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Skin wound infections are a significant health problem, and antibiotic resistance is on the rise. Mast cells (MCs) have been shown to contribute to host-defense responses in certain bacterial infections, but their role in skin wound superinfection is unknown. We subjected 2 MC-deficient mouse strains to Pseudomonas aeruginosa skin wound infection and found significantly delayed wound closure in infected skin wounds. This delay was associated with impaired bacterial clearance in the absence of MCs. Engraftment of MCs restored both bacterial clearance and wound closure. Bacterial killing was dependent on IL-6 released from MCs, and engraftment with IL-6-deficient MCs failed to control wound infection. Treatment with recombinant IL-6 enhanced bacterial killing and resulted in the control of wound infection and normal wound healing in vivo. Taken together, our results demonstrate a defense mechanism for boosting host innate immune responses, namely effects of MC-derived IL-6 on antimicrobial functions of keratinocytes.
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Queratinócitos/imunologia , Mastócitos/imunologia , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosa/imunologia , Pele/imunologia , Cicatrização/imunologia , Infecção dos Ferimentos/prevenção & controle , Animais , Antibacterianos/farmacologia , Células Cultivadas , Humanos , Interleucina-6/farmacologia , Queratinócitos/efeitos dos fármacos , Mastócitos/citologia , Camundongos , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Infecção dos Ferimentos/imunologia , Infecção dos Ferimentos/microbiologiaRESUMO
Functional movement disorders (FMD) represent a complex and disabling entity characterized by a broad range of clinical symptoms not explained by a classical neurological disease. In 2013, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) added a clinical criterion based on incongruence and inconsistency, supported by recent literature highlighting the role of "positive clinical signs". These clinical signs allow a "rule-in" procedure in making a diagnosis of FMD so that the diagnosis is no longer a "rule-out" or "by default" diagnosis made after exclusion of other neurological conditions. This review summarizes current evidence on common clinical features and highlights bedside signs in FMD, such as tremor, dystonia, myoclonus and parkinsonism. Tics, chorea and hemiballism are also briefly discussed.
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Transtornos dos Movimentos , Técnicas de Diagnóstico Neurológico/história , Técnicas de Diagnóstico Neurológico/tendências , Manual Diagnóstico e Estatístico de Transtornos Mentais , História do Século XXI , Humanos , Transtornos dos Movimentos/classificação , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/epidemiologiaRESUMO
This article was originally published under a CC BY-NC-ND 4.0 license, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly.
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Magnesium has a key role in osteoporosis and could enhance implant osseointegration in osteoporotic patients. Titanium implants impregnated with Mg ions were installed in the tibia of ovariectomized rats. The release of Mg induced a significant increase of bone formation and the expression of anabolic markers in the peri-implant bone. INTRODUCTION: The success of endosseous implants is highly predictable in patients possessing normal bone status, but it may be impaired in patients with osteoporosis. Thus, the application of strategies that adjuvate implant healing in compromized sites is of great interest. Magnesium has a key role in osteoporosis prevention and it is an interesting candidate for this purpose. In this study, the cellular and molecular effects of magnesium release from implants were investigated at the early healing stages of implant integration. METHODS: Osteoporosis was induced in 24 female rats by means of ovariectomy and low-calcium diet. Titanium mini-screws were coated with mesoporous titania films and were loaded with magnesium (test group) or left as native (control group). The implants were inserted in the tibia and femur of the rats. One, 2 and 7 days after implantation, the implants were retrieved and histologically examined. In addition, expression of genes was evaluated in the peri-implant bone tissue at day 7 by means of quantitative polymerase chain reactions with pathway-oriented arrays. RESULTS: The histological evaluation revealed that new bone formation started already during the first week of healing for both groups. However, around the test implants, new bone was significantly more abundant and spread along a larger surface of the implants. In addition, the release of magnesium induced a significantly higher expression of BMP6. CONCLUSIONS: These results provide evidence that the release of magnesium promoted rapid bone formation and the activation of osteogenic signals in the vicinity of implants placed in osteoporotic bone.
