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1.
Transpl Int ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31701582

RESUMO

BACKGROUND: Organ donor's age negatively influences graft survival of organs, increasing risk of complications. Aging occurs in both men and women; however the menopause marks a decrease in sex hormones and a sudden increase in the process of vascular aging. We investigated sex hormones influence on the lung inflammatory process induced by BD in female rats. METHODS: Wistar rats were grouped as: female rats from high estradiol to heat period (non-OVx) and ovariectomized (OVx) female rats. Ovariectomy was carried out 10 days before BD. BD was induced using intracranial balloon rapid inflation. Serum hormones and inflammatory mediators were quantified, leukocytes and platelets counted and lung samples were collected for RT-PCR, immunohistochemical and histological analysis. RESULTS: Female sex hormones and corticosterone were reduced 6h after BD in non-OVx group. The infiltration of leukocytes in female non-OVx lungs was higher compared to OVx. G-CSF, VEGF and CINC-1 were found increased in non-OVx group serum in comparison to OVx. Lung Mediators were increased in non-OVx rats compared to controls. CONCLUSIONS: The acute reduction of sex hormones induced by BD appears to have a worse effect on lung inflammation than a reduction that has happened over a prolonged period of time, allowing a physiological adaptation prior to BD.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31653422

RESUMO

OBJECTIVE: The study objective was to evaluate the effect of bilateral sympathectomy on ventricular remodeling and function in a rat model of dilated cardiomyopathy induced by doxorubicin. METHODS: Dilated cardiomyopathy was induced in male Wistar rats by weekly intraperitoneal injection of doxorubicin (2 mg/kg) for 9 weeks. Animals were divided into 4 groups: dilated cardiomyopathy; bilateral sympathectomy, submitted on day 15 of the protocol to bilateral sympathectomy; angiotensin-converting enzyme inhibitor, treated with enalapril through day 15 until the end of the experimental protocol; and sham, nonsubmitted through doxorubicin protocol, with weekly intraperitoneal injections of saline solution (0.9%). The left ventricular function was assessed, and the heart was collected for posterior analyses. RESULTS: The dilated cardiomyopathy group presented a significant decrease in the myocardial efficiency when compared with the sham group (33.4% vs 71.2%). Only the bilateral sympathectomy group was able to preserve it (57.5%; P = .0001). A significant dilatation in the left ventricular chamber was observed in the dilated cardiomyopathy group (15.9 µm2) compared with the sham group (10.2 µm2; P = .0053). Sympathectomy and enalapril prevented ventricular remodeling (9.5 and 9.6 µm2, respectively; P = .0034). There was a significant increase in interstitial myocardial fibrosis in the dilated cardiomyopathy group (14.8%) when compared with the sham group (2.4%; P = .0001). This process was significantly reduced with sympathectomy and enalapril (8.7 and 3.9%, respectively; P = .0001). CONCLUSIONS: Bilateral sympathectomy was effective in preventing remodeling and left ventricular dysfunction in a rat model of dilated cardiomyopathy induced by doxorubicin.

3.
J Heart Lung Transplant ; 37(11): 1381-1387, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30139547

RESUMO

BACKGROUND: Brain death elicits microvascular dysfunction and inflammation, and thereby compromises lung viability for transplantation. As 17ß-estradiol was shown to be anti-inflammatory and vascular protective, we investigated its effects on lung injury after brain death in male rats. METHODS: Wistar rats were assigned to: sham-operation by trepanation only (SH, n = 7); brain death (BD, n = 7); administration of 17ß-estradiol (280 µg/kg, iv) at 60 minutes after brain death (BD-E2, n = 7). Experiments were performed 180 minutes thereafter. Histopathological changes in the lung were evaluated by histomorphometry. Gene expression of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and endothelin-1 was measured by real-time polymerase chain reaction. Protein expression of NO synthases, endothelin-1, platelet endothelial cell adhesion molecule-1 (PECAM-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), BCL-2, and caspase 3 was assessed by immunohistochemistry. Cytokines were quantified by enzyme-linked immunosorbent assay. RESULTS: Treatment with 17ß-estradiol after brain death decreased lung edema and hemorrhage (p < 0.0001), and serum levels of cytokine-induced neutrophil chemoattractant-1 (CINC-1; p = 0.0020). iNOS (p < 0.0001) and VCAM-1 (p < 0.0001) also diminished at protein levels, while eNOS accumulated (p = 0.0002). However, gene expression of iNOS, eNOS, and endothelin-1 was comparable among groups, as was protein expression of endothelin-1, ICAM-1, BCL-2, and caspase 3. CONCLUSIONS: 17ß-Estradiol effectively reduces lung injury in brain-dead rats mainly due to its ability to regulate NO synthases. Thus, the drug may improve lung viability for transplantation.

