Protective Effects of Anti-IL17 on Acute Lung Injury Induced by LPS in Mice

Introduction: T helper 17 (Th17) has been implicated in a variety of inflammatory lung and immune system diseases. However, little is known about the expression and biological role of IL-17 in acute lung injury (ALI). We investigated the mechanisms involved in the effect of anti-IL17 in a model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice.Methods: Mice were pre-treated with anti-IL17, 1h before saline/LPS intratracheal administration alongside non-treated controls and levels of exhaled nitric oxide (eNO), cytokine expression, extracellular matrix remodeling and oxidative stress, as well as immune cell counts in bronchoalveolar lavage fluid (BALF), and respiratory mechanics were assessed in lung tissue.Results: LPS instillation led to an increase in multiple cytokines, proteases, nuclear factor-κB, and Forkhead box P3 (FOXP3), eNO and regulators of the actomyosin cytoskeleton, the number of CD4+ and iNOS-positive cells as well as the number of neutrophils and macrophages in BALF, resistance and elastance of the respiratory system, ARG-1 gene expression, collagen fibers, and actin and 8-iso-PGF2α volume fractions. Pre-treatment with anti-IL17 led to a significant reduction in the level of all assessed factors.Conclusions: Anti-IL17 can protect the lungs from the inflammatory effects of LPS-induced ALI, primarily mediated by the reduced expression of cytokines and oxidative stress. This suggests that further studies using anti-IL17 in a treatment regime would be highly worthwhile

Effects of Anti-IL-17 on Inflammation, Remodeling, and Oxidative Stress in an Experimental Model of Asthma Exacerbated by LPS

Inflammation plays a central role in the development of asthma, which is considered an allergic disease with a classic Th2 inflammatory profile. However, cytokine IL-17 has been examined to better understand the pathophysiology of this disease. Severe asthmatic patients experience frequent exacerbations, leading to infection, and subsequently show altered levels of inflammation that are unlikely to be due to the Th2 immune response alone. This study estimates the effects of anti-IL-17 therapy in the pulmonary parenchyma in a murine asthma model exacerbated by LPS. BALB/c mice were sensitized with intraperitoneal ovalbumin and repeatedly exposed to inhalation with ovalbumin, followed by treatment with or without anti-IL-17. Twenty-four hours prior to the end of the 29-day experimental protocol, the two groups received LPS (0.1 mg/ml intratracheal OVA-LPS and OVA-LPS IL-17). We subsequently evaluated bronchoalveolar lavage fluid, performed a lung tissue morphometric analysis, and measured IL-6 gene expression. OVA-LPS-treated animals treated with anti-IL-17 showed decreased pulmonary inflammation, edema, oxidative stress, and extracellular matrix remodeling compared to the non-treated OVA and OVA-LPS groups (p < 0.05). The anti-IL-17 treatment also decreased the numbers of dendritic cells, FOXP3, NF-kappa B, and Rho kinase 1-and 2-positive cells compared to the non-treated OVA and OVA-LPS groups (p < 0.05). In conclusion, these data suggest that inhibition of IL-17 is a promising therapeutic avenue, even in exacerbated asthmatic patients, and significantly contributes to the control of Th1/Th2/Th17 inflammation, chemokine expression, extracellular matrix remodeling, and oxidative stress in a murine experimental asthma model exacerbated by LPS.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)National Council of Scientific and the Technological Development (CNPq)Laboratory of Medical InvestigationsUniv Sao Paulo, Sch Med, Dept Med Sci, Sao Paulo, Brazil|Hosp Sirio Libanes, Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Biomed Sci, Dept Biol Sci, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Biol Sci, Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Biomed Sci, Dept Biol Sci, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Biol Sci, Sao Paulo, BrazilFAPESP: 2013/17944-1Laboratory of Medical Investigations: LIM-20 FMUSPWeb of Scienc

Measurement of the (π−\pi^-, Ar) total hadronic cross section at the LArIAT experiment

