RESUMO
BACKGROUND AND OBJECTIVE: Chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and excessive glucocorticoid hormone release have been associated with diabetes, altered immune responses and increased susceptibility to periodontitis. In the present study we tested the impact of streptozotocin (STZ)-induced diabetes on ligature-induced periodontitis and the effect of subsequent treatment with the glucocorticoid receptor (GR) antagonist, RU486. MATERIAL AND METHODS: A single dose of STZ [45 mg/kg, intraperitoneally (i.p.)] or vehicle was given 10 d before induction of ligature-induced periodontitis and implantation subcutaneously of a drug pellet containing the GR antagonist, RU486, or a placebo pellet. Periodontitis was assessed when the ligatures had been in place for 21 d. Two hours before decapitation all rats received gram-negative bacterial lipopolysaccharide (LPS) (150 µg/kg, i.p.) to induce a robust immune and stress response. RESULTS: Compared with control rats, STZ-treated rats developed significantly more periodontal bone loss, and RU486 treatment of STZ -treated rats significantly inhibited this effect. STZ-treated rats also showed significantly higher levels of the HPA axis-derived hormone, corticosterone, as well as of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α), but lower levels of the anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor-1beta (TGF-1ß) after LPS stimulation. GR blockade had no statistically significant effects on these measurements in diabetic rats, but tended to enhance the levels of TNF-α and TGF-1ß, and reduce the levels of IL-10 and blood glucose. CONCLUSION: In diabetic subjects, excessive GR activation as a result of chronic high levels of glucocorticoid hormones may alter immune-system responses in a manner that may increase the susceptibility to periodontitis.
Assuntos
Diabetes Mellitus Experimental/complicações , Antagonistas de Hormônios/uso terapêutico , Mifepristona/uso terapêutico , Periodontite/prevenção & controle , Receptores de Glucocorticoides/antagonistas & inibidores , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/prevenção & controle , Animais , Glicemia/análise , Peso Corporal , Corticosterona/sangue , Diabetes Mellitus Experimental/sangue , Implantes de Medicamento , Escherichia coli/imunologia , Antagonistas de Hormônios/administração & dosagem , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Interleucina-10/sangue , Lipopolissacarídeos/imunologia , Mifepristona/administração & dosagem , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Placebos , Radiografia , Distribuição Aleatória , Ratos , Estreptozocina , Fator de Crescimento Transformador beta1/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND AND OBJECTIVE: The complement activation product 5a (C5a) is a potent mediator of the innate immune response to infection, and may thus also importantly determine the development of periodontitis. The present study was designed to explore the effect of several novel, potent and orally active C5a receptor (CD88) antagonists (C5aRAs) on the development of ligature-induced periodontitis in an animal model. MATERIAL AND METHODS: Three different cyclic peptide C5aRAs, termed PMX205, PMX218 and PMX273, were investigated. Four groups of Wistar rats (n = 10 in each group) were used. Starting 3 d before induction of experimental periodontitis, rats either received one of the C5aRas (1-2 mg/kg) in the drinking water or received drinking water only. Periodontitis was assessed when the ligatures had been in place for 14 d. RESULTS: Compared with control rats, PMX205- and PMX218-treated rats had significantly reduced periodontal bone loss. CONCLUSION: The findings suggest that complement activation, and particularly C5a generation, may play a significant role in the development and progression of periodontitis. Blockade of the major C5a receptor, CD88, with specific inhibitors such as PMX205, may offer novel treatment options for periodontitis.
Assuntos
Perda do Osso Alveolar/prevenção & controle , Fatores Imunológicos/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Periodontite/prevenção & controle , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Perda do Osso Alveolar/imunologia , Animais , Ativação do Complemento , Modelos Animais de Doenças , Água Potável , Fatores Imunológicos/farmacologia , Imunoterapia/métodos , Ligadura , Peptídeos Cíclicos/imunologia , Peptídeos Cíclicos/farmacologia , Periodontite/imunologia , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
BACKGROUND: the mechanisms behind lipopolysaccharide (LPS) tolerance remain obscure. LPS signals through Toll-like receptor 4 (TLR4) and severe trauma/haemorrhage may influence binding and signalling through this receptor, e.g. by changing membrane expression or by releasing endogenous ligands like High Mobility Group Box 1 (HMGB1). The aim of this study was to examine these relations further in a porcine model with standardized trauma. METHODS: nine anaesthetized pigs sustained one gunshot through the femur and one pistol shot through the upper abdomen. Blood was sampled before and 90 min after shooting. The samples were stimulated for 4 h with LPS 10 ng/ml or an equivalent amount of normal saline. The leucocyte response was evaluated by measuring the tumour necrosis factor-α (TNF-α) and CXC ligand 8 (CXCL8) in the supernatant. Flow cytometry was used to measure the surface expression of TLR4 on CD14+ monocytes. HMGB1 concentrations were measured in the plasma. RESULTS: trauma and treatment caused a significant decline in the LPS-stimulated concentrations of TNF-α [4.53 ± 0.24 pg/ml (ln) at 0 min, 3.54 ± 0.35 pg/ml (ln) at 90 min, P=0.026], but did not modify the release of CXCL8. Monocyte TLR4 expression was unchanged. Plasma HMGB1 increased significantly [<0.92 vs. 3.02 ± 0.19 ng/ml (ln), P<0.001]. The concentrations of TNF-α and CXCL8 did not correlate with TLR4 expression or HMGB1 concentrations. CONCLUSION: the results suggest that trauma-induced LPS tolerance is not primarily regulated by TLR4 expression on circulating CD14+ monocytes or by the release of HMGB1 from damaged tissues.
