RESUMO
The aim of the study was to confirm whether cell substrate stiffness may participate in the regulation of fibrosis. The involvement of integrin α2ß1, focal adhesion kinase (FAK) and Src kinase in signal transmission was investigated. Human atrial fibroblasts and myofibroblasts were cultured in both soft (2.23 ± 0.8 kPa) and stiff (8.28 ± 1.06 kPa) polyacrylamide gels. The cells were derived from the right atrium of patients with aortal stenosis undergoing surgery. The isolated cells, identified as fibroblasts or myofibroblasts, were stained positively with α smooth muscle actin, vimentin and desmin. The cultures settled on stiff gel demonstrated lower intracellular collagen and collagen type I telopeptide (PICP) levels; however, no changes in α1 chain of procollagen type I and III expression were noted. Inhibition of α2ß1 integrin by TC-I 15 (10-7 and 10-8 M) or α2 integrin subunit silencing augmented intracellular collagen level. Moreover, FAK or Src kinase inhibitors increased collagen content within the culture. Lower TIMP4 secretion was reported within the stiff gel cultures but neither MMP 2 nor TIMP-1, 2 or 3 release was altered. The stiff substrate cultures also demonstrated lower interleukin-6 release. Substrate stiffness modified collagen deposition within the atrial fibroblast and myofibroblast cultures. The elasticity of the cellular environment exerts a regulatory influence on both synthesis and breakdown of collagen. Integrin α2ß1, FAK and Src kinase activity participates in signal transmission, which may influence fibrosis in the atria of the human heart.
Assuntos
Fibrilação Atrial , Quinases da Família src , Humanos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Quinases da Família src/metabolismo , Integrina alfa2beta1/metabolismo , Miofibroblastos/metabolismo , Fibrilação Atrial/metabolismo , Constrição Patológica/metabolismo , Colágeno/metabolismo , Fibroblastos/metabolismo , Átrios do Coração/metabolismo , Fibrose , Células CultivadasRESUMO
BACKGROUND: Preoperative atrial fibrillation is one of the predictors of increased morbidity and mortality in patients undergoing surgical revascularization, and consequently, prolongs the duration of stay in the ICU and of overall hospitalization. METHODS: The study included 3000 patients subjected to primary isolated coronary artery bypass grafting from 2000 to 2004. Of the 3000 patients, 5.8 % (n = 174) had electrocardiographically documented, preoperative atrial fibrillation. To evaluate the relationship between preoperative AF and postoperative outcome, all patients were observed for about three years. RESULTS: Patients with preoperative atrial fibrillation were older (P < 0.05), had a lower ejection fraction (P < 0.001), a higher incidence of heart failure (P < 0.001), hypertension (P < 0.001), and more coexistent morbidities including diabetes (P < 0.05), obturative pulmonary disease (P < 0.0001) and mild renal failure (P < 0.001). Statistical analysis showed that survival rates at 6 and 30 days, 6 and 12 months, and 3 years following surgical revascularization of patients with vs. those without preoperative atrial fibrillation were: 96.4% vs. 98.1%, and 94.5% vs. 97.3% (P = ns), 86.2% vs. 93.0% (P < 0.03), and 74.7% vs. 91.0% (P < 0.02), and 70.7% vs. 90.6% (P < 0.01). After 3 years' observation there was a survival difference of 19.9%. We showed that preoperative atrial fibrillation triple increased the risk of postoperative AF and was an independent risk factor for in-hospital death (P < 0.001). CONCLUSIONS: Preoperative atrial fibrillation is a predictor of postoperative complications, including death, and of a significant reduction in patients' long-term survival. Patients with preoperative atrial fibrillation should be considered as high-risk patients with potential postoperative complications and should be well protected with antiarrhythmic and anticoagulant therapy.
