RESUMO
OBJECTIVE: We determined the impact of maternal food restriction during gestation and lactation or lactation alone on basal inflammation and lipopolysaccharide (LPS)-stimulated cytokine induction in adult female offspring. STUDY DESIGN: From 10 days of gestation to term, pregnant rats received either ad libitum (control) feed or were 50% food restricted (FR). Pups were either nursed by their own dams or were cross-fostered to give three groups, namely, Control (AdLib/AdLib), FR during lactation (AdLib/FR) and FR during pregnancy and lactation (FR/FR). All offspring were weaned to ad libitum rat chow. At 9 months of age, basal inflammation and LPS-stimulated cytokine responsiveness were determined in female offspring. RESULTS: The basal CRP levels were elevated in AdLib/FR and FR/FR as compared to Controls. In contrast, LPS induction of IL-1beta and IL-6 was significantly attenuated in the AdLib/FR and FR/FR offspring as compared to the Control group. CONCLUSIONS: These findings suggest that early undernutrition, particularly during prenatal and postnatal periods, affects offspring immune competence by increasing basal inflammation while reducing cytokine induction to inflammatory stimuli.
Assuntos
Transtornos da Nutrição Fetal/sangue , Inflamação/sangue , Animais , Animais Recém-Nascidos , Peso Corporal/fisiologia , Proteína C-Reativa/análise , Citocinas/análise , Citocinas/sangue , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/imunologia , Transtornos da Nutrição Fetal/imunologia , Transtornos da Nutrição Fetal/fisiopatologia , Inflamação/imunologia , Inflamação/fisiopatologia , Mediadores da Inflamação/análise , Mediadores da Inflamação/sangue , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Evidence suggests that maternal infections may induce fetal inflammatory responses. Because cytokine actions may be mediated by oxidative stress, we determined whether N-acetylcysteine, an antioxidant, can blunt fetal inflammatory responses to maternal lipopolysaccharide. STUDY DESIGN: Sprague Dawley near-term rats (n = 16) received intraperitoneal lipopolysaccharide (100 microg/kg) at 30 minutes and saline solution or N-acetylcysteine (300 mg/kg) at 150 minutes. An additional group received N-acetylcysteine before and after lipopolysaccharide administration. At 6 hours, rats were killed, and fetal and maternal blood cytokines were determined. RESULTS: After maternal lipopolysaccharide administration, fetal blood interleukin-6 markedly increased (3 +/- 2 to 1265 +/- 574 pg/mL); N-acetylcysteine that was given before or before and after lipopolysaccharide administration reduced fetal interleukin-6 response to control levels. A similar trend was observed for interleukin-1beta. No effect of N-acetylcysteine on fetal interleukin-10 levels was observed. CONCLUSION: Maternal N-acetylcysteine inhibits fetal cytokine responses to maternal lipopolysaccharide, even when given 2 hours after lipopolysaccharide injection. These results suggest that N-acetylcysteine may protect the fetus from sequelae of maternal inflammation.
Assuntos
Acetilcisteína/farmacologia , Citocinas/biossíntese , Doenças Fetais/prevenção & controle , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Animais , Feminino , Interleucina-1/sangue , Interleucina-10/sangue , Interleucina-6/sangue , NF-kappa B/fisiologia , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Feeding dysregulation may manifest as either under-nourishment (e.g., anorexia) or excessive eating leading to obesity. Recent studies have suggested a gender-related variance in weight maintenance in response to chronic disease or obesity-related dietary regimens. However it is unclear whether these gender differences in weight management are secondary to appetite-mediated food intake or alternative mechanisms (e.g., exercise, metabolism). In this study, we explored gender-dependent feeding and hormonal responses to dietary restriction (12-h fast) or to an inflammatory stimulus (LPS, 100 microg/kg b.w.; i.p.) in rats. In response to a 12 h fast, female rats increased (p<0.05) total daily food intake above that of male rats by primarily increasing nighttime feeding by 40%, as compared to 10% in males. Consistent with the increased food intake, fasting induced a greater percent increase in female as compared to male plasma ghrelin (141 vs. 65%, p<0.001). In response to LPS, both male and female rats showed similar reductions in total daily food consumption. However LPS (6 h) induced a greater percent increase in plasma leptin in female than male rats (230 vs. 33%, p<0.01), whereas ghrelin was similarly decreased in both females and males (66 vs. 44%). These findings demonstrate sexual dimorphic responses in feeding and appetite-associated hormonal responses to fasting or LPS treatment. Our findings suggest that therapeutic interventions with ghrelin or leptin must be modified according to gender in order to optimally achieve either weight loss for obesity or weight gain/maintenance for chronic illness-associated anorexia.