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Implantes Experimentais , Magnésio/farmacologia , Osseointegração/efeitos dos fármacos , Osteoporose/fisiopatologia , Animais , Parafusos Ósseos , Materiais Revestidos Biocompatíveis , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Magnésio/administração & dosagem , Osseointegração/genética , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteoporose/genética , Osteoporose/patologia , Ovariectomia , Desenho de Prótese , Ratos Sprague-Dawley , Propriedades de Superfície , TitânioRESUMO
PURPOSE: The Needs Evaluation Questionnaire (NEQ) is a self-administered instrument with 23 dichotomous items that is used both in oncology clinical practice and in research. It was originally developed for use in setting of hospitalization. The aim of the present study was to assess the factor structure of the NEQ in an outpatient oncology sample and to compare the unmet needs of inpatients and outpatients in the Italian context. METHODS: In 6 Italian oncology departments, 783 patients completed the NEQ. Patients included in the study had different primary tumor sites and were in different phases of the disease and care process. There were 195 inpatients and 588 outpatients total. RESULTS: Confirmatory factor analysis (CFA) showed that, with outpatients, the NEQ retained the distribution of the items in five main areas previously described with inpatients. Cancer outpatients expressed high percentages of unmet needs primarily concerning "material needs" and "needs for psycho-emotional support." Our survey also suggested that, in addition to the 23 original items, four new items could be tested for specific use with outpatients. CONCLUSIONS: Our findings highlight the importance of establishing routine assessment of unmet needs also in clinical oncology settings different from wards-such as day hospitals, ambulatory rehabilitation, or follow-up ambulatory care-where, at least in the Italian context, the rate of unmet needs is currently considerably high. The NEQ could be an effective tool for this assessment.
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Avaliação das Necessidades/tendências , Neoplasias/psicologia , Pacientes Ambulatoriais/psicologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Inquéritos e Questionários , Adulto JovemRESUMO
Crown/implant (C/I) ratio has been proven to not affect the survival of the implants; however, it is also a fact that no evidence exists with regard to the use of single short implants in the mandibular molar. The aim of this study was to determine whether the crown/implant ratios of single implant-supported fixed restorations on implants of 6-8 mm in the mandibular molar have an impact on the implant survival and marginal bone maintenance. Twelve short dental implants (6-8 mm) were installed and restored with single crowns, loaded after 3 months of healing. The restorations were divided according to crown-to-implant ratio into two groups: Group 1: C/I < 2.0 and Group 2: C/I ⧠2.0. Alveolar bone loss was measured using CBCT scan, taken at the implant placement and after 12 months follow-up from loading. Reduced implant/crown ratio shown no statistic significant differences on implant survival and the alveolar bone level compared with recommended implant/crown ratio. Within the limitation of this study, it can be concluded that reduced C/I ratio could be used as a substitute for recommended C/I ratio in severely mandibular atrophic residual alveolar ridges.
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Perda do Osso Alveolar/patologia , Implantação Dentária Endóssea , Implantes Dentários para Um Único Dente , Prótese Dentária Fixada por Implante , Falha de Restauração Dentária , Arcada Parcialmente Edêntula/reabilitação , Coroas , Planejamento de Prótese Dentária , Humanos , Mandíbula , Dente Molar , Resultado do TratamentoRESUMO
BACKGROUND: Monophosphoryl lipid A (MPLA), a nontoxic TLR4 ligand derived from lipopolysaccharide (LPS), is used clinically as an adjuvant in cancer, hepatitis, and malaria vaccines and in allergen-specific immunotherapy. Nevertheless, its cell-activating effects have not been analyzed in a comprehensive direct comparison including a wide range of different immune cells. Therefore, the objective of this study was the side-by-side comparison of the immune-modulating properties of MPLA and LPS on different immune cells. METHODS: Immune-activating properties of MPLA and LPS were compared in human monocytes and mast cells (MCs), a mouse endotoxin shock model (ESM), and mouse bone marrow (BM)-derived myeloid dendritic cells (mDCs), T cells (TCs), B cells, and MCs. RESULTS: In a mouse in vivo ESM and a human ex vivo monocyte activation test (MAT), MPLA induced the same cytokine secretion pattern as LPS (ESM: IL-6, IL-12, TNF-α; MAT: IL-1ß, IL-6, TNF-α), albeit at lower levels. Mouse mDCs and ex vivo isolated B cells stimulated with MPLA required a higher threshold to induce TRIF-dependent cytokine secretion (IL-1ß, IL-6, IL-10, and TNF-α) than did LPS-stimulated cells. In mDC:DO11.10 CD4 TC cocultures, stimulation with MPLA, but not with LPS, resulted in enhanced OVA-specific IL-4 and IL-5 secretion from DO11.10 CD4 TCs. Unexpectedly, in both human and mouse MCs, MPLA, unlike LPS, did not elicit secretion of pro-inflammatory cytokines. CONCLUSIONS: Compared to LPS, MPLA induced a qualitatively similar, but less potent pro-inflammatory immune response, but was unable to activate human or mouse MCs.