Assuntos
Fibrilação Atrial/mortalidade , Ponte de Artéria Coronária/mortalidade , Revascularização Miocárdica/mortalidade , Complicações Pós-Operatórias/mortalidade , Idoso , Ponte de Artéria Coronária/métodos , Feminino , Seguimentos , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polônia/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Although the incidence of colon cancer increases with advancing age, reasons for this increase are not fully understood. Earlier studies have demonstrated that in Fischer-344 rats, aging is associated with increased crypt cell production in the colon, an event considered to be central to the initiation of carcinogenesis. Apoptosis also plays a critical role in the development and progression of colon cancer. Therefore, we have examined the age-related changes in proliferation and apoptosis in the colonic mucosa of 4-5, 12-14, and 22-24 month-old Fischer-344 rats. We have observed that proliferative activity in the colon, as assessed by proliferating cell nuclear antigen immunoreactivity, is higher (50-80%) in 12-14 and 22-24 month-old rats than in their 4-6 month-old counterparts. In contrast, the number of apoptotic cells, (as determined by TdT-mediated dUTP nick-end labeling assay) in the colonic mucosa of 12-14 and 22-24 month-old rats are considerably lower (50-60%) than in 4-6 month-old animals. These changes are accompanied by a concomitant reduction (75%) in pro-apoptotic Bak and stimulation (200%) of anti-apoptotic Bcl-xL levels. Since activation of caspases is associated with initiation and maintenance of apoptosis, we also analyzed the levels of pro and active forms of caspase-3, 8 and 9. The levels of active forms of caspase-3, 8 and 9 are found to be considerably (60-80%) lower in the colonic mucosa of 22-24 month-old rats, compared to their younger counterparts. This is accompanied by decreased cleavage of poly(ADP-ribose) polymerase, a substrate for caspases. In conclusion, our data show that aging enhances proliferation, but attenuates apoptosis in the colonic mucosa. These changes may partly be responsible for the age-related rise in colorectal cancer.
Assuntos
Envelhecimento/fisiologia , Apoptose , Colo/citologia , Mucosa Intestinal/citologia , Envelhecimento/metabolismo , Animais , Caspase 3 , Caspase 8 , Caspase 9 , Caspases/metabolismo , Divisão Celular , Colo/metabolismo , Nucleotídeos de Desoxiuracil , Marcação In Situ das Extremidades Cortadas , Mucosa Intestinal/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Endogâmicos F344 , Proteína Killer-Antagonista Homóloga a bcl-2 , Proteína bcl-XRESUMO
We have investigated the chemopreventive role of curcumin in gastrointestinal cancers by studying the regulation of proliferation and apoptosis in gastric (KATO-III) and colon (HCT-116) cancer cells. Curcumin inhibited cell proliferation and induced G2/M arrest in HCT-116 cells. Investigation of the levels of cyclins E, D and B by immunoblot analysis showed cyclin B level was unaffected, whereas cyclin D and E levels declined with curcumin in both cell lines. Investigation of cyclin-dependent kinases, Cdk2 and Cdc2, showed activity of Cdc2, but not Cdk2, increased markedly in response to curcumin. In both cell lines, immunoblot analysis indicated that curcumin caused induction of apoptosis as evidenced by cleavage of PARP, caspase-3, and reduction in Bcl-XL levels. Curcumin also stimulated the activity of caspase-8, which initiates Fas signalling pathway of apoptosis. Curcumin therefore appears to exert its anticarcinogenic properties by inhibiting proliferation and inducing apoptosis in certain gastric and colon cancer cells.
Assuntos
Antineoplásicos/farmacologia , Apoptose , Quinases relacionadas a CDC2 e CDC28 , Ciclo Celular/efeitos dos fármacos , Neoplasias do Colo/prevenção & controle , Curcumina/farmacologia , Inibidores do Crescimento/farmacologia , Neoplasias Gástricas/prevenção & controle , Antineoplásicos/metabolismo , Proteína Quinase CDC2/metabolismo , Caspase 3 , Caspase 8 , Caspase 9 , Caspases/metabolismo , Divisão Celular/efeitos dos fármacos , Curcumina/metabolismo , Ciclina B/metabolismo , Ciclina D1/metabolismo , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , Quinases Ciclina-Dependentes/metabolismo , Inibidores do Crescimento/metabolismo , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células Tumorais Cultivadas , Proteína bcl-XRESUMO
In Poland young and middle-aged men are a population at risk of premature development of ischemic heart disease (IHD). This prospective study was designed in order to estimate the effects of coronary artery bypass grafting (CABG) on survival and quality of life in this population. 60 men aged (mean&SD) 41 +/- 3.2 years, operated on in 1993 at the Department of Cardiosurgery, Medical University of Lódz, were enrolled into the study. The study protocol included two postoperative follow-up examinations: after 2 and 5 years. A perioperative mortality rate was 3.3%, 2-years survival rate 92% and 5-years one 87%. Asymptomatic survival rates were 75% et 44%, respectively. During the first follow-up examination a significant improvement of exercise performance compared with preoperative period, was observed. However, at the same time there was no improvement in left ventricular function, measured as its ejection fraction in echocardiography. The effects of CABG procedure on risk factors control, medical treatment and professional activity were also analysed. The long-term results of CABG operations in young men, as far as survival rates are concerned, are good. However, the longer follow-up period was analysed the less beneficial influence of the operations on patients' clinical state and quality of life was observed.