Assuntos
Biomarcadores/sangue , Imunidade Inata/imunologia , Ferimentos por Arma de Fogo/imunologia , Animais , Contagem de Células Sanguíneas , Volume Sanguíneo/fisiologia , Modelos Animais de Doenças , Endotoxinas/toxicidade , Citometria de Fluxo , Proteína HMGB1/sangue , Frequência Cardíaca/efeitos dos fármacos , Leucócitos/metabolismo , Receptores de Lipopolissacarídeos/biossíntese , Receptores de Lipopolissacarídeos/genética , Lipopolissacarídeos/toxicidade , Monócitos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Oxigênio/sangue , Análise de Sobrevida , Suínos , Receptor 4 Toll-Like/biossíntese , Receptor 4 Toll-Like/genéticaRESUMO
BACKGROUND AND OBJECTIVE: Smokers have an increased risk of developing periodontitis as well as showing more rapid progression and resistance to treatment of the disease, but the biological mechanisms are poorly understood. This study was designed to investigate putative biological mechanisms by which nicotine may enhance the susceptibility and thus the course of periodontitis in an animal model. MATERIAL AND METHODS: Ligature-induced periodontitis was applied in periodontitis-susceptible Fischer 344 rats. The animals were either given daily intraperitoneal injections of the nicotinic acetylcholine receptor antagonist mecamylamine (1 mg/kg) 45 min before subcutaneous injections in the neck skin of nicotine (0.8 mg/kg), or treated with the same amount of saline intraperitoneally and nicotine subcutaneously, or treated with mecamylamine and saline. Control animals received intraperitoneal and subcutaneous injections of saline only. Periodontal bone loss was assessed when the ligatures had been in place for 3 wk. Two hours before decapitation, all rats received lipopolysaccharide (LPS; 100 microg/kg, intraperitoneally) to induce a robust immune and stress response. RESULTS: Compared with saline/saline-treated control animals, saline/nicotine-treated rats developed significantly more periodontal bone loss, and LPS provoked a significantly smaller increase in circulating levels of the cytokines tumour necrosis factor-alpha, transforming growth factor-1beta and interleukin-10. Mecamylamine pretreatment of nicotine-treated rats abrogated the increased periodontal bone loss and the LPS-induced decrease in tumour necrosis factor-alpha, but had no significant effects on the levels of transforming growth factor-1beta and interleukin-10, or the stress hormone corticosterone. CONCLUSION: The results indicate that nicotine enhances the susceptibility to periodontitis via nicotinic acetylcholine receptors, which may act by suppressing protective immune responses through the cholinergic anti-inflammatory pathway.
Assuntos
Perda do Osso Alveolar/metabolismo , Nicotina/metabolismo , Nicotina/farmacologia , Periodontite/metabolismo , Receptores Nicotínicos/metabolismo , Perda do Osso Alveolar/imunologia , Animais , Corticosterona/sangue , Suscetibilidade a Doenças , Imunidade/efeitos dos fármacos , Interleucina-10/sangue , Lipopolissacarídeos , Masculino , Mecamilamina/farmacologia , Nicotina/antagonistas & inibidores , Antagonistas Nicotínicos/farmacologia , Perda da Inserção Periodontal/induzido quimicamente , Periodontite/imunologia , Ratos , Ratos Endogâmicos F344 , Fator de Crescimento Transformador beta1/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND AND OBJECTIVE: Smokers have an increased risk of developing periodontitis as well as showing more rapid progression and resistance to treatment of the disease, but the biological mechanisms are poorly understood. Our objective was to investigate putative biological mechanisms by which nicotine may enhance the susceptibility and thus the course of periodontitis in an animal model. MATERIAL AND METHODS: Ligature-induced periodontitis was applied in periodontitis-susceptible Fischer 344 rats. The animals were given daily intraperiotonal (i.p.) injections of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (1 mg/kg) 45 min before subcutaneous (s.c.) injections in the neck skin with nicotine (0.8 mg/kg), or treated with the same amount of saline i.p. and nicotine s.c., or with mecamylamine and saline. Control rats received i.p. and s.c. injections of saline only. Periodontal bone loss was assessed when the ligatures had been in place for 3 weeks. Two hours before decapitation, all rats received lipopolysaccharide (LPS; 100 microg/kg, i.p.) to induce a robust immune and stress response. RESULTS: Compared with saline/saline-treated control rats, saline/nicotine-treated rats developed significantly more periodontal bone loss, and LPS provoked a significantly smaller increase in circulating levels of the cytokines tumour necrosis factor alpha (TNF-alpha), transforming growth factor 1beta (TGF-1beta) and interleukin-10 (IL-10). Mecamylamine pretreatment of nicotine-treated rats abrogated the increased periodontal bone loss and the LPS-induced TNF-alpha decrease, but had no significant effects on the levels of TGF-1beta and IL-10, or the stress hormone corticosterone. CONCLUSION: The results indicate that nicotine enhances susceptibility to periodontitis via nAChRs, which may act via suppressing protective immune responses through the cholinergic anti-inflammatory pathway.