We present the first measurement of the negative pion total hadronic cross section on argon, which we performed at the Liquid Argon In A Testbeam (LArIAT) experiment. All hadronic reaction channels, as well as hadronic elastic interactions with scattering angle greater than 5~degrees are included. The pions have a kinetic energies in the range 100-700~MeV and are produced by a beam of charged particles impinging on a solid target at the Fermilab Test Beam Facility. LArIAT employs a 0.24~ton active mass Liquid Argon Time Projection Chamber (LArTPC) to measure the pion hadronic interactions. For this measurement, LArIAT has developed the ``thin slice method", a new technique to measure cross sections with LArTPCs. While generally higher than the prediction, our measurement of the ($\pi^-$,Ar) total hadronic cross section is in agreement with the prediction of the Geant4 model when considering a model uncertainty of $\sim$5.1\%.Comment: 15 pages, 15 figures, 3 tables, accepted by PR

The Liquid Argon In A Testbeam (LArIAT) Experiment

The LArIAT liquid argon time projection chamber, placed in a tertiary beam of charged particles at the Fermilab Test Beam Facility, has collected large samples of pions, muons, electrons, protons, and kaons in the momentum range 300-1400 MeV/c. This paper describes the main aspects of the detector and beamline, and also reports on calibrations performed for the detector and beamline components

Anti-IL17 with or without the use of the Rho kinase inhibitor in mice with chronic allergic pulmonary inflammation