Assuntos
Ponte de Artéria Coronária/métodos , Isquemia Miocárdica/cirurgia , Adulto , Fatores Etários , Humanos , Masculino , Estudos Prospectivos , Qualidade de Vida , Resultado do TratamentoRESUMO
Although in Fischer-344 rats, aging has been shown to be associated with increased crypt cell production in the colonic mucosa, no information is available about the responsible intracellular mechanisms for the age-related rise in colonic mucosal cell proliferation. To determine whether cell cycling events are affected by aging, the present investigation examines the age-related changes in Cdk2 activity and the regulation of this process in the colonic mucosa. Colonic mucosae from 4-, 13- and 24-month-old Fischer-344 rats were assayed for Cdk2 activity and protein expression of Cdk2, cyclin D1 and E, as well as p21(Waf1/Cip1) (total and the fraction bound to Cdk2), p53 and phosphorylated Rb. Kinase activity and protein levels of Cdk2, as well as cyclin D1 concentration in the colonic mucosa, rose steadily with advancing age. However, the levels of cyclin E in the colonic mucosa were found to be higher in 24-month-old than 13-month-old rats, compared to their 4-month-old counterparts. On the other hand, levels of mucosal p21(Waf1/Cip1) (total and the fraction bound to Cdk2), one of the universal inhibitors of Cdks, were found to be lower in aged than in young rats. This was accompanied by a parallel decrease in mucosal p53, a tumor suppressor protein that is known to regulate p21(Waf1/Cip1). Additionally, we observed that the levels of phosphorylated Rb protein, a form which is involved in regulating progression of cells through the S phase, are increased in the colonic mucosa of 24-month-old rats, but not in 13-month-old animals, when compared with their 4-month-old counterparts. Our data suggest that, G(1) to S phase transition, as well as progression through the S phase of the cell cycle are accelerated in the colonic mucosa of aged rats.
Assuntos
Envelhecimento/patologia , Quinases relacionadas a CDC2 e CDC28 , Colo/citologia , Fase G1 , Mucosa Intestinal/citologia , Envelhecimento/metabolismo , Animais , Divisão Celular , Colo/metabolismo , Ciclina D1/metabolismo , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p21 , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Endogâmicos F344 , Proteína do Retinoblastoma/química , Proteína do Retinoblastoma/metabolismo , Fase S , Proteína Supressora de Tumor p53/metabolismoRESUMO
Administration of pharmacological doses of epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) in young rats stimulates gastric mucosal proliferation, but, in aged rats, the same treatment inhibits proliferation. This may be due to enhanced ligand-induced internalization of EGF receptor (EGFR). In support of this, we demonstrated that although a single injection of EGF (10 microg/kg) or TGF-alpha (5 microg/kg) in young (4-6 mo old) rats greatly increased membrane-associated EGFR tyrosine kinase activity, the same treatment slightly inhibited the enzyme activity in aged (24 mo old) rats. This treatment also produced a greater abundance of punctate cytoplasmic EGFR staining in gastric epithelium of aged rats, consistent with EGFR internalization. In vitro analyses demonstrated that exposure of isolated gastric mucosal cells from aged but not young rats to 100 pM TGF-alpha resulted in marked increases in intracellular EGFR tyrosine kinase activity and that induction of EGFR tyrosine kinase activity in mucosal membranes from aged rats occurred at doses 1,000-fold less than those required in young rats. Our data suggest that aging enhances sensitivity of the gastric mucosa to EGFR ligands. This may partly explain EGFR-mediated inhibition of gastric mucosal proliferation in aged rats.