4.
Inflammation ; 41(4): 1488-1497, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29737476

RESUMO

Brain death (BD) affects organs by multiple mechanisms related to hemodynamic effects, hormonal changes, and the systemic inflammatory response, which reduce organ function and viability. BD reduces microcirculatory perfusion in rat mesentery; this disturbance is also observed in the pancreas and lungs. Sex hormones can affect microcirculatory function, altering tissue perfusion and influencing the inflammatory process. Here, we present differences between sexes in the microcirculatory alterations generated by BD and in inflammatory infiltrate. Male, female, and ovariectomized-female Wistar rats were submitted to BD by intracranial balloon catheter sudden inflation. BD was confirmed by maximally dilated and fixed pupils, apnea, absence of reflexes, and a drop in mean arterial pressure. Perfusion and flow of the mesenteric microcirculation were analyzed. Intestinal myeloperoxidase activity and leukocyte infiltration were quantified. ELISA quantified serum estradiol, corticosterone, and inflammatory mediators, whereas expression of eNOS, endothelin, and endothelial adhesion molecule was measured by immunohistochemistry. Male rats presented lower percentages of mesenteric perfused microvessels and reduced blood flow compared to females. The female group presented higher eNOS and endothelin expression. Leukocyte infiltration into intestinal walls was higher in females in comparison to that in males. Moreover, the female group showed higher mesenteric vessel ICAM-1 expression than males, whereas serum TNF-α, IL-1ß, and IL-10 levels did not differ between sexes. The high estradiol concentration before BD and high eNOS expression apparently favored the maintenance of microvascular perfusion/flow; however, BD caused an acute reduction of female sex hormone concentration and higher ICAM-1 level; thus, the proinflammatory organ status after BD is favored.


Assuntos
Morte Encefálica/fisiopatologia , Inflamação , Microcirculação , Fatores Sexuais , Animais , Velocidade do Fluxo Sanguíneo , Morte Encefálica/patologia , Endotelinas/metabolismo , Feminino , Hemodinâmica , Molécula 1 de Adesão Intercelular/metabolismo , Intestinos/patologia , Masculino , Óxido Nítrico Sintase Tipo III , Ratos , Ratos Wistar
5.
Shock ; 2018 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-29688986

RESUMO

BACKGROUND: Brain death (BD) induces hemodynamic instability with microcirculatory hypoperfusion, leading to increased organ inflammation and dysfunction. This study investigated the effects of 7.5% hypertonic saline solution (HSS) on mesenteric microcirculatory dysfunction and inflammation in a rat model of BD. METHODS: Male Wistar rats were anesthetized and mechanically ventilated. BD was induced by rapidly inflating an intracranial balloon catheter. The rats were randomly divided into: (1)SH, sham-operated rats subjected to trepanation; (2)NS, rats treated with NaCl 0.9%, 4 mL/kg immediately after BD; (3)T1, rats treated with HSS (NaCl 7.5%, 4 mL/kg) immediately or 60 min after BD, (4)T60. All groups were analyzed 180 minutes after the start of the experiment. RESULTS: Rats in BD groups presented with a similar hypertensive peak, followed by hypotension. Proportion of perfused small vessels was decreased in the NS group (46%) compared with the SH group (74%, p = 0.0039). HSS restored the proportion of perfused vessels (T1 = 71%, p = 0.0018). The eNOS protein expression significantly increased in rats given HSS (T1, and T60, p = 0.0002). Similar results were observed regarding endothelin-1 (p < 0.0001). Increased numbers of rolling (p = 0.0015) and migrated (p = 0.0063) leukocytes were observed in the NS group compared with the SH group. Rats given HSS demonstrated an overall reduction in leukocyte-endothelial interactions. The ICAM-1 levels increased in the NS group compared with the SH group, and decreased in the HSS-treated groups (p = 0.0002). CONCLUSIONS: HSS may improve the density of mesenteric perfused small vessels due to its effects on eNOS and endothelin-1 protein expression, and reduces inflammation by decreasing leukocyte adhesion and migration in a rat model of BD.

6.
PLoS One ; 13(1): e0190155, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29324806

RESUMO

Toxoplasma gondii (T. gondii) is the causative agent of toxoplasmosis, common zoonosis among vertebrates and high incidence worldwide. During the infection, the parasite needs to transpose the intestinal barrier to spread throughout the body, which may be a trigger for an inflammatory reaction. This work evaluated the inflammatory alterations of early T. gondii infection in peripheral blood cells, in the mesenteric microcirculation, and small intestinal tissue by measurement of MPO (myeloperoxidase) activity and NO (nitric oxide) level in rats. Animals were randomly assigned into control group (CG) that received saline orally and groups infected with 5,000 oocysts for 6 (G6), 12 (G12), 24 (G24), 48 (G48) and 72 hours (G72). Blood samples were collected for total and differential leukocyte count. Intravital microscopy was performed in the mesentery to evaluate rolling and adhesion of leukocytes. After euthanasia, 0.5cm of the duodenum, jejunum and ileum were collected for the determination of MPO activity, NO level and PCR to identify the parasite DNA and also the mesentery were collected to perform immunohistochemistry on frozen sections to quantify adhesion molecules ICAM-1, PECAM-1 and P-Selectin. The parasite DNA was identified in all infected groups and there was an increase in leukocytes in the peripheral blood and in expression of ICAM-1 and PECAM-1 in G6 and G12, however, the expression of P-selectin was reduced in G12. Leukocytes are in rolling process during the first 12 hours and they are adhered at 24 hours post-infection. The activity of MPO increased in the duodenum at 12 hours, and NO increased in the jejunum in G72 and ileum in G24, G48 and G72. Our study demonstrated that T. gondii initiates the infection precociously (at 6 hours) leading to a systemic activation of innate immune response resulting in mild inflammation in a less susceptible experimental model.