Assuntos
Nicotina/efeitos adversos , Periodontite/etiologia , Receptores Nicotínicos/efeitos dos fármacos , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/imunologia , Perda do Osso Alveolar/fisiopatologia , Animais , Corticosterona/sangue , Corticosterona/imunologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Escherichia coli/imunologia , Injeções Intraperitoneais , Injeções Subcutâneas , Interleucina-10/sangue , Interleucina-10/imunologia , Lipopolissacarídeos/imunologia , Masculino , Mecamilamina/administração & dosagem , Mecamilamina/farmacologia , Nicotina/administração & dosagem , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/farmacologia , Periodontite/imunologia , Periodontite/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Cloreto de Sódio , Fator de Crescimento Transformador beta1/sangue , Fator de Crescimento Transformador beta1/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Penetrating injuries are frequently combined with polybacterial soiling. Clearance of the microorganisms depends on the ability to activate immune responses, but post-traumatic hyporeactivity of immune cells is almost universal. The aim of this study was to map the early time course of this altered leukocyte reactivity, and to compare the reactions to subsequent Gram-positive or Gram-negative challenges. METHODS: Twelve juvenile pigs sustained two standardized rounds, one through the right femur and one through the left upper abdomen. First aid treatment and acute surgery were started immediately. Blood samples were drawn before trauma and after 10, 30, 60, and 90 min, and thereafter stimulated in ex vivo whole blood for 3 h with lipopolysaccharide (LPS, 10 ng/ml), peptidoglycan (PepG, 1 microg/ml), or an equivalent amount of normal saline. The leukocyte response was evaluated by measurement of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-8, and IL-10 in the supernatant. RESULTS: In the post-traumatic in vivo serum, the concentration of TNF-alpha increased steadily (significant after 60 min). A reduced ex vivo reaction to LPS was evident after 10 min, and was statistically significant after 30 min. The lowest levels were reached after 90 min. The ex vivo synthesis of TNF-alpha after stimulation with PepG remained unaltered. A similar development was seen for IL-6. IL-1 beta levels did not change, while IL-8 increased significantly only after 60 and 90 min. CONCLUSIONS: Trauma almost instantaneously reprogrammed circulating leukocytes. As measured with TNF-alpha, a profound hyporeactivity to LPS, but not to PepG, was induced. In addition, no global down-regulation of leukocyte function was found after stimulation with LPS.
Assuntos
Leucócitos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Peptidoglicano/farmacologia , Ferimentos por Arma de Fogo , Animais , Citocinas/sangue , Leucócitos/metabolismo , Taxa de Sobrevida , Suínos , Fatores de Tempo , Ferimentos e LesõesRESUMO
OBJECTIVE: Perturbation of immune homeostasis is an important determinant for organ dysfunction following multiple injuries. The aim of this study was to investigate the ability of glycine to influence the immediate post-traumatic inflammatory environment and altered reactivity of circulating leucocytes. MATERIAL AND METHODS: Twenty pigs were subjected to two standardized gunshots to the abdomen and thigh. Treatment was started immediately. The animals were randomized to receive either glycine 180 mg/kg i.v. over 30 min (n=10) or normal saline (n=10). Blood samples were drawn at baseline and 75 min after injury. In a follow-up study 12 pigs were exposed to an identical trauma. Blood was drawn at the same time-points and stimulated with lipopolysaccharide (LPS) or LPS plus glycine for 2 h in an ex vivo whole blood model. RESULTS: Selected physiologic variables and organ injury did not differ between groups 75 min after trauma. Reactive oxygen species decreased to 82.7+/-5.5 % of baseline (p<0.05) in the glycine group (unaltered in the controls). Liver glutathione concentrations decreased in parallel in both groups. In vivo production of TNF-alpha and IL-1-beta increased to the same extent regardless of treatment. Trauma induced a strong LPS tolerance. In whole blood challenged with LPS, glycine inhibited cytokine synthesis, but only in samples drawn at baseline. CONCLUSIONS: Post-traumatic infusion of glycine only modestly influenced the early post-traumatic inflammatory environment. Our ex vivo results confirm previous reports on the anti-inflammatory potential of glycine, but restricted to pre-trauma conditions.