Assuntos
Envelhecimento/fisiologia , Fator de Crescimento Epidérmico/farmacologia , Mucosa Gástrica/fisiologia , Fator de Crescimento Transformador alfa/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Citosol/metabolismo , Receptores ErbB/metabolismo , Mucosa Gástrica/citologia , Mucosa Gástrica/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos F344 , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
The number of granulocytes, their ability to generate superoxide anion (O2-) and the activities of Cu, Zn--superoxide dismutase (SOD-1), glutathione peroxidase (GSH-Px), catalase (CAT) as well as malonyldialdehyde (MDA) concentrations in erythrocytes in the blood extracted from the venous sinus and aorta under coronary artery bypass were examined with the use of St. Thomas Hospital cardioplegic solution. Specimens at the peak of ischemia of the right atrium for ultrastructural examination of the endothelial cells of capillary vessels and sarcomers were taken. The blood was obtained during cardiopulmonary bypass (CPB) before the aorta clamping and immediately after aorta declamping (peak of ischaemia) between 1-3 minute and 10-13 minute of reperfusion. Increase of the number of granulocytes both in the coronary sinus and aortal blood at all examined intervals as well as decrease in the number of ones in sinus compared with aortal blood was noted. The ability to produce superoxide anion radical decreased at the peak of ischemia and during reperfusion. The activity of SOD-1 was lower both after the period of ischemia and reperfusion. The increase in aortal blood activity during reperfusion was characteristic of GSH-Px; the activity was higher in the blood sample from the coronary sinus taken during ischemia and initial reperfusion. With the exception of the initial reperfusion the activity of CAT diminished in all observed cases. MDA concentration did not demonstrate any significant changes with the exception of the initial reperfusion in the aortal blood and later towards the end of reperfusion in the blood from the coronary sinus. Ultrastructural studies indicated overhydration of the cells both in the endothelium and the intercellular space. The obtained data demonstrate that the applied cardioplegic solution protects the myocardium from harmful effects of reactive oxygen species produced as a result of ischemia and reperfusion.
Assuntos
Ponte de Artéria Coronária/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Adulto , Idoso , Bicarbonatos , Cloreto de Cálcio , Soluções Cardioplégicas , Catalase/sangue , Temperatura Baixa , Ponte de Artéria Coronária/efeitos adversos , Eritrócitos/metabolismo , Glutationa Peroxidase/sangue , Granulócitos/metabolismo , Humanos , Hipotermia Induzida , Contagem de Leucócitos , Magnésio , Malondialdeído/sangue , Pessoa de Meia-Idade , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Cloreto de Potássio , Cloreto de Sódio , Superóxido Dismutase/sangue , Superóxidos/sangue , Fatores de TempoRESUMO
Although accumulating evidence suggests a chemopreventive role for folic acid in colon cancer, the regulation of this process in unknown. We hypothesize that supplemental folic acid exerts its chemopreventive role by inhibiting mucosal hyperproliferation, an event considered to be central to the initiation of carcinogenesis in the gastrointestinal tract. The present investigation examines the effect of supplemental folic acid on proliferation of Caco-2 and HCT-116 colon cancer cell lines. Furthermore, because certain tyrosine kinases, particularly epidermal growth factor receptor (EGFR), play a role in regulating cell proliferation, we also examined the folic acid-induced changes in tyrosine kinase activity and expression of EGFR. In Caco-2 and HCT-116 cells, maintained in RPMI 1640 medium containing 1 microg/ml folic acid, we observed that the supplemental folic acid inhibited proliferation in a dose-dependent manner. Pretreatment of HCT-116 and Caco-2 cell lines with supplemental folic acid (1.25 microg/ml) completely abrogated transforming growth factor-alpha (TGF-alpha)-induced proliferation in both cell lines. Tyrosine kinase activity and the relative concentration of EGFR were markedly diminished in both cell lines following a 24-h exposure to supplemental folic acid. The folic acid-induced inhibition of EGFR tyrosine kinase activity in colon cancer cell lines was also associated with a concomitant reduction in the relative concentration of the 14-kDa membrane-bound precursor form of TGF-alpha. In conclusion, our data suggest that supplemental folic acid is effective in reducing proliferation in two unrelated colon cancer cell lines and that EGFR tyrosine kinase appears to be involved in regulating this process.
