MILTON DE ARRUDA MARTINS
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/20 - Laboratório de Terapêutica Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/20 - Laboratório de Terapêutica Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
10 resultados
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conferenceObject Reduction In Vacht Levels Induced Pulmonary Inflammation In Experimental Model Of Pulmonary Emphysema(2015) BANZATO, R.; PINHEIRO, N. M.; OLIVO, C.; RANCON, F.; LOPES, F.; CAPERUTO, L.; CAMARA, N.; MARTINS, M.; TIBERIO, I.; PRADO, M.; PRADO, V.; PRADO, C.conferenceObject Alpha-7 Nicotinic Acetylcholine Receptor Agonist Attenuates Acute Lung Injury Induced By LPS(2013) PINHEIRO, N. M.; SANTANA, F. R.; TIBERIO, I.; MARTINS, M.; PRADO, V.; PRADO, M.; PRADO, C. M.- Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema(2021) BANZATO, Rosana; PINHEIRO, Nathalia M.; OLIVO, Clarice R.; SANTANA, Fernanda R.; LOPES, Fernanda D. T. Q. S.; CAPERUTO, Luciana C.; CAMARA, Niels O.; MARTINS, Milton A.; TIBERIO, Iolanda F. L. C.; PRADO, Marco Antonio M.; PRADO, Vania F.; PRADO, Carla M.Acetylcholine (ACh), the neurotransmitter of the cholinergic system, regulates inflammation in several diseases including pulmonary diseases. ACh is also involved in a non-neuronal mechanism that modulates the innate immune response. Because inflammation and release of pro-inflammatory cytokines are involved in pulmonary emphysema, we hypothesized that vesicular acetylcholine transport protein (VAChT) deficiency, which leads to reduction in ACh release, can modulate lung inflammation in an experimental model of emphysema. Mice with genetical reduced expression of VAChT (VAChT KDHOM 70%) and wild-type mice (WT) received nasal instillation of 50 uL of porcine pancreatic elastase (PPE) or saline on day 0. Twenty-eight days after, animals were evaluated. Elastase instilled VAChT KDHOM mice presented an increase in macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid and MAC2-positive macrophages in lung tissue and peribronchovascular area that was comparable to that observed in WT mice. Conversely, elastase instilled VAChT KDHOM mice showed significantly larger number of NF-kappa B-positive cells and isoprostane staining in the peribronchovascular area when compared to elastase-instilled WT-mice. Moreover, elastase-instilled VAChT-deficient mice showed increased MCP-1 levels in the lungs. Other cytokines, extracellular matrix remodeling, alveolar enlargement, and lung function were not worse in elastase-instilled VAChT deficiency than in elastase-instilled WT-controls. These data suggest that decreased VAChT expression may contribute to the pathogenesis of emphysema, at least in part, through NF-kappa B activation, MCP-1, and oxidative stress pathways. This study highlights novel pathways involved in lung inflammation that may contribute to the development of chronic obstrutive lung disease (COPD) in cholinergic deficient individuals such as Alzheimer's disease patients.
- Increased Airway Reactivity and Hyperinsulinemia in Obese Mice Are Linked by ERK Signaling in Brain Stem Cholinergic Neurons(2015) LEIRIA, Luiz O. S.; ARANTES-COSTA, Fernanda M.; CALIXTO, Marina C.; ALEXANDRE, Eduardo C.; MOURA, Rodrigo F.; FOLLI, Franco; PRADO, Carla M.; PRADO, Marco Antonio; PRADO, Vania F.; VELLOSO, Licio A.; DONATO JR., Jose; ANTUNES, Edson; MARTINS, Milton A.; SAAD, Mario J. A.Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR). In obesity-associated asthma, AHR may be regulated by non-T(H)2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV)-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KDHOM-/-), mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK) normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA), which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre-ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma.
- Vesicular acetylcholine transport deficiency potentiates some inflammatory responses induced by diesel exhaust particles(2019) SANTANA, Fernanda P. R.; PINHEIRO, Nathalia M.; BITTENCOURT-MERNAK, Marcia I.; PERINI, Adenir; YOSHIZAKI, Kelly; MACCHIONE, Mariangela; SALDIVA, Paulo H. N.; MARTINS, Milton A.; TIBERIO, Iolanda F. L. C.; PRADO, Marco Antonio M.; PRADO, Vania F.; PRADO, Carla M.Endogenous acetylcholine (ACh), which depends of the levels of vesicular ACh transport (VAChT) to be released, is the central mediator of the cholinergic anti-inflammatory system. ACh controls the release of cytokine in different models of inflammation. Diesel exhaust particles (DEP) are one of the major environmental pollutants produced in large quantity by automotive engines in urban center. DEP bind the lung parenchyma and induce inflammation. We evaluated whether cholinergic dysfunction worsens DEP-induced lung inflammation. Male mice with decreased ACh release due to reduced expression of VAChT (VAChT-KD mice) were submitted to DEP exposure for 30 days (3 mg/mL of DEP, once a day, five days a week) or saline. Pulmonary function and inflammation as well as extracellular matrix fiber deposition were evaluated. Additionally, airway and nasal epithelial mucus production were quantified. We found that DEP instillation worsened lung function and increased lung inflammation. Higher levels of mononuclear cells were observed in the peripheral blood of both wild-type (WT) and VAChT-KD mice. Also, both wild-type (WT) and VAChT-KD mice showed an increase in macrophages in bronchoalveolar lavage fluid (BALF) as well as increased expression of IL-4, IL-6, IL-13, TNF-alpha, and NF-kappa B in lung cells. The collagen fiber content in alveolar septa was also increased in both genotypes. On the other hand, we observed that granulocytes were increased only in VAChT-KD peripheral blood. Likewise, increased BALF lymphocytes and neutrophils as well as increased elastic fibers in alveolar septa, airway neutral mucus, and nasal epithelia acid mucus were observed only in VAChT-KD mice. The cytokines IL-4 and TNF-alpha were also higher in VAChT-KD mice compared with WT mice. In conclusion, decreased ability to release ACh exacerbates some of the lung alterations induced by DEP in mice, suggesting that VAChT-KD animals are more vulnerable to the effects of DEP in the lung.