Assuntos
Glicinérgicos/uso terapêutico , Glicina/uso terapêutico , Inflamação/prevenção & controle , Ferimentos por Arma de Fogo/tratamento farmacológico , Doença Aguda , Animais , Pressão Sanguínea/fisiologia , Citocinas/metabolismo , Glutationa/metabolismo , Glicina/farmacologia , Glicinérgicos/farmacologia , Frequência Cardíaca/fisiologia , Inflamação/etiologia , Inflamação/imunologia , Injeções Intravenosas , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , Modelos Animais , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Consumo de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Suínos , Ferimentos por Arma de Fogo/complicações , Ferimentos por Arma de Fogo/imunologiaRESUMO
BACKGROUND: Glycine, the simplest of the amino acids, is an essential component of important biological molecules, a key substance in many metabolic reactions, the major inhibitory neurotransmitter in the spinal cord and brain stem, and an anti-inflammatory, cytoprotective, and immune modulating substance. MATERIAL AND METHODS: Based on available literature, we discuss some of the important biological properties of glycine. In addition, we describe some clinical disorders where glycine plays a central role, either as an essential structural element, or through its metabolism or receptors. RESULTS: The past few years have witnessed a broadening of glycine research. The traditional prime interest in aspects related to its role as an inhibitory neurotransmitter in the central nervous system has been expanded to equally emphasize other organs and tissues. With the demonstration of glycine-gated chloride channels on neurons in the central nervous system, on most leukocytes, and subsequently on other cells as well, a unifying mechanism of action accounting for many of the widespread effects of glycine has been found. CONCLUSIONS: Glycine is a simple, easily available, and inexpensive substance with few and innocuous side-effects. The diversity of biological activities is well documented in the literature. Despite this, glycine has only gained a modest place in clinical medicine.
Assuntos
Citoproteção/efeitos dos fármacos , Glicina , Neurotransmissores/fisiologia , Glicina/química , HumanosRESUMO
PURPOSE: The purpose of this study was to use an established porcine model to investigate the effects on immune function of severe gunshot injury. METHODS: Twelve pigs sustained two standardised rounds, one through right femur and one through left upper abdomen. First aid treatment and acute surgery was started immediately. Blood samples were drawn before shooting and after 75 min. Circulating neutrophils were isolated and reactive oxygen species (ROS) measured. Serum levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and IL-10 were determined at 0, 75 min, as well as 2h after incubation with 1 microg/ml endotoxin in an ex vivo whole blood model. RESULTS: TNF-alpha, IL-1beta, and IL-6 significantly increased at 75 min. ROS in circulating granulocytes tended to increase (NS). Incubation with endotoxin led to a more than 100-fold increase of TNF-alpha pre-trauma, compared to a three-fold increase post-trauma (p<0.0001 between groups). A similar pattern was obtained for IL-1beta, and IL-6. IL-10 was below detection in all samples. The granulocytes maintained their ability to react to the protein kinase C activator phorbol myristate acetate (PMA) after trauma. CONCLUSION: Severe gunshot injury and peritraumatic stress rapidly activate circulating immune cells, but reduce their capacity to react to a subsequent challenge to endotoxin.
Assuntos
Hemorragia/imunologia , Interleucinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/análise , Ferimentos por Arma de Fogo/imunologia , Traumatismos Abdominais/sangue , Traumatismos Abdominais/imunologia , Animais , Hemorragia/sangue , Macrófagos/metabolismo , Neutrófilos/metabolismo , Suínos , Ferimentos por Arma de Fogo/sangue , Ferimentos por Arma de Fogo/cirurgiaRESUMO
BACKGROUND: Major insults may trigger generalized inflammatory responses that contribute to progressive multiple organ dysfunction. The present study was performed to test the potential of early hydrocortisone treatment to influence these responses as well as organ function following an episode of rapid and profound blood loss. METHODS: In isoflurane anaesthesia, 35 spontaneously breathing male Sprague-Dawley rats were bled 2.5 ml 100 g-1 body weight over 10 min. Immediately following withdrawal of blood, one group (n = 17) was given 2 mg of hydrocortisone, and the other (n = 18) had the same amount of normal saline. Seventy-five minutes after initiation of bleeding, two-thirds of the blood was retransfused, together with a new injection of hydrocortisone or saline. Thereafter the rats were observed for 2 h. Key mediators of systemic inflammation and plasma markers of organ function and integrity were measured. Internal organs were weighed and scored for visible pathology. Leukocyte infiltration of the liver was counted in a light microscope. RESULTS: Hydrocortisone reduced the plasma levels of IL-6 (P < 0.05); non-significant reductions of TNF-alpha (P = 0.12) and IL-10 (P = 0.44) were noted. The synthesis of reactive oxygen species in peritoneal cells was unaffected. Relative organ weights and organ injury scores tended to be reduced, but only wet organ weight for the lungs reached statistical significance. Leukocyte infiltration of the liver was equal in both groups. Plasma levels of ALT, AST, alpha-GST and creatinine did not differ significantly between groups. Two of the hydrocortisone treated rats died compared with four controls. CONCLUSION: Early treatment with hydrocortisone had a limited organ protective effect in this model of controlled haemorrhagic shock. Although a general tendency for better outcome in the hydrocortisone group was noted, clear-cut and significant advantages of the treatment were not obtained.