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Lipídeo A/análogos & derivados , Lipopolissacarídeos/imunologia , Mastócitos/imunologia , Mastócitos/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Antígenos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Citocinas/biossíntese , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Lipídeo A/imunologia , Lipídeo A/farmacologia , Lipopolissacarídeos/farmacologia , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Choque Séptico/genética , Choque Séptico/imunologia , Choque Séptico/metabolismo , Células Th2/imunologia , Células Th2/metabolismoRESUMO
OBJECTIVE: Formaldehyde is an effective and popular semipermanent hair straightener, but the severe consequences for human health due to its toxicity have prompted the search for safer alternatives. Different carbonyl compounds, including glyoxylic acid, have recently been proposed as promising candidates. Despite the interest in this topic, there is a lack of information about the interactions between hair keratin and straightener agents. This study addresses this issue to gain new insights useful in the development of new products for safe, semipermanent hair deformation. METHODS: The possible reactions occurring between carbonyl groups and nucleophilic sites on amino acid residues belonging to the keratin were investigated using as model compounds some aldehydes and amino acid derivatives. Raman and IR analyses on yak hair subjected to the straightening treatment with glyoxylic acid in different conditions were carried out. Scanning electron microscope (SEM) analyses were carried out on yak and curly human hair after each step of the straightening procedure. RESULTS: The reactions between aldehydes and N-α-acetyl-L-lysine revealed the importance of the carbonyl electrophilicity and temperature to form imines. Raman and IR analyses on yak hair subjected to the straightening treatment evidenced rearrangements in the secondary structure distribution, conformational changes to the disulphide bridges, a decrease of the serine residues and formation of imines. It was also indicated that straightening produced major conformational rearrangements within the hair fibre rather than on the cuticle. CONCLUSION: This investigation revealed the role played by the electrophilicity of the carbonyl on the straightener agent and of the temperature, closely related to the dehydration process. Raman and IR studies indicated the involvement of imine bonds and the occurrence of a sequence of conformational modifications during the straightening procedure. SEM analyses showed the effectiveness of the treatment at the cuticular level.