Assuntos
Imunocompetência , Inflamação/patologia , Intestinos/patologia , Toxoplasma/patogenicidade , Toxoplasmose Animal/patologia , Doença Aguda , Animais , Molécula 1 de Adesão Intercelular/metabolismo , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Toxoplasma/genética , Toxoplasma/isolamento & purificação
7.
J Surg Res ; 221: 1-7, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29229114

RESUMO

BACKGROUND: Lung inflammation is one of the main consequences of intestinal ischemia reperfusion (intestinal IR) and, in severe cases, can lead to acute respiratory distress syndrome and death. We have previously demonstrated that estradiol exerts a protective effect on lung edema and cytokine release caused by intestinal IR in male rats. MATERIALS AND METHODS: We investigated the role of estradiol on the generation of interleukin (IL)-1ß, IL-10, vascular endothelial growth factor (VEGF), and cytokine-induced neutrophil chemoattractant 1 (CINC-1) in a female rat model of intestinal IR. Blood and bone marrow leukocytes were also quantified. Seven-days-ovariectomized rats were subjected to intestinal IR by occlusion of the superior mesenteric artery for 45 min. After reperfusion of the tissue for 2 h, the rats were sacrificed. Lung tissue was collected, cultured for 24 h and assayed. RESULTS: We observed a significant increase in serum levels of IL-10, CINC-1, uric acid and circulating, but not bone marrow, leukocyte numbers. In addition, intestinal IR induced a significant increase in the ex-vivo lung levels of IL-1ß, IL-10, and VEGF. Treatment with 17ß-estradiol before the induction of intestinal IR prevented the systemic release of IL-10, CINC-1, and uric acid, but it did not affect the leukocytosis. In addition, 17ß-estradiol significantly prevented the ex-vivo release of IL-1ß and VEGF from lung tissue. CONCLUSIONS: We demonstrated that intestinal IR interferes with lung homeostasis, priming the tissue to generate proinflammatory mediators for at least 24 h postischemia. Furthermore, our data confirm that the inflammatory responses caused by intestinal IR are estradiol mediated.


Assuntos
Estradiol/fisiologia , Enteropatias/complicações , Intestinos/irrigação sanguínea , Pneumopatias/etiologia , Traumatismo por Reperfusão/complicações , Animais , Citocinas/sangue , Feminino , Enteropatias/sangue , Contagem de Leucócitos , Pulmão/metabolismo , Pneumopatias/sangue , Ratos Wistar , Traumatismo por Reperfusão/sangue , Ácido Úrico/sangue
8.
J Vasc Surg ; 67(2): 597-606, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28385296

RESUMO

OBJECTIVE: In surgical aortic repair or cardiac surgery with aorta occlusion, the occurrence of mesenteric ischemia and bowel injury has been associated with higher short-term mortality. The vascular protection of estrogens has been investigated and is mainly mediated by increasing the availability of nitric oxide (NO). Therefore, this study investigated the role of 17ß-estradiol on visceral ischemia-reperfusion (I/R) injury after descending aorta occlusion in male rats. METHODS: Mesenteric ischemia was induced in male Wistar rats by placing a 2F Fogarty arterial embolectomy catheter (Edwards Lifesciences, Irvine, Calif) in the descending aorta, which remained occluded for 15 minutes, followed by reperfusion for up to 2 hours. Rats were divided into four groups: (1) rats that underwent surgical manipulation only (sham, n = 22); (2) rats that underwent I/R injury (n = 22); (3) rats treated with intravenous 17ß-estradiol (280 µg/kg) 30 minutes before I/R (n = 22); (4) or at the beginning of reperfusion (n = 22). Intestinal histopathologic changes were evaluated by histomorphometry. Mesenteric microcirculatory alterations were assessed by laser Doppler flowmetry and intravital microscopy technique. Protein expression of intercellular adhesion molecule-1, P-selectin, endothelial NO synthase (eNOS), and endothelin-1 was evaluated by immunohistochemistry; in addition, eNOS and endothelin-1 gene expressions were quantified by real-time polymerase chain reaction. Serum cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: Relative to the sham group, the I/R group exhibited a highly pronounced loss of intestine mucosal thickness, a reduction in mesenteric blood flow (P = .0203), increased migrated leukocytes (P < .05), and high mortality rate (35%). Treatment with 17ß-estradiol before aorta occlusion preserved intestine mucosal thickness (P = .0437) and mesenteric blood flow (P = .0251), reduced the number of migrated leukocytes (P < .05), and prevented any fatal occurrence. Furthermore, 17ß-estradiol downregulated the expression of intercellular adhesion molecule-1 (P = .0001) and P-selectin (P < .0001) on the endothelium and increased the protein expression of eNOS (P < .0001). The gene expressions of eNOS and endothelin-1 did not differ between the groups. CONCLUSIONS: The prophylactic treatment with 17ß-estradiol showed better overall repercussions and was able to prevent any fatal occurrence, increase eNOS expression, thus preserving mesenteric perfusion and intestinal integrity, and reduce inflammation.