Assuntos
Hidrocortisona/uso terapêutico , Choque Hemorrágico/tratamento farmacológico , Animais , Pressão Sanguínea/efeitos dos fármacos , Hipóxia Celular , Corticosterona/sangue , Leucócitos/fisiologia , Fígado/patologia , Masculino , Insuficiência de Múltiplos Órgãos/prevenção & controle , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Choque Hemorrágico/complicações , Choque Hemorrágico/fisiopatologiaRESUMO
In this study nine elite athletes each participated in three different 24- h trials, as follows: (1) complete bed rest (REST), (2) one bout of exercise at 1515 hours (ONE-EX), (3) two exercise bouts, one at 1100 hours and one at 1515 hours (TWO-EX-3 h), and (4) two exercise bouts, one at 0800 hours and one at 1515 hours (TWO-EX-6 h). Exercise was performed on a cycle ergometer with 10 min of warm-up and then 65 min at an exercise intensity of 75% of maximum oxygen uptake (VO(2max)). The polymorphonuclear neutrophil (PMN) counts increased consistently in response to exercise, and more in trial TWO-EX-3 h than in the two other exercise trials (P < 0.01). The respiratory burst of PMN was measured as chemiluminescence (CL), obtained with phorbol myristate (PMA) and serum-opsonised zymosan (SOZ) as stimulators. Exercise triggered the CL response for a defined number of PMN, significantly above baseline (REST) values (P < 0.05) for ONE-EX and TWO-EX-3 h, but not for TWO-EX-6 h. The strongest response was observed for TWO-EX-3 h, but the difference between exercise procedures was not significant. However, as a novel approach, a comparison was made using total oxidative potentials per litre of blood, as obtained by combining CL values and PMN numbers. TWO-EX-3 h yielded significantly higher values than the other experimental treatments. Thus, by this measure the total oxidative potential of PMN x l(-1) blood remains at a higher level with short intervals between exercise bouts (i.e. 3 h instead of 6 h), possibly due to a combined effect of cell number increase and the priming state of PMN. This may suggest that for intensive training twice a day, a recovery phase of 5-6 h is preferable. The elevation in cell number is best explained by a combined effect of catecholamines and cortisol. Growth hormone is one probable candidate as a stimulator of CL, but other molecular participants that respond to exercise may exert roles as either stimulators or inhibitors of CL.
Assuntos
Exercício Físico/fisiologia , Neutrófilos/fisiologia , Aptidão Física , Esportes , Adenosina Desaminase/sangue , Adulto , Citidina Desaminase/metabolismo , Hormônios/sangue , Humanos , Contagem de Leucócitos , Medições Luminescentes , Masculino , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Óxido Nítrico/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Zimosan/farmacologiaRESUMO
Organisms respond to inflammatory conditions by mounting a co-ordinated complex series of adaptive responses involving the immune, nervous and endocrine systems that are aimed at restoring the homeostatic balance. We have recently shown in a rat model that inappropriate hypothalamic-pituitary-adrenal (HPA) axis regulation and a subsequent inability to mount a suitable glucocorticoid response to gingival inflammation may influence susceptibility to periodontal disease. This study was designed to investigate whether ligature- and bacterial lipopolysaccharide (LPS)-induced inflammation in the gingival connective tissues may activate this physiological axis, and to further explore the significance of HPA regulation in periodontal disease. Experimental periodontal disease was induced in major histocompatibility complex (MHC)-identical but HPA low (LEW) and high (F344) responding rat strains. We tested (1) whether ongoing periodontal disease activates the HPA axis as measured by corticosterone levels, and (2) whether genetic differences in HPA regulation modulate periodontal disease progression. In the F344 strain. the periodontal tissue destruction was more severe. This observation was associated with a significant increase of corticosterone levels in F344 rats only. Addition of LPS at the gingival inflammatory site led to a further increase of corticosterone levels and disease severity in F344 rats. These findings illustrate a positive feedback loop between the HPA axis and periodontal disease: the disease activates the HPA axis, and a genetically determined high HPA responsivity further increases disease susceptibility.
