ADENIR PERINI
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- Inflammation and Remodeling in Infantile, Juvenile, and Adult Allergic Sensitized Mice(2011) CARNIELI, Denise S.; YOSHIOKA, Eliane; SILVA, Luiz Fernando F.; LANCAS, Tatiana; ARANTES, Fernanda M.; PERINI, Adenir; MARTINS, Milton A.; SALDIVA, Paulo Hilario N.; DOLHNIKOFF, Marisa; MAUAD, ThaisBackground: Airway structural changes occur early in childhood asthma, but it is unknown whether the development of airway alterations in children is similar to that of adults. We compared inflammation and remodeling parameters in allergic sensitized infantile, juvenile, and adult mice. Methods: Infantile mice (18D) were sensitized with three intraperitoneal injections (i.p.) of ovalbumin (OVA) at days 5 and 7 and challenged with OVA at days 14-16. The 18D1 group received an additional challenge at days 9-11. The juvenile mice (40D) received challenges at days 22-24 and 36-38. Adult mice (100D) were sensitized at days 60-62 and received three inhalations at days 77-79 and 96-98. Animals were submitted to whole body plethysmography. Airway eosinophils, CD3+ T-lymphocytes, IL-5+ cells, mucus content, collagen and reticular fibers density, and smooth muscle thickness were quantified. Results: All sensitized animals presented with airway hyperresponsiveness, without differences in eosinophil cell density The density of CD3+ T-cells was higher in the 100D and 1801 groups than in the 18D and 40D groups. Infantile sensitized groups demonstrated increased interleukin-5 expression in the airways. Infantile mice demonstrated more mucus in the bronchiolar epithelium than the 40D and 100D mice. The 18D animals demonstrated less collagen than the 18D1 group. Juvenile and adult mice had increased airway smooth muscle thickness when compared to age-matched controls, but no differences were observed in the infantile groups. Conclusion: We have shown that infantile mice develop inflammatory and structural alterations in the airways that are partially different from those developed in older animals. Pediatr Pulmonol. 2011;46:650-665. (C) 2011 Wiley-Liss, Inc.
- 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.
- 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.
- Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation(2012) POSSA, Samantha Souza; CHARAFEDDINE, Homar Toledo; RIGHETTI, Renato Fraga; SILVA, Patricia Angeli da; ALMEIDA-REIS, Rafael; SARAIVA-ROMANHOLO, Beatriz Mangueira; PERINI, Adenir; PRADO, Carla Maximo; LEICK-MALDONADO, Edna Aparecida; MARTINS, Milton A.; TIBERIO, Iolanda de Fatima Lopes CalvoPossa SS, Charafeddine HT, Righetti RF, da Silva PA, Almeida-Reis R, Saraiva-Romanholo BM, Perini A, Prado CM, Leick-Maldonado EA, Martins MA, Tiberio ID. Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation. Am J Physiol Lung Cell Mol Physiol 303: L939-L952, 2012. First published September 21, 2012; doi:10.1152/ajplung.00034.2012.-Several studies have demonstrated the importance of Rho-kinase in the modulation of smooth muscle contraction, airway hyperresponsiveness, and inflammation. However, the effects of repeated treatment with a specific inhibitor of this pathway have not been previously investigated. We evaluated the effects of repeated treatment with Y-27632, a highly selective Rho-kinase inhibitor, on airway hyperresponsiveness, oxidative stress activation, extracellular matrix remodeling, eosinophilic inflammation, and cytokine expression in an animal model of chronic airway inflammation. Guinea pigs were subjected to seven ovalbumin or saline exposures. The treatment with Y-27632 (1 mM) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the animals' pulmonary mechanics were evaluated, and exhaled nitric oxide (E-NO) was collected. The lungs were removed, and histological analysis was performed using morphometry. Treatment with Y-27632 in sensitized animals reduced E-NO concentrations, maximal responses of resistance, elastance of the respiratory system, eosinophil counts, collagen and elastic fiber contents, the numbers of cells positive for IL-2, IL-4, IL-5, IL-13, inducible nitric oxide synthase, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta, NF-kappa B, IFN-gamma, and 8-iso-prostaglandin F2 alpha contents compared with the untreated group (P < 0.05). We observed positive correlations among the functional responses and inflammation, remodeling, and oxidative stress pathway activation markers evaluated. In conclusion, Rho-kinase pathway activation contributes to the potentiation of the hyperresponsiveness, inflammation, the extracellular matrix remodeling process, and oxidative stress activation. These results suggest that Rho-kinase inhibitors represent potential pharmacological tools for the control of asthma.
- 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.