Assuntos
Aorta/fisiopatologia , Oclusão com Balão/efeitos adversos , Estradiol/farmacologia , Íleo/irrigação sanguínea , Íleo/efeitos dos fármacos , Isquemia Mesentérica/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Circulação Esplâncnica/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Endotelina-1/metabolismo , Íleo/metabolismo , Íleo/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Isquemia Mesentérica/etiologia , Isquemia Mesentérica/metabolismo , Isquemia Mesentérica/fisiopatologia , Óxido Nítrico Sintase Tipo III/metabolismo , Selectina-P/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
9.
Interact Cardiovasc Thorac Surg ; 26(2): 196-201, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29049608

RESUMO

OBJECTIVES: Despite research into protective pharmacological adjuncts, paraplegia persists as a dreaded complication after thoracic and thoracoabdominal aortic interventions. Reports on gender-related neurological outcomes after ischaemic and traumatic brain injuries have led to increased interest in hormonal neuroprotective effects and have generated other studies seeking to prove the neuroprotective effects of the therapeutic administration of 17ß-oestradiol and of progesterone. We hypothesised that acute administration of oestradiol or progesterone would prevent or attenuate spinal cord ischaemic injury induced by occlusion of the descending thoracic aorta. METHODS: Male rats were divided into groups receiving 280 µg/kg of 17ß-oestradiol or 4 mg/kg of progesterone or vehicle 30 min before transitory endovascular occlusion of the proximal descending thoracic aorta for 12 min. Hindlimb motor function was assessed by a functional grading scale (that of Basso, Beattie and Bresnahan) for 14 days after reperfusion. On the 14th day, a segment of the thoracolumbar spinal cord was harvested and prepared for histological and immunohistochemical analyses. RESULTS: There was significant impairment of the motor function of the hindlimb in the 3 study groups, with partial improvement noticed over time, but no difference was detected between the groups. On Day 1 of assessment, the 17ß-oestradiol group had a functional score of 9.8 (0.0-16.5); the progesterone group, a score of 0.0 (0-17.1) and the control group, a score of 6.5 (0-16.9); on the 14th day, the 17ß-oestradiol group had a functional score of 18.0 (4.4-19.4); the progesterone group had a score of 7.5 (0-18.5) and the control group had a score of 17.0 (0-19.9). Analysis of the grey matter showed that the number of viable neurons per section was not different between the study groups on the 14th day. Immunostaining of the spinal cord grey matter was also similar among the 3 groups. CONCLUSIONS: Acute administration of oestradiol or of progesterone 30 min before transitory occlusion of the proximal descending thoracic aorta of male rats could not prevent or attenuate spinal cord ischaemic injury based on an analysis of functional and histological outcomes.

10.
Shock ; 48(4): 477-483, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28915217

RESUMO

Intestinal ischemia and reperfusion (I/R) triggers a systemic inflammatory response characterized by leukocyte mobilization from the bone marrow, release of cytokines to the circulation, and increased microvascular permeability, leading to high mortality. Females have shown attenuated inflammatory response to trauma when compared with males, indicating a role for female sex hormones in this process. Here, we have evaluated the effect of estradiol on the local gut injury induced by I/R in male rats. I/R was induced by the clamping of the superior mesenteric artery for 45 min, followed by 2 h of reperfusion. A group received 17ß-estradiol (280 µg/kg, i.v., single dose) at 30 min of ischemia. Morphometric analysis of the gut showed I/R induced a reduction of villous height that was prevented by estradiol. White blood cells, notably granulocytes, were mobilized from the circulation to the intestine by I/R, which was also prevented by estradiol treatment. Groups had the intestine wrapped in a plastic bag to collect intestinal fluid, where leukocytes count, TNF-α, and IL-10 levels were increased by I/R. Serum chemokines (CINC-1, MIP-1α, MIP-2), ICAM-1 expression in the mesenteric tissue, and neutrophils spontaneous migration measured in vitro were also increased after I/R. Estradiol treatment reduced leukocytes numbers and TNF-α on intestinal fluid, serum chemokine release and also downregulated MIP-1α, MIP-2 gene expression, and spontaneous in vitro neutrophil migration. In conclusion, estradiol blunts intestinal injury induced by I/R by modulating chemokines release and leukocyte trafficking.


Assuntos
Estradiol/farmacologia , Enteropatias , Mucosa Intestinal , Intestinos , Traumatismo por Reperfusão , Síndrome de Resposta Inflamatória Sistêmica , Animais , Quimiocinas/metabolismo , Enteropatias/tratamento farmacológico , Enteropatias/metabolismo , Enteropatias/patologia , Mucosa Intestinal/metabolismo , Intestinos/lesões , Intestinos/patologia , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/patologia
11.
J Thorac Cardiovasc Surg ; 153(4): 855-863.e1, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27998611