Assuntos
Sistema Hipotálamo-Hipofisário/fisiopatologia , Doenças Periodontais/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Perda do Osso Alveolar/fisiopatologia , Análise de Variância , Animais , Distribuição de Qui-Quadrado , Corticosterona/sangue , Retroalimentação Fisiológica , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Ligadura , Lipopolissacarídeos/farmacologia , Masculino , Doenças Maxilares/fisiopatologia , Neuroimunomodulação , Perda da Inserção Periodontal/fisiopatologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos LewRESUMO
BACKGROUND: Reduced body temperature is a common companion to trauma/haemorrhage. Several clinical studies have identified hypothermia as an independent risk variable predisposing to increased morbidity and mortality. At the same time it is known that most enzymatic reactions are downregulated at temperatures below 37 degrees C. Theoretically this should restrain the inflammatory response and protect the host from remote organ injury. The study was performed to test this hypothesis. METHODS: Twenty-six male Sprague Dawley rats were used for the experiments. Volume controlled haemorrhagic shock was induced by withdrawal of 2.5 ml blood/100 g body weight over 10 min. Half of the animals (n=13) were then cooled to 32.5-33 degrees C, the other half (n=13) were kept normothermic (37.5+/-0.5 degrees C). Seventy-five minutes after initiation of bleeding, two-thirds of the blood was retransfused. Thereafter the rats were observed for 2 h. Key substances of systemic inflammation were determined (plasma values of TNF-alpha, IL-6, IL-10, and corticosterone; reactive oxygen species in peritoneal phagocytes), plasma markers of organ function and integrity (AST, ALT, alphaGST, creatinine, urea), and survival. RESULTS: Hypothermia reduced the release of IL-6 (P<0.01). The reductions of plasma levels of TNFalpha (P=0.07) and IL-10 (P=0.09) were less clear-cut. The release of reactive oxygen species diminished (P<0.01). Organ injury was ameliorated, as reflected by decreased levels of AST (P<0.01), alphaGST (P<0.01), and creatinine (P<0.01). Both groups experienced an almost identical increase of plasma corticosterone. None of the hypothermic rats died, compared to two normothermic. CONCLUSION: Moderate hypothermia had an organ protective effect in this model of controlled haemorrhagic shock. This coincided with a significant reduction of the proximal cytokine IL-6 and reactive oxygen species, which conceivably influenced the outcome.
Assuntos
Hipotermia Induzida , Inflamação/prevenção & controle , Choque Hemorrágico/imunologia , Animais , Hemodinâmica , Sistema Hipotálamo-Hipofisário/fisiologia , Interleucina-10/sangue , Interleucina-6/sangue , Medições Luminescentes , Masculino , Sistema Hipófise-Suprarrenal/fisiologia , Ratos , Ratos Sprague-Dawley , Choque Hemorrágico/complicações , Fator de Necrose Tumoral alfa/análiseRESUMO
This study was designed to examine the relationship between seasonal changes in training and competition load, and changes in leukocyte subsets, stress hormones, and interleukin-6 (IL-6) in response to a standardised bout of endurance exercise. In addition, changes in mood states were monitored. Ten male, international Nordic skiers, age 20-29, maximal oxygen uptake 70-82 ml x kg(-1) x min(-1) performed the same incremental treadmill tests to exhaustion at the same time of day (+/-1 h), during the competitive season (in-season HI test) and the recovery season (off-season LO test). The subject filled out a training and competition log (TC score) for three weeks prior to each test and a 65-item Profile of Mood State (POMS) test on arrival at the laboratory. Venous blood for haematological, hormonal, and IL-6 analysis was drawn before and at 0, 15, 30, 60, 120 and 240 min after the test. TC score was more than twice as high during the competitive season (16.0 +/- 3.9) compared to the off-season period (7.0 +/- 4.4). An ANOVA procedure for repeated measures showed no difference in exercise induced changes in concentrations of neutrocytes, lymphocytes, epinephrine, ACTH or cortisol between the in-season HI and off-season LO tests; however, norepinephrine and the IL-6 concentrations were elevated at the in-season HI test compared to the off-season LO test. There were no significant differences in POMS global mood score or sub-scores between the in-season HI and the off-season LO tests. Thus, in a group of elite Nordic skiers, we conclude that a doubling of the training and competition load during the winter season does not alter the leukocyte and stress hormone responses to an incremental exercise test to exhaustion.