Assuntos
Anticarcinógenos/farmacologia , Receptores ErbB/metabolismo , Ácido Fólico/farmacologia , Hematínicos/farmacologia , Western Blotting , Células CACO-2/citologia , Células CACO-2/enzimologia , Divisão Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Receptores ErbB/análise , Humanos , Fator de Crescimento Transformador alfa/fisiologiaRESUMO
Although in Fischer 344 rats aging is found to be associated with increased gastric mucosal proliferative activity, little is known about specific changes in the regulatory mechanisms of this process. To determine whether changes in cell cycling events could partly contribute to the age-related rise in gastric mucosal proliferative activity, the present investigation examines changes in cyclin-dependent kinase (Cdk2) activity and the regulation of this process in the gastric mucosa of Fischer 344 rats aged 4 (young), 13 (middle aged), and 24 (old) mo. We observed that aging is associated with a progressive rise in activity and protein levels of Cdk2 in the gastric mucosa. This is also found to be accompanied by a concomitant increase in cyclin E but not cyclin D1 levels. On the other hand, the levels of p21(Waf1/Cip1) (total as well as the fraction associated with Cdk2), a nuclear protein that is known to inhibit different cyclin-Cdk complexes, are found to decline in the gastric mucosa with advancing age. In contrast, with aging, there was a steady rise in p53 levels in the gastric mucosa. We have also observed that the levels of phosphorylated retinoblastoma protein, a form that participates in regulating progression through the S phase, are markedly elevated in the gastric mucosa of aged rats. In conclusion, our data suggest that, in the gastric mucosa, aging enhances transition of G(1) to S phase as well as progression through the S phase of the cell cycle. However, the age-related decline in p21(Waf1/Cip1) in the gastric mucosa appears to be independent of p53 status.
Assuntos
Envelhecimento/fisiologia , Quinases relacionadas a CDC2 e CDC28 , Fase G1/fisiologia , Mucosa Gástrica/citologia , Animais , Western Blotting , Ciclina D1/análise , Ciclina D1/metabolismo , Ciclina E/análise , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p21 , Quinases Ciclina-Dependentes/análise , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/análise , Ciclinas/metabolismo , Ativação Enzimática/fisiologia , Mucosa Gástrica/enzimologia , Masculino , Proteínas Serina-Treonina Quinases/análise , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Endogâmicos F344 , Proteína do Retinoblastoma/análise , Proteína do Retinoblastoma/metabolismo , Fase S/fisiologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
Diabetes mellitus is associated with spontaneous gastric mucosal injury and enhanced susceptibility of the mucosa to damaging agents. Little information is available about the biochemical changes that occur in the gastric mucosa of diabetes mellitus. Evidence is accumulating that tyrosine kinases, particularly the EGF-receptor (EGFR), are involved in regulating a variety of structural and functional properties of the gastric mucosa. The primary objectives of this investigation were to determine whether diabetes induces morphological changes in the gastric mucosa, and if so, whether these changes are associated with alterations in EGFR tyrosine kinase. Diabetes-induced changes in gastric mucosal morphology were also examined. Diabetes was induced in 3- to 4-month-old male Fischer-344 rats by streptozotocin (STZ; 45 mg/kg; i.v.). Four weeks after induction of diabetes mellitus, the gastric mucosa of overnight-fasted rats was found to be slightly atrophic. A reduction in gastric mucosal thickness with deposition of fibrous tissue above the muscularis layer was observed in the stomach of overnight-fasted diabetic rats. These changes were associated with a marked stimulation in tyrosine kinase activity and protein expression of EGFR. The relative concentrations of several precursor forms of TGF-alpha in both membrane and cytosolic fractions from the gastric mucosa of overnight-fasted diabetic rats were also found to be significantly above the corresponding controls. This suggests that endogenous TGF-alpha may play a critical role in regulating mucosal EGFR tyrosine kinase through a juxtacrine/paracrine mechanism.
Assuntos
Diabetes Mellitus Experimental/enzimologia , Receptores ErbB/biossíntese , Mucosa Gástrica/enzimologia , Proteínas Tirosina Quinases/metabolismo , Animais , Western Blotting , Diabetes Mellitus Experimental/patologia , Mucosa Gástrica/patologia , Imuno-Histoquímica , Masculino , Ratos , Ratos Endogâmicos F344 , Fator de Crescimento Transformador alfa/metabolismoRESUMO
Although the incidence of most human malignancies including cancer of the gastrointestinal tract increases dramatically with advancing age, the precise role of aging in that increase remains a matter of continued controversy. Many probable explanations for the age-related rise in cancer incidence have been offered including altered carcinogen metabolism and the cumulative effects of protracted exposure to cancer-causing agents. Neoplasia of the stomach or colon is a multi-stage process with hyperproliferation being central to the initiation of carcinogenesis. Since aging is associated with increased gastrointestinal mucosal cell proliferation, the possibility that aging itself may render target cells more susceptible to carcinogenic transformation continues to be an area of intense interest and study. This review will examine the evidence for age-related alterations in the structural and functional properties of the gastric and colonic mucosa in an effort to further elucidate the potential mechanisms of carcinogenesis which may be involved during the aging process.