RESUMO

OBJECTIVES: To evaluate the influence of bilateral or left sympathectomy on left ventricular remodeling and function after myocardial infarction in rats. METHODS: Myocardial infarction was induced in rats by ligation of the left anterior descending coronary. Seven days later, rats were divided into 4 groups: the myocardial infarction, myocardial infarction with left sympathectomy, myocardial infarction with bilateral sympathectomy, and sham groups. After 8 weeks, left ventricular function was evaluated with the use of a pressure-volume conductance catheter under steady-state conditions and pharmacological stress. Infarct size and extracellular matrix fibrosis were evaluated, and cardiac matrix metalloproteinases and myocardial inflammatory markers were analyzed. RESULTS: The myocardial infarction and left sympathectomy group had an increased end diastolic volume, whereas the bilateral sympathectomy group had a mean end-diastolic volume similar to that of the sham group (P < .002). Significant reduction in ejection fraction was observed in the myocardial infarction and left sympathectomy group, whereas it was preserved after bilateral sympathectomy (P < .001). In response to dobutamine, left ventricular contractility increased in sham rats, rising stroke work, cardiac output, systolic volume, end-diastolic volume, ejection fraction, and dP/dt max. Only bilateral sympathectomy rats had significant increases in ejection fraction (P < .001) with dobutamine. Fibrotic tissue and matrix metalloproteinase expression decreased in the bilateral sympathectomy group compared to that in the myocardial infarction group (P < .001) and was associated with left ventricular wall thickness maintenance and better apoptotic markers in noninfarcted myocardium. CONCLUSIONS: Bilateral sympathectomy effectively attenuated left ventricular remodeling and preserved systolic function after myocardial infarction induction in rats.

12.
Acta Cir Bras ; 31(4): 278-85, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27168541

RESUMO

PURPOSE: To investigate gender differences in the evolution of the inflammatory process in rats subjected to brain death (BD). METHODS: Adult Wistar rats were divided into three groups: female; ovariectomized female; and male rats. BD was induced using intracranial balloon inflation and confirmed by maximal pupil dilatation, apnea, absence of reflex, and drop of mean arterial pressure. Six hours after BD, histological evaluation was performed in lungs, heart, liver and kidneys, and levels of inflammatory proteins, estrogen, progesterone, and corticosterone were determined in plasma. RESULTS: In the lungs, females presented more leukocyte infiltration compared to males (p<0.01). Ovariectomized female rat lungs were more hemorrhagic compared to other groups (p<0.001). In the heart, females had higher leukocyte infiltration and tissue edema compared to males (p<0.05). In the liver and kidneys, there were no differences among groups. In female group estradiol and progesterone were sharply reduced 6 hours after BD (p<0.001) to values observed in ovariectomized females and males. Corticosterone levels were similar. CONCLUSIONS: Sex hormones influence the development of inflammation and the status of organs. The increased inflammation in lungs and heart of female rats might be associated with the acute reduction in female hormones triggered by BD.


Assuntos
Morte Encefálica/patologia , Rim/patologia , Fígado/patologia , Pulmão/patologia , Miocárdio/patologia , Caracteres Sexuais , Animais , Quimiocina CXCL1/análise , Quimiocina CXCL2/análise , Edema/patologia , Estradiol/sangue , Feminino , Inflamação/patologia , Masculino , Especificidade de Órgãos , Ovariectomia , Progesterona/sangue , Ratos Wistar , Valores de Referência , Fatores Sexuais , Fatores de Tempo
13.
Acta cir. bras ; 31(4): 278-285, Apr. 2016. tab, graf
Artigo em Inglês | LILACS-Express | ID: lil-781333

RESUMO

PURPOSE: To investigate gender differences in the evolution of the inflammatory process in rats subjected to brain death (BD). METHODS: Adult Wistar rats were divided into three groups: female; ovariectomized female; and male rats. BD was induced using intracranial balloon inflation and confirmed by maximal pupil dilatation, apnea, absence of reflex, and drop of mean arterial pressure. Six hours after BD, histological evaluation was performed in lungs, heart, liver and kidneys, and levels of inflammatory proteins, estrogen, progesterone, and corticosterone were determined in plasma. RESULTS: In the lungs, females presented more leukocyte infiltration compared to males (p<0.01). Ovariectomized female rat lungs were more hemorrhagic compared to other groups (p<0.001). In the heart, females had higher leukocyte infiltration and tissue edema compared to males (p<0.05). In the liver and kidneys, there were no differences among groups. In female group estradiol and progesterone were sharply reduced 6 hours after BD (p<0.001) to values observed in ovariectomized females and males. Corticosterone levels were similar. CONCLUSIONS: Sex hormones influence the development of inflammation and the status of organs. The increased inflammation in lungs and heart of female rats might be associated with the acute reduction in female hormones triggered by BD.

14.
J Surg Res ; 200(2): 714-21, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26547667

RESUMO

BACKGROUND: Donor sex has been suggested to be a factor influencing organ transplantation outcome. Sex hormones possess inflammatory and immune-mediating properties; therefore, immune responses may differ between males and females. Brain death (BD) affects organ function by numerous mechanisms including alterations in hemodynamics, hormonal changes, and increased systemic inflammation. In this study, we investigated sex-dependent differences in the evolution of lung inflammation in a rat model of BD. MATERIALS AND METHODS: BD was induced by a sudden increase in intracranial pressure by rapidly inflating a balloon catheter inserted into the intracranial space. Groups of male, female, and ovariectomized (OVx) female rats were used. Lung vascular permeability, inducible nitric oxide synthase, and intercellular adhesion molecule 1 expression were analyzed 6 h after BD. Serum female sex hormones, vascular endothelial growth factor, and cytokine-induced neutrophil chemoattractant 1 levels were also quantified. Lung sections were analyzed by histology. RESULTS: After 6 h of BD, serum estradiol and progesterone concentrations in female rats were significantly reduced. Lung microvascular permeability was increased in females compared to males. Cytokine-induced neutrophil chemoattractant 1 and vascular endothelial growth factor concentrations were increased in female rats compared to males. Furthermore, female rats showed higher levels of leukocyte infiltration and inducible nitric oxide synthase expression in the lung parenchyma. CONCLUSIONS: Our results indicate that the more severe lung inflammation in female animals after BD might be related to acute estradiol reduction. Based on our findings, we believe that, in a future study, a group of female treated with estradiol after BD could indicate a possible therapy for the control of lung inflammation in the female donor.