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Formaldeído , Glioxilatos , Preparações para Cabelo , Aldeídos/química , Aminoácidos/química , Humanos , Microscopia Eletrônica de Varredura , Modelos Químicos , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral RamanRESUMO
BACKGROUND & AIMS: After prolonged hospitalization, the assessment of nutritional status and the identification of adequate nutritional support is of paramount importance. In this observational study, we aimed at assessing the presence of a malnutrition condition in SARS-Cov2 patients after the acute phase and the effects of a multidisciplinary rehabilitation program on nutritional and functional status. METHODS: We recruited 48 patients (26 males/22 females) admitted to our Rehabilitation Unit after discharge from acute Covid Hospitals in northern Italy with negative swab for SARS-Cov2. We used the Global Leadership Initiative on Malnutrition (GLIM) criteria to identify patients with different degrees of malnutrition. Patients underwent a 3 to 4-week individual multidisciplinary rehabilitation program consisting of nutritional intervention (energy intake 27to30 kcal/die/kg and protein intake 1-1.3 g/die/kg), exercise for total body conditioning and progressive aerobic exercise with cycle- and arm-ergometer (45 min, 5 days/week). At admission and discharge from our Rehabilitation Unit, body composition and phase angle (PhA) (BIA101 Akern), muscle strength (handgrip, HG) and physical performance (Timed-Up-and-Go, TUG) were assessed. RESULTS: At admission in all patients the mean weight loss, as compared to the habitual weight, was -12.1 (7.6)%, mean BMI was 25.9 (7.9) kg/m2, mean Appendicular Skeletal Muscle Index (ASMI) was 6.6 (1.7) kg/m2 for males and 5.4 (1.4) kg/m2 for females, mean phase angle was 2.9 (0.9)°, mean muscle strength (HG) was 21.1 (7.8) kg for males and 16.4 (5.9) kg for females, mean TUG value was 23.7 (19.2) s. Based on GLIM criteria 29 patients (60% of the total) showed a malnutrition condition. 7 out of those 29 patients (24%) presented a mild/moderate grade and 22 patients (76%) a severe grade. After a rehabilitation program of an average duration of 25 days (range 13-46) ASMI increased, with statistically significant differences only in females (p = 0.001) and HG improved only in males (p = 0.0014). In all of the patients, body weight did not change, CRP/albumin (p < 0.05) and TUG (p < 0.001) were reduced and PhA increased (p < 0.01). CONCLUSIONS: We diagnosed a malnutrition condition in 60% of our post SARS-Cov2 patients. An individualized nutritional intervention with adequate energy and protein intake combined with tailored aerobic and strengthening exercise improved nutritional and functional status.
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COVID-19 , Desnutrição , Masculino , Feminino , Humanos , Estado Nutricional , RNA Viral , Força da Mão , SARS-CoV-2 , Desnutrição/diagnóstico , Desnutrição/etiologiaRESUMO
BACKGROUND: Percutaneous coronary interventions (PCI) in calcified coronary artery lesions are associated with impaired stent expansion, higher rate of periprocedural complications and cardiac mortality. Lesion preparation using calcium modifying techniques such as Rotational Atherectomy (RA) or Intravascular Lithotripsy (IVL) has been advocated. Studies comparing these technologies are lacking. We aimed to compare in-stent pressure gradients, evaluated by vessel fractional flow reserve (vFFR), in calcific lesions treated using either RA or IVL. METHODS: Patients undergoing either RA- or IVL-assisted PCI from two European centers were included. Propensity score matching (1:2) was performed to control for potential bias. Primary outcome was post-PCI in-stent pressure gradients calculated by vFFR (vFFRgrad). Secondary outcomes included the proportion of patients with complete functional revascularization defined as distal vFFR post-PCI (vFFRpost) ≥ 0.90. RESULTS: From a cohort of 210 patients, 105 matched patients (70 RA and 35 IVL) were included. Pre-PCI vFFR did not differ between groups (0.65 ± 0.13 RA and 0.67 ± 0.11 IVL). After PCI, in-stent pressure gradients were significantly lower in the IVL group (0.032 ± 0.026 vs 0.043 ± 0.026 in the RA group, p = 0.024). The proportions of vessels with functional complete revascularization was similar between the two groups (32.9% vs. 37.1% in the RA and IVL group, respectively; p = 0.669). CONCLUSIONS: Calcific lesions preparation with IVL is effective and resulted in lower in-stent pressure gradients compared to RA. Approximately one third of the patients undergoing PCI for a severely calcified lesion achieved functional revascularization with no difference between rotational RA and IVL.
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Aterectomia Coronária , Doença da Artéria Coronariana , Reserva Fracionada de Fluxo Miocárdico , Litotripsia , Intervenção Coronária Percutânea , Calcificação Vascular , Aterectomia Coronária/métodos , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Humanos , Resultado do Tratamento , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/cirurgiaRESUMO
Excimer Laser Coronary Atherectomy (ELCA) is a well-established therapy that emerged for the treatment of peripheral vascular atherosclerosis in the late 1980s, at a time when catheters and materials were rudimentary and associated with the most serious complications. Refinements in catheter technology and the introduction of improved laser techniques have led to their effective use for the treatment of a wide spectrum of complex coronary lesions, such as thrombotic lesions, severe calcific lesions, non-crossable or non-expandable lesions, chronic occlusions, and stent under-expansion. The gradual introduction of high-energy strategies combined with the contrast infusion technique has enabled us to treat an increasing number of complex cases with a low rate of periprocedural complications. Currently, the use of the ELCA has also been demonstrated to be effective in acute coronary syndrome (ACS), especially in the context of large thrombotic lesions.