- Sleepiness, sleep deprivation, quality of life, mental symptoms and perception of academic environment in medical students(2021) PEROTTA, Bruno; ARANTES-COSTA, Fernanda M.; ENNS, Sylvia C.; FIGUEIRO-FILHO, Ernesto A.; PARO, Helena; SANTOS, Itamar S.; LORENZI-FILHO, Geraldo; MARTINS, Milton A.; TEMPSKI, Patricia Z.BackgroundIt has been previously shown that a high percentage of medical students have sleep problems that interfere with academic performance and mental health.MethodsTo study the impact of sleep quality, daytime somnolence, and sleep deprivation on medical students, we analyzed data from a multicenter study with medical students in Brazil (22 medical schools, 1350 randomized medical students). We applied questionnaires of daytime sleepiness, quality of sleep, quality of life, anxiety and depression symptoms and perception of educational environment.Results37.8% of medical students presented mild values of daytime sleepiness (Epworth Sleepiness Scale - ESS) and 8.7% presented moderate/severe values. The percentage of female medical students that presented ESS values high or very high was significantly greater than male medical students (p< 0.05). Students with lower ESS scores presented significantly greater scores of quality of life and perception of educational environment and lower scores of depression and anxiety symptoms, and these relationships showed a dose-effect pattern. Medical students reporting more sleep deprivation showed significantly greater odds ratios of presenting anxiety and depression symptoms and lower odds of good quality of life or perception of educational environment.ConclusionsThere is a significant association between sleep deprivation and daytime sleepiness with the perception of quality of life and educational environment in medical students.
- Effects of VAChT reduction and alpha 7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation(2020) PINHEIRO, Nathalia M.; MIRANDA, Claudia J. C. P.; SANTANA, Fernanda R.; BITTENCOURT-MERNAK, Marcia; ARANTES-COSTA, Fernanda M.; OLIVO, Clarice; PERINI, Adenir; FESTA, Sergio; CAPERUTO, Luciana C.; TIBERIO, Iolanda F. L. C.; PRADO, Marco Antonio M.; MARTINS, Milton A.; PRADO, Vania F.; PRADO, Carla M.The cholinergic anti-inflammatory pathway has been shown to regulate lung inflammation and cytokine release in acute models of inflammation, mainly via alpha 7 nicotinic receptor (alpha 7nAChR). We aimed to evaluate the role of endogenous acetylcholine in chronic allergic airway inflammation in mice and the effects of therapeutic nAChR stimulation in this model. We first evaluated lung inflammation and remodeling on knock-down mice with 65% of vesicular acetylcholine transport (VAChT) gene reduction (KDVAChT) and wild-type(WT) controls that were subcutaneously sensitized and then inhaled with ovalbumin(OVA). We then evaluated the effects of PNU282987(0.5-to-2mg/kg),( alpha 7nAChR agonist) treatment in BALB/c male mice intraperitoneal sensitized and then inhaled with OVA. Another OVA-sensitized-group was treated with PNU-282987 plus Methyllycaconitine (MLA,1 mg/kg, alpha 7nAChR antagonist) to confirm that the effects observed by PNU were due to alpha 7nAChR. We showed that KDVAChT-OVA mice exhibit exacerbated airway inflammation when compared to WT-OVA mice. In BALB/c, PNU-282987 treatment reduced the number of eosinophils in the blood, BAL fluid, and around airways, and also decreased pulmonary levels of IL-4,IL-13,IL-17, and IgE in the serum of OVA-exposed mice. MLA pretreatment abolished all the effects of PNU-282987. Additionally, we showed that PNU-282987 inhibited STAT3phosphorylation and reduced SOCS3 expression in the lung. These data indicate that endogenous cholinergic tone is important to control allergic airway inflammation in a murine model. Moreover, alpha 7nAChR is involved in the control of eosinophilic inflammation and airway remodeling, possibly via inhibition of STAT3/SOCS3 pathways. Together these data suggest that cholinergic anti-inflammatory system mainly alpha 7nAChR should be further considered as a therapeutic target in asthma.
