopically and histopathologically confirmed endometriosis, including 40 women with pelvic adhesions, and 37 control women without pelvic pathology. INTERVENTION(S): Peritoneal fluid aspirated during routine diagnostic laparoscopic examination. MAIN OUTCOME MEASURE(S): Cytokines evaluated in the peritoneal fluid via specific enzyme-linked immunosorbent assays. RESULT(S): Endometriosis and the revised American Fertility Society score of this disease were associated with statistically significantly increased levels of peritoneal IL-6 and IL-8 whereas the incidence and score of endometriosis-related pelvic adhesions were negatively associated with increased levels of VEGF-A. Notably, the concentration of VEGF-A predicted adhesion development and severity after adjustment for endometriosis severity. The adhesion score also correlated with increased levels of IL-6; however, after adjustment for endometriosis severity, the effect of this cytokine was no longer statistically significant. CONCLUSION(S): Increased levels of VEGF-A may be associated with a decreased rate of pelvic adhesion formation in the course of endometriosis.
Asunto(s)
Líquido Ascítico/metabolismo , Citocinas/metabolismo , Endometriosis/metabolismo , Adherencias Tisulares/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Líquido Ascítico/inmunología , Estudios de Casos y Controles , Endometriosis/inmunología , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Peritonitis/inmunología , Peritonitis/metabolismo , Índice de Severidad de la Enfermedad , Adherencias Tisulares/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVES: To evaluate the effect of bladder flap formation (BFF) during caesarean section (CS) on the uterine scar, assessed during repeat CS. STUDY DESIGN: One hundred and fifteen women undergoing their first CS were divided into two groups: 58 women had a CS with BFF (Group 1) and 57 women had a CS without BFF (Group 2). During the repeat CS, four specimens from the uterine scar from the first CS were collected from each woman, and evaluated by light microscopy and transmission electron microscopy (TEM). RESULTS: Adhesions were found in 28 (48.3) women in Group 1 and 14 (24.1%) women in Group 2 (p<0.01). Of the women with adhesions in Group 1, 20 (71.4%) had mild adhesions and eight (28.6%) had severe adhesions. Of the women with adhesions in Group 2, eight (57.1%) had mild adhesions and six (42.9%) had severe adhesions. Light microscopy revealed significant differences in submesothelial fibrosis (39.6% vs 12.2%; p<0.01) and neo-angiogenesis of the mesothelial stroma (46.5% vs 21%; p<0.01) in Groups 1 and 2, respectively. TEM revealed more specimens with inflammatory cells in Group 1 compared with Group 2 {mean 29.7 [standard deviation (SD) 1.3] vs 18.2 (SD 1.9) patients; p<0.01}. CONCLUSION: BFF during CS leads to an inflammatory and fibrotic reaction, resulting in inflammation reactive and regenerative processes, mesothelial hyperplasia and submesothelial fibrosis. CS without BFF reduces the inflammatory processes and the subsequent intraperitoneal adhesions and adhesions between the bladder and uterus.
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Cesárea Repetida/efectos adversos , Cesárea/métodos , Peritoneo/cirugía , Colgajos Quirúrgicos/efectos adversos , Adherencias Tisulares/prevención & control , Vejiga Urinaria/cirugía , Útero/patología , Adulto , Femenino , Fibrosis , Humanos , Hiperplasia/prevención & control , Italia , Microscopía Electrónica de Transmisión , Neovascularización Patológica/prevención & control , Peritoneo/patología , Embarazo , Adherencias Tisulares/inmunología , Adherencias Tisulares/patología , Adherencias Tisulares/cirugía , Vejiga Urinaria/patología , Útero/cirugía , Útero/ultraestructuraRESUMEN
Postoperative intra-abdominal adhesions represent a serious clinical problem. In this review, we have focused on recent progress in the cellular and humoral mechanisms underpinning adhesion formation, and have reviewed strategies that interfere with these pathways as a means to prevent their occurrence. Current and previous English-language literature on the pathogenesis of adhesion formation was identified. As the burden of surgical disease in the world population increases, and the frequency of reoperation increases, prevention of adhesion formation has become a pressing goal in surgical research.