Assuntos
Envelhecimento/fisiologia , Mucosa Gástrica/fisiologia , Mucosa Intestinal/fisiologia , Envelhecimento/patologia , Divisão Celular , Doenças do Colo/patologia , Doenças do Colo/fisiopatologia , Neoplasias do Colo/patologia , Neoplasias do Colo/fisiopatologia , Mucosa Gástrica/anatomia & histologia , Humanos , Mucosa Intestinal/anatomia & histologia , Gastropatias/patologia , Gastropatias/fisiopatologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/fisiopatologiaRESUMO
In a 17-year-old youth, exploratory laparotomy for acute abdominal pain was complicated by circulatory arrest related to pulmonary embolism. Echocardiography after resuscitation revealed a hitherto "silent" right atrial myxoma, fragmentation of which had blocked the right atrioventricular ostium, causing the pain. Operation was successful. As only a few similar cases have been reported, pulmonary embolism due to fragmentation of a right atrial myxoma may account for some unexplained sudden deaths beyond medical help.
Assuntos
Abdome Agudo/etiologia , Neoplasias Cardíacas/complicações , Mixoma/complicações , Embolia Pulmonar/etiologia , Adolescente , Ecocardiografia , Parada Cardíaca/etiologia , Átrios do Coração , Neoplasias Cardíacas/diagnóstico por imagem , Neoplasias Cardíacas/cirurgia , Humanos , Complicações Intraoperatórias/etiologia , Masculino , Mixoma/diagnóstico por imagem , Mixoma/cirurgiaRESUMO
Aging is associated with decreased reparative ability of the gastric mucosa. Our recent data suggest a role for epidermal growth factor receptor (EGFR) in the mucosal reparative processes. Thus we examined changes in EGFR tyrosine kinase activity as well as expression and subcellular localization of EGFR and its ligand transforming growth factor-alpha (TGF-alpha) in the gastric mucosa of young (4-mo-old) and aged (24-mo-old) Fischer 344 male rats during the early reparative phase after acute injury induced by 2 M NaCl. Within 240 min of injury, significant epithelial restitution was observed in the gastric mucosa of young but not of aged rats. Expansion of the neck region and initiation of foveolar cell migration could be seen within 45 min of injury in young rats but not until 90 min in aged rats. In young rats mucosal EGFR tyrosine kinase activity increased at 45 min after injury and subsequently fell to basal levels. Mucosal EGFR mRNA increased throughout the reparative phase as did content of the EGFR ligand TGF-alpha. In contrast, although the basal tyrosine kinase activity and levels of EGFR mRNA and TGF-alpha were elevated in the gastric mucosa of aged rats, injury did not cause increases in these parameters. Immunofluorescent localization suggests that internalization and/or degradation of EGFR may be higher in aged than in young rats. We suggest that diminished induction of EGFR tyrosine kinase activity and increased EGFR internalization after injury may in part be responsible for the age-related decrease in the reparative capacity of the gastric mucosa.
Assuntos
Envelhecimento/metabolismo , Receptores ErbB/genética , Mucosa Gástrica/lesões , Mucosa Gástrica/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Animais , Formaldeído , Mucosa Gástrica/crescimento & desenvolvimento , Masculino , Ratos , Ratos Endogâmicos F344 , Fatores de TempoRESUMO
Although in Fischer-344 rats aging is found to be associated with increased gastric mucosal proliferative activity, little is known about the intracellular events that regulate this process. The present investigation examines the age-related changes in gastric mucosal tyrosine kinase activity and expression of epidermal growth factor receptor(EGFR) and its structural and functional analog p185c-erbB-2, the protein product of c-erbB-2/c-neu protooncogene. We observed a significantly higher intrinsic tyrosine kinase activity and tyrosine phosphorylation of EGFR and p185c-erbB-2 in the gastric mucosa of 24-mo-old (aged) rats than in that of their 4- or 12-mo-old counterparts. This was associated with increased levels of EGFR protein and steady-state mRNA levels of EGFR and p185c-erbB-2. In addition, we also observed threefold higher steady-state mRNA levels of transforming growth factor-alpha (TGF-alpha; one of the primary ligands of EGFR) in the gastric mucosa of aged rats than in that of 4-mo-old (young) animals. This was accompanied by a fivefold increase in the relative concentration of the 18-kDa precursor form of TGF-alpha in gastric mucosal membranes but not in the cytosol. In conclusion, our data demonstrate that aging is associated with increased tyrosine kinase activity of EGFR and p185c-erbB-2 in the gastric mucosa. Moreover, the observation that aging results in increased accumulation of TGF-alpha in gastric mucosal membranes raises the possibility that the membrane-bound TGF-alpha could partly be responsible for the constitutively active EGFR-induced signaling pathway in the gastric mucosa of aged rats and, in turn, for stimulation of mucosal proliferative activity.