conferenceObject Reduction of endogenous acetylcholine contributes to pulmonary inflammation in a model of emphysema in mice(2012) BANZATO, Rosana; PINHEIRO, Nathalia; OLIVO, Clarice; SANTANA, Fernanda; TIBERIO, Iolanda; PRADO, Vania; PRADO, Marco Antonio; MARTINS, Milton; LOPES, Fernanda; PRADO, Carla- Pulmonary Inflammation Is Regulated by the Levels of the Vesicular Acetylcholine Transporter(2015) PINHEIRO, Nathalia M.; MIRANDA, Claudia J. C. P.; PERINI, Adenir; CAMARA, Niels O. S.; COSTA, Soraia K. P.; ALONSO-VALE, Maria Isabel C.; CAPERUTO, Luciana C.; TIBERIO, Iolanda F. L. C.; PRADO, Marco Antonio M.; MARTINS, Milton A.; PRADO, Vania F.; PRADO, Carla M.Acetylcholine (ACh) plays a crucial role in physiological responses of both the central and the peripheral nervous system. Moreover, ACh was described as an anti-inflammatory mediator involved in the suppression of exacerbated innate response and cytokine release in various organs. However, the specific contributions of endogenous release ACh for inflammatory responses in the lung are not well understood. To address this question we have used mice with reduced levels of the vesicular acetylcholine transporter (VAChT), a protein required for ACh storage in secretory vesicles. VAChT deficiency induced airway inflammation with enhanced TNF-alpha and IL-4 content, but not IL-6, IL-13 and IL-10 quantified by ELISA. Mice with decreased levels of VAChT presented increased collagen and elastic fibers deposition in airway walls which was consistent with an increase in inflammatory cells positive to MMP-9 and TIMP-1 in the lung. In vivo lung function evaluation showed airway hyperresponsiveness to methacholine in mutant mice. The expression of nuclear factor-kappa B (p65-NF-kappa B) in lung of VAChT-deficient mice were higher than in wild-type mice, whereas a decreased expression of janus-kinase 2 (JAK2) was observed in the lung of mutant animals. Our findings show the first evidence that cholinergic deficiency impaired lung function and produce local inflammation. Our data supports the notion that cholinergic system modulates airway inflammation by modulation of JAK2 and NF-kappa B pathway. We proposed that intact cholinergic pathway is necessary to maintain the lung homeostasis.
- Acute lung injury is reduced by the alpha 7nAChR agonist PNU-282987 through changes in the macrophage profile(2017) PINHEIRO, Nathalia M.; SANTANA, Fernanda P. R.; ALMEIDA, Rafael Ribeiro; GUERREIRO, Marina; MARTINS, Milton A.; CAPERUTO, Luciana C.; CAMARA, Niels O. S.; WENSING, Lislaine A.; PRADO, Vania F.; TIBERIO, Iolanda F. L. C.; PRADO, Marco Antonio M.; PRADO, Carla M.Nicotinic alpha-7 acetylcholine receptor (nAChR alpha 7) is a critical regulator of cholinergic anti-inflammatory actions in several diseases, including acute respiratory distress syndrome (ARDS). Given the potential importance of alpha 7nAChR as a therapeutic target, we evaluated whether PNU-282987, an alpha 7nAChR agonist, is effective in protecting the lung against inflammation. We performed intratracheal instillation of LPS to generate acute lung injury (ALI) in C57BL/6mice. PNU-282987 treatment, either before or after ALI induction, reduced neutrophil recruitment and IL1 beta, TNF-alpha, IL-6, keratinocyte chemoattractant (KC), and IL-10 cytokine levels in the bronchoalveolar lavage fluid (P<0.05). In addition, lung NF-kappa B phosphorylation decreased, along with collagen fiber deposition and the number of matrix metalloproteinase-9(+) and -2(+) cells, whereas the number of tissue inhibitor of metalloproteinase-1(+) cells increased (P < 0.05). PNU-282987 treatment also reduced lung mRNA levels and the frequency of M1 macrophages, whereas cells expressing the M2-related markers CD206 and IL-10 increased, suggesting changes in the macrophage profile. Finally, PNU-282987 improved lung function in LPS-treated animals. The collective results suggest that PNU-282987, anagonist of alpha 7nAChR, reduces LPS-induced experimental ALI, thus supporting the notion that drugs that act on alpha 7nAChRs should be explored for ARDS treatment in humans.-Pinheiro, N. M., Santana, F. P. R., Almeida, R. R., Guerreiro, M., Martins, M. A., Caperuto, L. C., Camara, N. O. S., Wensing, L. A., Prado, V. F., Tiberio, I. F. L. C., Prado, M. A. M., Prado, C. M. Acute lung injury is reduced by the alpha 7nAChR agonist PNU-282987 through changes in the macrophage profile.