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Aterectomia Coronária , Intervenção Coronária Percutânea , Aterectomia Coronária/métodos , Angiografia Coronária , Humanos , Lasers de Excimer/uso terapêutico , Intervenção Coronária Percutânea/métodos , Tecnologia , Resultado do TratamentoRESUMO
Serum hepatitis B virus surface antigen (HBsAg) levels have been suggested to predict interferon response in chronic hepatitis B. A few data are available on the role of HBsAg measurement in nucleos(t)ide analogues (NA) treatment. We retrospectively investigated the relation between HBsAg changes and main treatment outcomes during long-term lamivudine treatment in hepatitis e antigen (HBeAg)-negative chronic hepatitis B. A total of 42 HBeAg-negative patients were consecutively enrolled in an open-label study on long-term lamivudine monotherapy (150 mg/die). Serum HBsAg levels were quantified every 6 months by Architect assay (Abbott Diagnostics). HBV-DNA was quantified quarterly by real-time PCR (Roche Diagnostics). The median duration of lamivudine treatment was 66 months (20-153). One patient (2%) was a primary nonresponder, 35 (83%) developed virological breakthrough (VB) and the remaining six patients (14%) were classified as long-term on-treatment responders. During treatment, HBsAg levels decreased only in long-term on-treatment responders, while no changes were observed in resistant patients. Failure to achieve a decrease of 0.7 log(10) IU/mL in serum HBsAg at month six of lamivudine had a positive predictive value of developing VB of 90% and a negative predictive value of 100%. These high predictive values were also maintained in the subgroup of patients negative for HBV-DNA at month six. The results of this study with a small sample size suggest a role of on-treatment HBsAg quantification in the management of lamivudine-treated patients. If validated prospectively in a larger patient cohort, HBsAg measurements would be a useful adjunct to optimize antiviral therapy.
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Antivirais/administração & dosagem , Monitoramento de Medicamentos/métodos , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Lamivudina/administração & dosagem , Adulto , DNA Viral/sangue , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Soro/química , Resultado do TratamentoRESUMO
In this work, the effects of a new class of polymers generally used in hair and skin cleansing products, the SoftCAT (SofCAT SL and SoftCAT SX), on the dye uptake on the hair fibre and the fading effects has been studied. These polymers, based on quaternary ammonium salts of hydroxyethylcellulose, are cationic products that differ in viscosity, hydrophobic substitution index (HS) and/or cationic substitution (CS, % N). UV-Vis spectroscopy has been used to analyse the extracted dyes from the hair cuticle and the cortex. The results indicate that the presence of polymers in the dye bath improve both the quality of the dyeing process and the anti-fading effect during the washing cycles. This phenomenon is postulated to be attributable to the polymers hydrophobically bonding with the dyes and so facilitating their increased penetration into the hair.