Assuntos
Morte Encefálica/metabolismo , Pneumonia/metabolismo , Animais , Biomarcadores/metabolismo , Estradiol/sangue , Feminino , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pneumonia/etiologia , Pneumonia/patologia , Progesterona/sangue , Ratos , Ratos Wistar , Fatores Sexuais , Obtenção de Tecidos e Órgãos
15.
Clinics (Sao Paulo) ; 70(7): 508-14, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26222821

RESUMO

OBJECTIVES: Experimental studies on sepsis have demonstrated that ethyl pyruvate is endowed with antioxidant and anti-inflammatory properties. This study aimed to investigate the effects of ethyl pyruvate on leukocyte-endothelial interactions in the mesenteric microcirculation in a live Escherichia coli-induced sepsis model in rats. METHODS: Male Wistar rats were administered an intravenous suspension of E. coli bacteria or were subjected to a sham procedure. Three hours after bacterial infusion, the rats were randomized into the following groups: a control group without treatment, a group treated with lactated Ringer's solution (4 mL/kg, i.v.), and a group treated with lactated Ringer's solution (4 mL/kg, i.v.) plus ethyl pyruvate (50 mg/kg). At 24 h after bacterial infusion, leukocyte-endothelial interactions were investigated using intravital microscopy, and the expression of P-selectin and intercellular adhesion molecule-1 was evaluated via immunohistochemistry. White blood cell and platelet counts were also determined at baseline and 3 h and 24 h after E. coli inoculation. RESULTS: The non-treated and lactated Ringer's solution-treated groups exhibited increases in the numbers of rolling leukocytes (∼2.5-fold increase), adherent cells (∼3.0-fold), and migrated cells (∼3.5-fold) compared with the sham group. In contrast, treatment with Ringer's ethyl pyruvate solution reduced the numbers of rolling, adherent and migrated leukocytes to the levels observed in the sham group. Additionally, the expression of P-selectin and intercellular adhesion molecule-1 was significantly increased on mesenteric microvessels in the non-treated group compared with the sham group (p<0.001). The expression of both adhesion molecules was reduced in the other groups, with ethyl pyruvate being more effective than lactated Ringer's solution. Infusion of bacteria caused significant leukopenia (3 h), followed by leukocytosis with granulocytosis (24 h). There was also an intense and progressive reduction in the number of platelets. However, no differences were observed after treatment with the different solutions. CONCLUSIONS: The presented data suggest that ethyl pyruvate efficiently reduces the inflammatory response in the mesenteric microcirculation in an experimental model of sepsis induced by live E. coli and is associated, at least in part, with down-regulation of P-selectin and intercellular adhesion molecule-1.


Assuntos
Comunicação Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Piruvatos/farmacologia , Sepse/tratamento farmacológico , Animais , Comunicação Celular/fisiologia , Modelos Animais de Doenças , Células Endoteliais/citologia , Infecções por Escherichia coli , Leucócitos/citologia , Masculino , Veias Mesentéricas/citologia , Microcirculação , Ratos , Ratos Wistar
16.
Clinics ; 70(7): 508-514, 2015. tab, graf
Artigo em Inglês | LILACS | ID: lil-752397

RESUMO

OBJECTIVES: Experimental studies on sepsis have demonstrated that ethyl pyruvate is endowed with antioxidant and anti-inflammatory properties. This study aimed to investigate the effects of ethyl pyruvate on leukocyte-endothelial interactions in the mesenteric microcirculation in a live Escherichia coli-induced sepsis model in rats. METHODS: Male Wistar rats were administered an intravenous suspension of E. coli bacteria or were subjected to a sham procedure. Three hours after bacterial infusion, the rats were randomized into the following groups: a control group without treatment, a group treated with lactated Ringer’s solution (4 mL/kg, i.v.), and a group treated with lactated Ringer’s solution (4 mL/kg, i.v.) plus ethyl pyruvate (50 mg/kg). At 24 h after bacterial infusion, leukocyte-endothelial interactions were investigated using intravital microscopy, and the expression of P-selectin and intercellular adhesion molecule-1 was evaluated via immunohistochemistry. White blood cell and platelet counts were also determined at baseline and 3 h and 24 h after E. coli inoculation. RESULTS: The non-treated and lactated Ringer’s solution-treated groups exhibited increases in the numbers of rolling leukocytes (∼2.5-fold increase), adherent cells (∼3.0-fold), and migrated cells (∼3.5-fold) compared with the sham group. In contrast, treatment with Ringer’s ethyl pyruvate solution reduced the numbers of rolling, adherent and migrated leukocytes to the levels observed in the sham group. Additionally, the expression of P-selectin and intercellular adhesion molecule-1 was significantly increased on mesenteric microvessels in the non-treated group compared with the sham group (p<0.001). The expression of both adhesion molecules was reduced in the other groups, with ethyl pyruvate being more effective than lactated Ringer’s solution. Infusion of bacteria caused significant leukopenia (3 h), followed ...