Assuntos
Anorexia/etiologia , Apetite/fisiologia , Peso Corporal/fisiologia , Jejum/fisiologia , Comportamento Alimentar/fisiologia , Animais , Anorexia/sangue , Apetite/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Grelina , Leptina/sangue , Lipopolissacarídeos/farmacologia , Masculino , Hormônios Peptídicos/sangue , Ratos , Ratos Sprague-Dawley , Fatores SexuaisRESUMO
OBJECTIVE: Maternal infections may induce placental, amniotic and, potentially, fetal inflammatory responses. As cytokine responses may be mediated by oxidative stress, we determined whether the antioxidant N-acetyl-cysteine (NAC), can attenuate maternally induced amniotic and placental cytokine responses to maternal infection (modeled by lipopolysaccharide [LPS]). STUDY DESIGN: Gestation day 18 pregnant rats were (1) treated with LPS (100 microg/kg, body weight; intraperitoneally) alone; (2) pretreated with NAC (300 mg/kg body weight; intraperitoneally) 30 minutes before LPS; (3) posttreated with NAC 120 minutes after LPS; or (4) treated with NAC 30 minutes before and 120 minutes after LPS. Six hours after LPS administration, maternal serum and amniotic fluid interleukin-6 (IL-6) and IL-10 levels, and placental IL-6 messenger RNA levels were determined. RESULTS: LPS increased maternal serum IL-6 (50 +/- 25 to 3444 +/- 584 pg/mL) and IL-10 (40 +/- 20 to 958 +/- 339 pg/mL) and amniotic fluid IL-6 (59 +/- 25 to 891 +/- 128 pg/mL). Pretreatment and/or posttreatment with NAC attenuated IL-6 in the maternal serum and amniotic fluid and IL-10 in the amniotic fluid. LPS also induced placental IL-6 messenger RNA that was inhibited by treatment with NAC before and after LPS. CONCLUSION: NAC inhibition of inflammatory responses may protect the fetus from potential long-term sequelae.
Assuntos
Acetilcisteína/farmacologia , Líquido Amniótico/metabolismo , Antioxidantes/farmacologia , Citocinas/antagonistas & inibidores , Mediadores da Inflamação/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Placenta/metabolismo , Animais , Feminino , Interleucina-10/sangue , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/metabolismo , Gravidez , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Fetal and amniotic fluid (AF) proteins (eg, alpha fetoprotein [AFP]) are measurable in the maternal circulation. Elevated maternal serum AFP levels indicate a risk for fetal anomalies or for obstetrical complications that are often associated with inflammation (eg, preterm labor). However, little is known of the mechanism of protein exchange between the fetus, AF, and maternal circulation. Nephrin and Neph1 are cell membrane proteins that restrict glomerular protein filtration and which are differentially expressed with renal inflammation. We sought to investigate whether nephrin and Neph1 were expressed in placenta and fetal membranes, and whether inflammation modified the expression. METHODS: Pregnant rats at 18 days' gestation were injected with lipopolysacchride (LPS) or control saline intraperitoneally (IP) and killed at 1, 6, and 12 hours after injection. Placenta and fetal membranes were obtained and real-time polymerase chain reaction (PCR) performed for determination of nephrin and Neph1 levels. RESULTS: Nephrin and Neph1 were expressed in both placenta and fetal membranes. Following maternal LPS administration, nephrin mRNA significantly increased in the membranes (0.22 +/- 0.02 to 0.51 +/- 0.050, P <.05), while Neph1 expression significantly declined in the placenta (0.19 +/- 0.05 to 0.10 +/- 0.01, P <.05). CONCLUSION: Fetal membranes and placenta of the rat express mRNA for the protein barriers nephrin and Neph 1, suggesting a role in the regulation of protein transfer from the fetus to mother. Under basal conditions, AF AFP transfer across fetal membranes may account for maternal serum AFP levels, whereas gestational inflammatory conditions (eg, preterm labor, threatened abortion) may augment AFP transfer across the placenta.
Assuntos
Proteínas de Membrana/biossíntese , Placenta/fisiologia , Prenhez/fisiologia , Animais , Membranas Extraembrionárias , Feminino , Inflamação , Troca Materno-Fetal , Reação em Cadeia da Polimerase , Gravidez , Prenhez/imunologia , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Fatores de Risco , alfa-Fetoproteínas/metabolismoRESUMO
PURPOSE OF REVIEW: The onset of cancer anorexia and the accompanying neurological symptoms and signs involve the general influence of cytokines on the brain. Using methylcholanthrene to induce tumors in Fischer 344 rats, we measured various specific components of the cytokine-induced anorectic reaction, including: (1) IL-1beta system components (ligand, signaling receptor, receptor accessory proteins, and receptor antagonist); (2) TNF-alpha; (3) TGF-beta1; and (4) IFN-gamma in the tumor tissue, the liver and the brain. RECENT FINDINGS: The data show that IL-1beta, TNF-alpha and IFN-gamma messenger RNA were detected in the tumor tissue of anorectic tumor-bearing rats. In brain regions, anorexia is associated with the upregulation of IL-1beta and its receptor mRNA. All other mRNA remained unchanged in the brain regions examined. SUMMARY: This suggests that IL-1beta and its receptor may play a significant role in this model of cancer-associated anorexia. In vivo, the characterization of cytokine components in the brain may provide data for potential pharmacological interventions to ameliorate the anorexia of disease.