Assuntos
Sistema Endócrino/fisiologia , Exercício Físico/fisiologia , Sistema Imunitário/fisiologia , Educação Física e Treinamento/métodos , Estações do Ano , Esqui/fisiologia , Adaptação Fisiológica/fisiologia , Adaptação Psicológica , Corticosteroides/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Exercício Físico/psicologia , Humanos , Interleucina-6/sangue , Leucócitos/metabolismo , Masculino , Neutrófilos/metabolismo , Esqui/psicologiaRESUMO
Inappropriate hypothalamic pituitary adrenal (HPA) axis regulation of immune responses to bacterial challenges has been found to play an important role in infections and inflammatory disease susceptibility and progression. In the present study we investigated the tissue effects of experimental periodontitis in Fischer 344 rats, which were subcutaneously (s.c.) injected with 20 mg/kg of the glucocorticoid receptor antagonist and active antiglucocorticoid agent RU 486 every second day over a period of 14 d. Periodontitis was induced by placing a bacterial plaque retentive silk ligature in the gingival sulcus around the neck of maxillary right 2nd molar teeth 1 d after the first injection in 10 RU 486-treated and 10 vehicle (1,2-propanediol)-treated control animals. The contralateral maxillary left 2nd molars served as internal control teeth for naturally occurring periodontitis. Disease progression was evaluated radiographically and histometrically. The average level of corticosterone in blood at sacrifice was significantly lower in the RU 486-treated animals as compared to controls. The experimental animals also developed significantly less periodontal breakdown at both experimental and control teeth compared to the vehicle-treated control animals. The results support our recent findings showing that HPA hyper-reactivity, either genetically determined or experimentally induced, stimulates periodontal disease susceptibility. These findings suggest that central nervous regulation of inflammatory responses to dental plaque microorganisms in the gums may modulate periodontal disease susceptibility and progression.
Assuntos
Antagonistas de Hormônios/uso terapêutico , Mifepristona/uso terapêutico , Periodontite/tratamento farmacológico , Animais , Modelos Animais de Doenças , Glucocorticoides/antagonistas & inibidores , Antagonistas de Hormônios/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Mifepristona/farmacologia , Neuroimunomodulação/efeitos dos fármacos , Periodontite/fisiopatologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344RESUMO
The aim of this study was to test the hypothesis of an association between hypothalamic-pituitary-adrenal (HPA) axis reactivity and progression of periodontal disease. Histocompatible Lewis and Fischer 344 rats respond to stressful stimuli with low and high HPA axis reactivity, respectively. Experimental periodontitis was induced by tying a silk ligature around the neck of maxillary 2nd right molar teeth in 10 Lewis and 10 Fischer 344 rats with contralateral non-manipulated teeth as controls. Twenty non-manipulated animals were included. Also, experimental periodontitis was induced in 10 adrenalectomized Wistar rats and in 10 sham-operated rats. Furthermore, corticosterone pellets were subcutaneously implanted in 9 Lewis rats, while placebo pellets were implanted in 8 animals. Disease progression was evaluated histometrically and radiographically. The low-responding Lewis rats developed significantly less periodontal breakdown than did the high-responding Fischer 344 rats. Administration of corticosterone increased the disease development. while adrenalectomy reduced the disease severity. Our findings demonstrate the importance of genetic factors in the development of periodontal disease, and suggest that HPA axis hyper-activation is one mechanism by which periodontal disease susceptibility may be increased.
Assuntos
Sistema Hipotálamo-Hipofisário/fisiologia , Periodontite/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiologia , Corticosteroides/administração & dosagem , Corticosteroides/farmacologia , Adrenalectomia , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/patologia , Perda do Osso Alveolar/fisiopatologia , Processo Alveolar/diagnóstico por imagem , Processo Alveolar/patologia , Animais , Progressão da Doença , Implantes de Medicamento , Masculino , Perda da Inserção Periodontal/diagnóstico por imagem , Perda da Inserção Periodontal/patologia , Perda da Inserção Periodontal/fisiopatologia , Periodontite/diagnóstico por imagem , Periodontite/patologia , Placebos , Radiografia , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Ratos Wistar , Pele , Estresse Fisiológico/fisiopatologia , Colo do Dente/diagnóstico por imagem , Colo do Dente/patologiaRESUMO
Alterations in duodenal immunoglobulin (Ig-)producing cells after excessive physical stress (marathon running) were studied by immunohistochemistry in 11 well-trained male adults, both shortly after running (race time, approximately 3.00 h) and later on after a "resting period" of 8-12 weeks with normal training (7-20 h/week). The ratios of IgA-, IgM- and IgG-producing cells were similar in the two biopsy specimens and virtually identical to those in eight normal duodenal controls (medians 77.6% IgA, 18.6% IgM, and 2.5% IgG). However, in the first sample the total number of positive cells per intestinal length unit was increased in five for IgA and in seven for IgM, while it was decreased in eight for IgG compared with the second biopsy. Also, the IgA cell number tended to be slightly increased immediately after the race (median 128 cells/unit) compared with that in normal controls (median 111 cells/unit); the same tendency was found for all Ig classes considered together. This apparent change was not explained by a thickening of the mucosa. Our study showed that marathon runners seem to maintain or even enhance their intestinal IgA and IgM-production, in contrast to the IgA decrease reported for other compartments such as salivary secretions and peripheral blood. The tendency to slightly increased intestinal IgA and IgM immunocyte populations in some runners might reflect a stress-induced hormonal influence on the homing of primed B cells to the mucosa, or perhaps an immune response to elevated influx of stimulatory luminal antigens.