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Celulose/análogos & derivados , Tinturas para Cabelo/química , Cabelo/química , Compostos de Amônio Quaternário/química , Animais , Celulose/química , Interações Hidrofóbicas e Hidrofílicas , Espectrofotometria Ultravioleta , Propriedades de SuperfícieRESUMO
Chronic allergic diseases and other disorders associated with mast cell activation can also be associated with tissue fibrosis, but a direct link between mast cell mediator release and fibroblast collagen gene expression has not been established. Using in situ hybridization, we show that the elicitation of an IgE-dependent passive cutaneous anaphylaxis (PCA) reaction in mice results in a transient, but marked augmentation of steady state levels of type alpha-1 (I) collagen mRNA in the dermis. While peak levels of collagen mRNA expression in the skin are observed 16-24 h after mast cell activation, substantial numbers of dermal cells are strongly positive for collagen mRNA at 1 and 2 h after antigen challenge, before circulating inflammatory cells are recruited into the tissues. Furthermore, experiments in mast cell-reconstituted or genetically mast cell-deficient WBB6F1-W/Wv mice demonstrate that the increased expression of collagen mRNA at sites of PCA reactions is entirely mast cell dependent. In vitro studies show that the supernatants of mouse serosal mast cells activated via the Fc epsilon RI markedly increase type alpha-1 (I) collagen mRNA levels in mouse embryonic skin fibroblasts, and also upregulate collagen secretion by these cells. The ability of mast cell supernatants to induce increased steady state levels of collagen mRNA in mouse skin fibroblasts is markedly diminished by absorption with antibodies specific for either of two mast cell-derived cytokines, transforming growth factor beta (TGF-beta 1) or tumor necrosis factor alpha (TNF-alpha), and is eliminated entirely by absorption with antibodies against both cytokines. Taken together, these findings demonstrate that IgE-dependent mouse mast cell activation can induce a transient and marked increase in steady state levels of type alpha-1 (I) collagen mRNA in dermal fibroblasts and that mast cell-derived TGF-beta 1 and TNF-alpha importantly contribute to this effect.
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Colágeno/biossíntese , Expressão Gênica , Mastócitos/fisiologia , Receptores de IgE/fisiologia , Pele/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Anticorpos/farmacologia , Células Cultivadas , Fibroblastos/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Hibridização In Situ , Inflamação/fisiopatologia , Cinética , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Camundongos , Anafilaxia Cutânea Passiva/imunologia , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Receptores de IgE/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Pele/efeitos dos fármacos , Fatores de Tempo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/fisiologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
The importance of mast cells in the development of the allergen-induced airway hyperreactivity and inflammation associated with asthma remains controversial. We found that genetically mast cell-deficient WBB6F(1)-W/W(v) mice that were sensitized to ovalbumin (OVA) without adjuvant, then challenged repetitively with antigen intranasally, exhibited much weaker responses in terms of bronchial hyperreactivity to aerosolized methacholine, lung tissue eosinophil infiltration, and numbers of proliferating cells within the airway epithelium than did identically treated WBB6F(1)-+/+ normal mice. However, W/W(v) mice that had undergone selective reconstitution of tissue mast cells with in vitro-derived mast cells of congenic +/+ mouse origin exhibited airway responses that were very similar to those of the +/+ mice. By contrast, W/W(v) mice that were sensitized with OVA emulsified in alum and challenged with aerosolized OVA exhibited levels of airway hyperreactivity and lung tissue eosinophil infiltration that were similar to those of the corresponding +/+ mice. Nevertheless, these W/W(v) mice exhibited significantly fewer proliferating cells within the airway epithelium than did identically treated +/+ mice. These results show that, depending on the "asthma model" investigated, mast cells can either have a critical role in, or not be essential for, multiple features of allergic airway responses in mice.
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Asma/imunologia , Mastócitos/imunologia , Alérgenos/imunologia , Animais , Modelos Animais de Doenças , Cloreto de Metacolina/imunologia , Camundongos , Ovalbumina/imunologia , Hipersensibilidade Respiratória/imunologia , Cloreto de Sódio/imunologiaRESUMO
Mast cell-associated mediators are generally classified into two groups: the preformed mediators, which are stored in the cells' cytoplasmic granules and are released upon exocytosis, and the newly synthesized mediators, which are not stored but are produced and secreted only after appropriate stimulation of the cell. We now report that tumor necrosis factor alpha (TNF-alpha)/cachectin represents a new type of mast cell-associated mediator, in that IgE-dependent mast cell activation results in the rapid release of preformed stores of the cytokine followed by the synthesis and sustained release of large quantities of newly formed TNF-alpha. We also demonstrate that challenge with specific antigen induces higher levels of TNF-alpha mRNA at skin sites sensitized with IgE in normal mice or mast cell-reconstituted genetically mast cell-deficient WBB6F1-W/W1' mice than at identically treated sites in WBB6F1-W/W1' mice that are devoid of mast cells. These findings identify mast cells as a biologically significant source of TNF-alpha/cachectin during IgE-dependent responses and define a mechanism whereby stimulation of mast cells via the FC epsilon RI can account for both the rapid and sustained release of this cytokine.