Assuntos
Envelhecimento/metabolismo , Receptores ErbB/metabolismo , Mucosa Gástrica/metabolismo , Animais , Western Blotting , Receptores ErbB/genética , Masculino , Fosforilação , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptor ErbB-2/metabolismo , Fator de Crescimento Transformador alfa/genética , Fator de Crescimento Transformador alfa/metabolismoRESUMO
With estimates that about 14% of the U.S. population will be over 65 years old by the end of this century, scientific research has attempted to achieve a better understanding of the aging process and of diseases that are expressed in higher incidence with advancing age. Because of its high rate of cell turnover and continual renewal, the mucosa of the gastrointestinal (GI) tract appears particularly susceptible to age-related disruptions in the normal cell proliferative process. This may translate into altered function that may result in the induction of malnutrition or malabsorption of particular nutrients, or a greater incidence of GI diseases, such as neoplasia. This review will examine the evidence for age-related alterations in the structural and functional properties of different regions of the GI tract and the pancreas, and how they may relate to malnutrition or disease processes.
Assuntos
Envelhecimento , Fenômenos Fisiológicos do Sistema Digestório , Pâncreas/fisiologia , Animais , Colo/fisiologia , Mucosa Gástrica/fisiologia , Humanos , Intestino Delgado/fisiologiaRESUMO
Although the gastric mucosa of healthy adult animals possesses the inherent capacity to promptly repair (often within 24 h) after a minor to moderate injury, aging appears to diminish its reparative capacity. At least two different repair mechanisms are thought to participate in full repair of the damaged gastric mucosa: the initial rapid process of mucosal restitution begins by migration of viable epithelial cells from gastric pits and glands; the subsequent slower process is replacement of lost cells by cell division. Intracellular events that regulate these processes are poorly understood, nor do we know how they may be affected by aging. However, evidence is accumulating which suggests that a number of gastrointestinal hormones/growth factors, most notably EGF and TGF-alpha may play a critical role in regulating gastric mucosal reparative processes. Since EGF and TGF-alpha exert their physiological actions by activating the intrinsic tyrosine kinase (Tyr-k) activity of their common receptor, the EGF-R, studies have been performed to assess the role of EGF-R Tyr-k in regulating mucosal reparative processes during aging. Recent data suggest that the age-related decline in mucosal repair after acute injury could in part be due to decreased activation of EGF-R Tyr-k. In addition, polyamines and prostaglandins are also thought to be involved in gastric mucosal reparative processes. Although the involvement of polyamines in gastric mucosal reparative processes during aging has not yet been studied, decreased mucosal prostaglandin levels in the aged are thought to be a causative factor for the increased susceptibility of the mucosa to injury. These and other relevant matters are discussed in the current review.
Assuntos
Envelhecimento/patologia , Mucosa Gástrica/patologia , Animais , Divisão Celular/fisiologia , Humanos , Úlcera Péptica/patologiaRESUMO
In vivo and in vitro experiments were performed to examine the responsiveness of the proximal and distal colonic mucosa to the growth-promoting action of gastrin. Infusion (osmotic minipump) of gastrin G-17-I (250 ng/kg/h) for 5 days to 4-month-old male Fischer-344 rats resulted in a significant (90-150%) increase in proliferative activity (as assessed by BrdU or PCNA immunoreactivity) in the distal colonic mucosa. In contrast, gastrin caused no apparent change in proliferative activity in the proximal colon. Because tyrosine kinases (Tyr-ks) are thought to be critically involved in regulating the trophic action of gastrin, responsiveness of isolated colonocytes from both segments of the colon to gastrin (1 x 10(-9) M) was also examined. Exposure of isolated colonocytes from the distal, but not from the proximal, colon to gastrin for 2 min resulted in a significant (73%) stimulation in Tyr-k activity. This was also accompanied by a marked rise in phosphorylation of at least six membrane proteins with M, of 55, 60, 70, 94, and 170 kDa. Tyr-k activity induced by gastrin in colonocytes from the distal colon was inhibited by tyrphostin (3.2 microM) but not by staurosporine (20 nM). In colonocytes from the distal colon, gastrin also stimulated phospholipase C (PLC) activity, which could also be inhibited by tyrphostin, but not by staurosporine. We conclude that mucosa of the distal, but not the proximal, colon responds to the trophic action of gastrin. Tyr-ks are thought to be involved in the regulation of this process.