Assuntos
Animais , Masculino , Ratos , Comunicação Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Piruvatos/farmacologia , Sepse/tratamento farmacológico , Comunicação Celular/fisiologia , Modelos Animais de Doenças , Infecções por Escherichia coli , Células Endoteliais/citologia , Leucócitos/citologia , Microcirculação , Veias Mesentéricas/citologia , Ratos Wistar
17.
Shock ; 41(3): 208-13, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24220282

RESUMO

Intestinal ischemia and reperfusion (intestinal I/R) causes acute lung inflammation that is characterized by leukocyte migration, increased lung microvascular permeability, and, in severe forms, noncardiogenic pulmonary edema and acute respiratory distress syndrome. Female sex hormones interfere with immune response, and experimental and clinical evidence shows that females are more resistant than males to organ injury caused by gut trauma. To reduce the lung inflammation caused by intestinal I/R, we have acutely treated male rats with estradiol. Intestinal I/R was performed by the clamping (45 min) of the superior mesenteric artery (SMA), followed by 2 h of intestinal reperfusion (unclamping SMA). Groups of rats received 17ß estradiol (E2, 280 µg/kg, i.v., single dose) 30 min after the SMA occlusion (ischemia period) or 1 h after the unclamping of SMA (reperfusion period). Leukocytes influx into the lung and microvascular leakage were assessed by lung myeloperoxidase activity and Evans blue dye extravasation, respectively. The lung expression of adhesion molecules (intercellular adhesion molecule 1, platelet endothelial cell adhesion molecule 1, and vascular cell adhesion molecule [VCAM]) was evaluated by immunohistochemistry. Interleukin 1ß (IL-1ß), IL-10, and NOx concentrations were quantified in supernatants of cultured lung tissue. We have found that intestinal I/R increased the lung myeloperoxidase activity and Evans blue dye extravasation, which were reduced by treatment of rats with E2. Intestinal I/R increased ICAM-1 expression only, and it was decreased by E2 treatment. However, E2 treatment reduced the basal expression of platelet endothelial cell adhesion molecule 1. E2 treatment during intestinal ischemia was effective to reduce the levels of IL-10 and IL-1ß in explant supernatant, but only IL-10 levels were reduced by E2 at reperfusion phase. The treatment with E2 did not affect NOx concentration. Taken together, our data suggest that estradiol modulates the lung inflammatory response induced by lung injury, likely by acute effects. Thus, acute estradiol treatment could be considered as a potential therapeutic agent in ischemic events.


Assuntos
Estradiol/farmacologia , Estrogênios/farmacologia , Enteropatias/tratamento farmacológico , Intestinos/irrigação sanguínea , Isquemia/tratamento farmacológico , Pneumonia/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/biossíntese , Interleucina-10/sangue , Interleucina-1beta/sangue , Enteropatias/complicações , Enteropatias/patologia , Intestinos/patologia , Isquemia/sangue , Isquemia/complicações , Isquemia/patologia , Masculino , Óxido Nítrico/sangue , Pneumonia/sangue , Pneumonia/etiologia , Pneumonia/patologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia
18.
Clinics ; 68(12): 1528-1536, dez. 2013. tab, graf
Artigo em Inglês | LILACS | ID: lil-697702

RESUMO

OBJECTIVE: Formaldehyde exposure during the menstrual cycle is known to affect the course of allergic lung inflammation. Because our previous data demonstrated that formaldehyde combined with an ovariectomy reduced allergic lung inflammation, we investigated the putative role of ovary removal and progesterone treatment when considering the effect of formaldehyde on allergic lung inflammation. METHOD: Ovariectomized rats and their matched controls were exposed to formaldehyde (1%, 3 days, 90 min/day) or vehicle, and immediately after exposure, the rats were sensitized to ovalbumin by a subcutaneous route. After 1 week, the rats received a booster by the same route, and after an additional week, the rats were challenged with ovalbumin (1%) by an aerosol route. The leukocyte numbers, interleukin-10 (IL-10) release, myeloperoxidase activity, vascular permeability, ex vivo tracheal reactivity to methacholine and mast cell degranulation were determined 24 h later. RESULTS: Our results showed that previous exposure to formaldehyde in allergic rats decreased lung cell recruitment, tracheal reactivity, myeloperoxidase activity, vascular permeability and mast cell degranulation while increasing IL-10 levels. Ovariectomy only caused an additional reduction in tracheal reactivity without changing the other parameters studied. Progesterone treatment reversed the effects of formaldehyde exposure on ex vivo tracheal reactivity, cell influx into the lungs and mast cell degranulation. CONCLUSION: In conclusion, our study revealed that formaldehyde and ovariectomy downregulated allergic lung inflammation by IL-10 release and mast cell degranulation. Progesterone treatment increased eosinophil recruitment and mast cell degranulation, which in turn may be responsible for tracheal hyperreactivity and allergic lung inflammation. .