Assuntos
Duodeno/imunologia , Imunoglobulina A/biossíntese , Imunoglobulina M/biossíntese , Corrida/fisiologia , Adolescente , Adulto , Linfócitos B/imunologia , Biópsia , Distribuição de Qui-Quadrado , Duodeno/citologia , Corantes Fluorescentes , Seguimentos , Humanos , Imunidade nas Mucosas/imunologia , Imunoglobulina A/sangue , Imunoglobulina A Secretora/biossíntese , Imunoglobulina G/biossíntese , Imuno-Histoquímica , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Receptores de Retorno de Linfócitos/imunologia , Descanso/fisiologiaRESUMO
Moderate exercise appears to stimulate the immune system, but there is good evidence that intense exercise can cause immune deficiency. In the present study the authors examined the effect of continuous physical exercise (35% of VO2 max), calorie deficiency and sleep deprivation on the immune system of young men participating in a 5-7 days military training course. There was a two-three fold increase of neutrophils from day 1, the values remained high and decreased slightly at the end of the course. Monocyte counts also increased with a pattern similar to that of neutrophils. Eosinophils decreased to 30% of control and lymphocyte numbers decreased by 30-40%. All the major subgroups (CD4 T cells, CD8 T cells, B cells, NK cells) were reduced. Neutrophil function, as tested by measuring chemotaxis, was significantly stimulated during the first days of the course, in particular in the group with the lowest calorie intake. The mitogenic response of lymphocytes to PHA and Con A was variable, ranging from stimulation during one course to no effect in another course. Serum levels of immunoglobulins decreased significantly during the course. IgG was reduced by 6-7%, IgA by 10-20% and IgM by 20-35%. The authors found no changes of interleukin 1, 2 and 4 during the course, but a (12-20%) reduction (P less than 0.01) of interleukin 6, and an increase (P less than 0.01) of granulocyte-macrophage colony stimulating factor. Altogether the results from the ranger course present a mixed-up picture. The non-specific phagocyte-related immunity was enhanced. On the other hand, the data indicate that even a moderate physical activity, around the clock, caused significant suppression of a number of parameters reflecting the status of the specific, lymphocyte-related immunity. It is noteworthy, however, that there was no significantly increased infection rate during the course or in the first 4-5 weeks thereafter.
Assuntos
Citocinas/sangue , Ingestão de Energia/imunologia , Imunoglobulinas/sangue , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/etiologia , Contagem de Leucócitos , Esforço Físico , Privação do Sono , Proteínas de Fase Aguda/análise , Adulto , Quimiotaxia de Leucócito , Humanos , Masculino , MilitaresRESUMO
The chemiluminescence response of granulocytes to serum opsonized zymosan particles (SOZ) ex vivo was investigated during two ranger training courses lasting 7 days with continuous moderate physical activities corresponding to about 32% of maximal oxygen uptake or 35000 kJ.24 h-1, with energy deficiency (energy supply 0-4000 kJ.24 h-1), and less than 3-h sleep during the 7 days. Significant granulocytosis in combination with a lymphopenia in peripheral blood was observed during the whole course. A priming of the granulocytes for accentuated chemiluminescence response to SOZ was observed during the first days of the course with a maximal increase on day 3 in course A (+35% of control response) and on day 1 in course B (+12%). Thereafter, reduced responses to SOZ compared to control values (-28% and -21% in course A and B) were observed. In course A, a group (n = 8) receiving 5000 kJ.24 h-1 of additional energy, showed a more pronounced priming (maximum +57% versus +21% of control response) during the first days. In course B, all the cadets had 3 h of organised rest/sleep on day 5, and a second priming of the chemiluminescence response was observed on the subsequent 2 days. These data indicated that moderate, continuous, predominantly aerobic physical activities for 1-3 days around the clock primed the production of reactive oxygen species in granulocytes. This priming may be beneficial for, for example, host defence against micro-organisms, but may also contribute to inflammatory damage to normal tissues such as muscle, tendons and joints during exercise. However, when the moderate exercise continued for several more days, a down-modulation of the granulocyte response was observed. The findings of this study further support the possibility that moderate physical activity stimulates immunity, while more extreme duration of the same activities may result in a down-modulation of non-specific (and specific) immunity.