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Antígenos de Diferenciação de Linfócitos B/fisiologia , Imunoglobulina E/fisiologia , Mastócitos/fisiologia , Receptores Fc/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Sequência de Bases , Northern Blotting , Linhagem Celular , Células Cultivadas , Cinética , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Sondas de Oligonucleotídeos , Anafilaxia Cutânea Passiva , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Receptores de IgE , Serotonina/metabolismo , Pele/imunologia , Fenômenos Fisiológicos da Pele , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genéticaRESUMO
It has been suggested that reserpine blocks expression of delayed hypersensitivity (DH) by depleting tissue mast cells of serotonin (5-HT), thereby preventing a T cell-dependent release of mast cell 5-HT necessary to localize and to amplify the DH response. However, reserpine blocks expression of DH in mast cell-deficient mice. We therefore decided to reevaluate the mechanism by which reserpine abrogates expression of cellular immunity, and investigated whether the drug might interfere with T cell activity in vitro or in vivo. At concentrations as low as 4 microM, reserpine profoundly suppressed baseline or antigen-augmented levels of [3H]thymidine incorporation by immune lymph node cells obtained from mice sensitized to the contactant oxazolone [I-LNC(Ox)]. This effect was observed both with I-LNC derived from normal mice and with I-LNC derived from congenitally mast cell-deficient W/Wv mice, cell preparations that lacked detectable mast cells, histamine, and 5-HT. Furthermore, treatment of I-LNC with reserpine (20 microM) for 1 h in vitro virtually abolished the ability of these cells to transfer CS to naive mice. This was not a cytolytic effect, as the viability of the I-LNC treated with reserpine was not affected, and washing of the reserpine-treated I-LNC before transfer fully restored their ability to orchestrate a CS response. The action of the drug was not mediated by an effect on mast cells, since the experiment could be performed using mast cell-deficient W/Wv mice as both donors and recipients of I-LNC. In addition, the effect was specific for the treated cells: mice that received reserpine-treated I-LNC(Ox) intravenously together with untreated I-LNC(DNFB) did not develop CS to Ox but responded normally to DNFB; and local intradermal injection of reserpine-treated I-LNC(Ox) which failed to transfer reactivity to Ox, did not interfere with the development of CS to DNFB at the same site. Finally, cotransfer experiments indicated that the effect of reserpine on the transfer of CS was not due to activation of suppressor cells. Our findings strongly suggest that whatever effects reserpine might have on immunologically nonspecific host cells, the drug's effects on sensitized T cells are sufficient to explain its ability to block cell-mediated immune responses in vivo.
Assuntos
Dermatite de Contato/imunologia , Imunossupressores/farmacologia , Mastócitos/efeitos dos fármacos , Reserpina/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Feminino , Idoxuridina/metabolismo , Imunização Passiva , Imunossupressores/administração & dosagem , Injeções Intraperitoneais , Linfonodos/citologia , Ativação Linfocitária/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Reserpina/administração & dosagem , Linfócitos T/metabolismo , Linfócitos T/transplante , Linfócitos T Reguladores/imunologiaRESUMO
Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function.
Assuntos
Fatores de Crescimento de Células Hematopoéticas/farmacologia , Mastócitos/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Transdução de Sinais , Animais , Transplante de Medula Óssea/fisiologia , Células CHO , Cricetinae , Escherichia coli/genética , Fibrina/metabolismo , Fatores de Crescimento de Células Hematopoéticas/genética , Inflamação , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Camundongos Mutantes , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit , Ratos , Receptores de Superfície Celular/fisiologia , Proteínas Recombinantes/farmacologia , Fator de Células-Tronco , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
The long-accepted notion that alloimmune cytolytic T cells (CTL) mediate transplantation immunity has recently been called into question. In order to ascertain directly whether alloimmune CTL can mediate destruction of foreign tissue, we tested the ability of mouse CTL expanded as cloned populations in vitro to destroy allogeneic skin in vivo. The results of these studies prove unequivocally that cloned Lyt-2+ CTL can perform this task in an immunologically specific, H-2-restricted, and dose-dependent fashion.