Assuntos
Animais , Feminino , Ratos , Formaldeído/efeitos adversos , Pulmão/efeitos dos fármacos , Ovariectomia , Ovalbumina/efeitos adversos , Pneumonia/induzido quimicamente , Progesterona/uso terapêutico , Degranulação Celular/efeitos dos fármacos , Modelos Animais de Doenças , /análise , Contagem de Leucócitos , Mastócitos/efeitos dos fármacos , Peroxidase/análise , Peroxidase/efeitos dos fármacos , Distribuição Aleatória , Ratos Wistar , Hipersensibilidade Respiratória , Fatores de Tempo
19.
Food Chem Toxicol ; 59: 731-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23871789

RESUMO

Bronchial hyperresponsiveness is a hallmark of asthma and many factors modulate bronchoconstriction episodes. A potential correlation of formaldehyde (FA) inhalation and asthma has been observed; however, the exact role of FA remains controversial. We investigated the effects of FA inhalation on Ovalbumin (OVA) sensitisation using a parameter of respiratory mechanics. The involvement of nitric oxide (NO) and cyclooxygenase-derived products were also evaluated. The rats were submitted, or not, to FA inhalation (1%, 90 min/day, 3 days) and were OVA-sensitised and challenged 14 days later. Our data showed that previous FA exposure in allergic rats reduced bronchial responsiveness, respiratory resistance (Rrs) and elastance (Ers) to methacholine. FA exposure in allergic rats also increased the iNOS gene expression and reduced COX-1. L-NAME treatment exacerbated the bronchial hyporesponsiveness and did not modify the Ers and Rrs, while Indomethacin partially reversed all of the parameters studied. The L-NAME and Indomethacin treatments reduced leukotriene B4 levels while they increased thromboxane B2 and prostaglandin E2. In conclusion, FA exposure prior to OVA sensitisation reduces the respiratory mechanics and the interaction of NO and PGE2 may be representing a compensatory mechanism in order to protect the lung from bronchoconstriction effects.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Hiper-Reatividade Brônquica/tratamento farmacológico , Modelos Animais de Doenças , Eicosanoides/metabolismo , Óxido Nítrico/metabolismo , Insuficiência Respiratória/prevenção & controle , Mucosa Respiratória/efeitos dos fármacos , Administração por Inalação , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Broncoconstritores/farmacologia , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Dinoprostona/agonistas , Dinoprostona/metabolismo , Formaldeído/administração & dosagem , Formaldeído/toxicidade , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Leucotrieno B4/antagonistas & inibidores , Leucotrieno B4/metabolismo , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar , Insuficiência Respiratória/etiologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/fisiopatologia , Tromboxano B2/agonistas , Tromboxano B2/metabolismo
20.
Shock ; 40(3): 203-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23846411

RESUMO

INTRODUCTION: It has been shown that the innate immune system mediates acute lung inflammation triggered by intestinal trauma. Sexual dimorphism modulates the profile of TH1 and TH2 lymphocytes, and accordingly sex hormones may modulate acute lung inflammation by intestinal ischemia/reperfusion (I/R). Studies indicate that female rats are relatively resistant to organ injury caused by hemorrhagic shock and that the gut of female is more resistant than that of the male to deleterious effects of ischemic injury. At the present study, we investigated the effect of estradiol (E(2)) on the lung inflammation after intestinal I/R and its interaction with the nitric oxide (NO) pathway. METHODS: Anesthetized female rats submitted or not to 7 days ovariectomy (OVx) were subjected to occlusion of the superior mesenteric artery during 45 min, followed by 2 h of reperfusion. Groups of rats were treated with E(2) (17ß-estradiol, 280 µg/kg, s.c.) 24 h before ischemia and/or with the nonselective NO synthase inhibitor L-NAME (Nω-nitro-L-arginine methyl ester hydrochloride) (5 mg/kg, i.v.). In a parallel set of experiments, the selective NO synthase inhibitor, aminoguanidine (50 mg/kg i.v.), was given 1 h before ischemia. In all groups, lung vascular permeability (LVP) was assessed using the Evans blue dye extravasation method, neutrophil recruitment to the tissues by the standard myeloperoxidase (MPO) method, and endothelial NO synthase (eNOS) protein expression by Western blot. RESULTS: In OVx rats, LVP and MPO were increased after intestinal I/R as compared with intact controls. Estradiol reverted the LVP, but not MPO. Aminoguanidine reduced LVP in OVx rats. The E(2) protective effect on LVP was abolished by L-NAME; moreover, an increase in LVP even when compared with OVx rats treated only with L-NAME was observed. In addition, lung eNOS protein expression was reduced in OVx-I/R rats in comparison to intact controls and the E(2) inhibited this effect. CONCLUSIONS: Estradiol treatment is able to reduce lung inflammation due to intestinal I/R, but with the concomitant blockade of NOS activity, this effect is abolished. Nitric oxide probably reduces the vascular deleterious effects of intestinal I/R, and E(2) pretreatment reduces lung inflammation after intestinal I/R and exerts these effects by modulating eNOS protein expression in the lungs.


Assuntos
Estradiol/uso terapêutico , Intestinos/irrigação sanguínea , Óxido Nítrico/metabolismo , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Animais , Feminino , Masculino , Ratos , Ratos Wistar
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