Assuntos
Colo/efeitos dos fármacos , Gastrinas/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Animais , Colo/citologia , Avaliação Pré-Clínica de Medicamentos , Bombas de Infusão Implantáveis , Mucosa Intestinal/citologia , Masculino , Fosforilação , Ratos , Ratos Endogâmicos F344RESUMO
UNLABELLED: PTCA was introduced into our hospital in June 1991. Since then till the end of 1996 emergency CABG operations were performed in fourteen patients. They were indicated because of acute myocardial ischaemia and hemodynamic deterioration that was the result of the dissection and occlusion of a coronary artery during angioplasty. There were 11 male and 3 female patients in this group aged 34 to 65 average 50 years. Twenty-three grafts were performed in total (18 saphenous, 5 using internal mammary artery), that is 1.6 graft per patient. A female patient died of myocardial infarction on the first postoperative day. All other patients survived and are under outpatient clinic's care. Over the analysed 6 years' period of time 1079 PTCAs were performed. The low rate of the unsuccessful procedures (1.3%) that required the emergency CABG is noteworthy. Since 1995, when the implantation of stents was introduced into our hospital, there were only 2 such procedures (0.4% of all PTCAs). CONCLUSIONS: The CABG operation performed shortly after a dissection and occlusion of the coronary artery underwent angioplasty usually prevents myocardial infarction and saves the patient's live. The introduction of implantation of the stents significantly diminished a number of patients who required an emergency CABG operation.
Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Ponte de Artéria Coronária/métodos , Morte Súbita Cardíaca/prevenção & controle , Isquemia Miocárdica/cirurgia , Adulto , Idoso , Dissecção Aórtica/etiologia , Dissecção Aórtica/cirurgia , Aneurisma Coronário/etiologia , Aneurisma Coronário/cirurgia , Emergências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/mortalidade , Reoperação , Stents/efeitos adversos , Taxa de SobrevidaRESUMO
Although induction of mucosal cell proliferation is a crucial event in gastric mucosal regeneration after injury, intracellular regulatory processes have not been fully elucidated. We hypothesize that tyrosine kinases (Tyr-k)--specifically the enzyme associated with epidermal growth factor receptor (EGF-R)--play an important role in mucosal regeneration. Utilizing tyrphostin--a Tyr-k inhibitor with a greater specificity for EGF-R Tyr-k than for other Tyr-ks--we have examined the role of EGF-R Tyr-k in gastric mucosal regeneration after injury. Gastric mucosal injury in 3-to 4-month-old rats was induced by orogastric administration of 2 mol/L NaCl, whereas the control animals received an equivalent volume of water. The animals were killed 24 hours later. During this 24-hour experimental period (reparative phase), one of the groups was also injected (IP) with tyrphostin-51 (0.65 mg/kg in 30% dimethyl sulfoxide), whereas the control group received the vehicle. In the absence of tyrphostin, the gastric mucosa showed signs of extensive regeneration, whereas in its presence the degree of regeneration was greatly attenuated. These changes were accompanied by parallel alterations in the number of proliferating cell nuclear antigen-immunoreactive cells and the Tyr-k activity of EGF-R. In water-fed control animals, tyrphostin also caused a significant 30% reduction in proliferating cell nuclear antigen-immunoreactive cells. In these animals, the Tyr-k activity of EGF-R was also decreased by 30%. At 24 hours after injury, EGF-R mRNA levels were increased 36-fold over the water-fed controls, and this increase was not significantly affected by tyrphostin. Our current data suggest that activation of EGF-R is an important event in mucosal regeneration.