Assuntos
Anorexia/metabolismo , Citocinas/biossíntese , Interleucina-1/fisiologia , Neoplasias/metabolismo , Animais , Anorexia/etiologia , Anorexia/fisiopatologia , Encéfalo/metabolismo , Caquexia/etiologia , Interferon gama/biossíntese , Interleucina-1/biossíntese , Fígado/metabolismo , Masculino , Neoplasias/complicações , Neoplasias/fisiopatologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Fator de Crescimento Transformador beta/biossíntese , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Perinatal infections are a risk factor for fetal neurological pathologies, including cerebral palsy and schizophrenia. Cytokines that are produced as part of the inflammatory response are proposed to partially mediate the neurological injury. This study investigated the effects of intraperitoneal injections of lipopolysaccharide (LPS) to pregnant rats on the production of cytokines and stress markers in the fetal environment. Gestation day 18 pregnant rats were treated with LPS (100 microg/kg body wt i.p.), and maternal serum, amniotic fluid, placenta, chorioamnion, and fetal brain were harvested at 1, 6, 12, and 24 h posttreatment to assay for LPS-induced changes in cytokine protein (ELISA) and mRNA (real-time RT-PCR) levels. We observed induction of proinflammatory cytokines interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) as well as the anti-inflammatory cytokine IL-10 in the maternal serum within 6 h of LPS exposure. Similarly, proinflammatory cytokines were induced in the amniotic fluid in response to LPS; however, no significant induction of IL-10 was observed in the amniotic fluid. LPS-induced mRNA changes included upregulation of the stress-related peptide corticotropin-releasing factor in the fetal whole brain, TNF-alpha, IL-6, and IL-10 in the chorioamnion, and TNF-alpha, IL-1 beta, and IL-6 in the placenta. These findings suggest that maternal infections may lead to an unbalanced inflammatory reaction in the fetal environment that activates the fetal stress axis.
Assuntos
Líquido Amniótico/metabolismo , Química Encefálica/efeitos dos fármacos , Hormônio Liberador da Corticotropina/metabolismo , Citocinas/biossíntese , Lipopolissacarídeos/farmacologia , Líquido Amniótico/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Ensaio de Imunoadsorção Enzimática , Feminino , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Fisiológico/metabolismoRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Although the exact mechanisms responsible for this cell loss are unclear, emerging evidence suggests the involvement of inflammatory events. In the present study, we characterized the effects of the proinflammatory bacteriotoxin lipopolysaccharide (LPS) on the number of tyrosine hydroxylase immunoreactive (THir) cells (used as an index for DA neurons) in primary mesencephalic cultures. LPS (10-80 microg/ml) selectively decreased THir cells and increased culture media levels of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) as well as nitrite (an index of nitric oxide (NO) production). Cultures exposed to both LPS and neutralizing antibodies to IL-1beta or TNF-alpha showed an attenuation of the LPS-induced THir cell loss by at least 50% in both cases. Inhibition of the inducible form of nitric oxide synthase (iNOS) by L-NIL did not affect LPS toxicity, but increased the LPS-induced levels of both TNF-alpha and IL-1beta. These findings suggest that neuroinflammatory stimuli which lead to elevations in cytokines may induce DA neuron cell loss in a NO-independent manner and contribute to PD pathogenesis.
Assuntos
Morte Celular/imunologia , Citocinas/imunologia , Dopamina/metabolismo , Encefalite/complicações , Neurônios/imunologia , Doença de Parkinson/etiologia , Substância Negra/imunologia , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Encefalite/imunologia , Encefalite/fisiopatologia , Feminino , Interleucina-1/imunologia , Interleucina-1/metabolismo , Lipopolissacarídeos/farmacologia , Neurônios/metabolismo , Óxido Nítrico/imunologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/imunologia , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Doença de Parkinson/imunologia , Doença de Parkinson/fisiopatologia , Ácido Peroxinitroso/imunologia , Ácido Peroxinitroso/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We investigated whether in utero exposure to the Gram(-) bacteriotoxin lipopolysaccharide (LPS) induces dopamine (DA) neuron loss in rats. The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) kills DA neurons and is elevated in the brains of patients with Parkinson's disease (PD). LPS is a potent inducer of TNF-alpha, and both are increased in the chorioamniotic environment of women who have bacterial vaginosis (BV) during pregnancy, suggesting that BV might interfere with the normal development of fetal DA neurons. Gravid female rats were injected intraperitoneally with either LPS or normal saline at embryonic day 10.5 and their pups were killed at postnatal day 21. The brains of the pups were assessed for DA and TNF-alpha levels and DA cell counts in the mesencephalon using tyrosine hydroxylase immunoreactive (THir) cells as a DA neuron marker. Prenatal LPS exposure significantly reduced striatal DA (29%) and increased DA activity (72%) as well as TNF-alpha (101%). Stereological cell counts in the mesencephalon were also significantly reduced (27%) by prenatal LPS exposure. Prenatal exposure to LPS, as might occur in humans with BV, produces a significant loss of THir cells in rats that is still present 33 days following a single injection of LPS. Since this cell loss is well past the normal phase of DA neuron apoptosis that occurs in early postnatal life, rats so exposed may have a permanent loss of DA neurons, suggesting that prenatal infections may represent risk factors for PD.