INTRODUÇÃO: Indivíduos com asma possuem infiltração aumentada de células inflamatórias, produção de quimiocinas e hiperresponsividade de vias aéreas. Estes apresentam níveis aumentados de interleucina (IL)-17, importante na regulação da expressão de mediadores inflamatórios e recrutamento de células inflamatórias, outra característica é aumento da atividade da proteína Rho-quinase em suas vias aéreas. A modulação da IL-17 e da proteína Rho-quinase pode ser promissora para o tratamento desta doença. OBJETIVO: Estudar os efeitos dos tratamentos realizados com anticorpo neutralizador anti-IL17 e do inibidor da Rho-quinase, associados ou não, em camundongos com inflamação pulmonar alérgica crônica. MÉTODOS: Foram utilizados 64 camundongos BALB/c, divididos em 8 grupos (8 animais por grupo): SAL (solução salina); OVA (ovoalbumina), SAL-RHOi (salina e inibidor de Rho-quinase), OVA - RHOi (ovoalbumina e inibidor de Rho-quinase), SAL - anti-IL17 (salina e anti-IL17), OVA - anti-IL17 (ovoalbumina e anti-IL17), SAL - RHOi - anti-IL17 (salina, anti-IL17 e inibidor de Rho-quinase), OVA - RHOi - anti-IL17 (ovoalbumina, anti-IL17 e inibidor de Rho-quinase). O protocolo de sensibilização e indução da inflamação pulmonar por ovoalbumina teve duração de 28 dias. O Anti-IL17A (clone 50104 - 7,5 ug por dose) foi administrado via intraperitoneal e inibidor de Rho-quinase (Y-27632) intranasal (10 mg/kg), 1h antes de cada desafio com ovoalbumina (22, 24, 26 e 28 dias). RESULTADOS: Houve um aumento na resistência do sistema respiratório e na elastância, nos marcadores inflamatórios CD4+, CD8+, ROCK1 e ROCK2, IL-1-beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, TNFalfa, em vias sinalizadoras NF-kappaB, FOXP-3 e células dendríticas, em marcadores de remodelamento MMP9, MMP12, TIMP1, iNOS, TGF-beta, no conteúdo de isoprostano, decorina, biglicano, fibronectina e fibras colágenas e na expressão gênica de VAChT, IL-17 e arginase, no grupo OVA em comparação com o grupo controle. O tratamento dos animais sensibilizados, de forma individualizada ou a associação dos dois, atenuou estas respostas quando comparados ao grupo sensibilizado com ovoalbumina e não tratado (p < 0,05). O tratamento do inibidor de Rho-quinase associado ao anti-IL17 gerou potencialização do controle da resposta de hiperresponsividade à metacolina, assim como nas vias aéreas a redução do número de células positivas TNF-alfa, IL-4, IL-5 e nos septos alveolares o número de células positivas IL-4, IL-5, TGF-beta, FOXP3, ROCK1 e ROCK2 (p < 0,05). CONCLUSÃO: O tratamento com anti-IL17 associado ao inibidor da Rho-quinase modula a hiperresponsividade das vias aéreas, inflamação, e remodelamento e estresse oxidativo em animais com inflamação pulmonar alérgica crónicaRATIONALE: Individuals with asthma have increased infiltration of inflammatory cells, chemokines production, and airway hyperresponsiveness. Asthmatics have elevated levels of interleukin (IL)-17, which plays an important role in regulating the expression of inflammatory mediators and recruitment of inflammatory cells, these individuals also have increased Rho-kinase protein activity in their airways. The modulation of IL-17 and Rho-kinase protein may be promising for the treatment of this disease. OBJECTIVE: To study the effects of anti-IL17 neutralizing antibody and Rho-kinase inhibitor treatments, associated or not, on mice with chronic allergic lung inflammation. METHODS: Were used 64 BALB/c mice, divided into eight groups (n=8 in each group): SAL (saline-instilled); OVA (exposed-ovalbumin); SAL-RHOi (saline and Rho-kinase inhibitor), OVA-RHOi (exposed-ovalbumin and Rho-kinase inhibitor); SAL - anti-IL17 (saline and anti-IL17), OVA - anti-IL17 (exposed-ovalbumin and anti-IL17); SAL - RHOi -anti-IL17(saline, Rho-kinase inhibitor and anti-IL17), OVA - RHOi - anti-IL17 (exposed-ovalbumin, anti-IL17 and Rho kinase inhibitor). The protocol for sensitization and induction of pulmonary inflammation by ovalbumin has the duration of 28 days. The Anti-IL17A neutralizing antibody (clone 50104-7.5 ug per dose) was administered via the intraperitoneal, and Rho-kinase inhibitor (Y-27632) intranasal (10 mg/kg), 1h before each ovalbumin challenge (22, 24, 26 and 28 day). RESULTS: There was an increase in respiratory system resistence and elastance, in the positive cells evaluated CD4+, CD8+, ROCK1 and ROCK2, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, TNFalpha, TGF-beta, MMP9, MMP12, TIMP1 and isoprostane, decorin, biglican, fibronectin, collagen fibers content, signaling pathways NF-kappaB, FOX-P3, dendrict cells and gene expression of VAChT, IL-17 and arginase in the OVA group compared to the control group. Treatment of the sensitized animals with the Rho-kinase inhibitor or with the anti-IL17 or with the combination of the two, attenuated these responses when compared to the ovalbumin-sensitized and untreated group (p < 0,05). The treatment of the anti-IL17 associated Rho-kinase inhibitor generated potentiation of the hyper responsiveness response to methacholine, as well as in the airways the reduction of the number of TNF-alpha, IL-4, IL-5 positive cells and in the alveolar septa the number of IL-4, IL-5, FOXP3, TGF-beta, ROCK1 and ROCK2 (p < 0.05). CONCLUSION: Anti-IL17 treatment associated with the Rho-kinase inhibitor modulates airway hyperresponsiveness, inflammation, remodeling and oxidative stress in animals with chronic allergic pulmonary inflammatio

Effects of exposure to environmental pollution from pelletizing of iron ore in chronic allergic lung inflammation: possible participation of the cholinergic system in lung mechanics, inflammation, extracellular matrix remodeling and oxidative stress in genetically modified mice

Introdução: A exposição ao pó de minério em períodos curtos, sazonais ou prolongados pode produzir efeitos nocivos à saúde de indivíduos com doenças alérgicas crônicas, como a asma. Pouco se sabe sobre os efeitos da via anti-inflamatória colinérgica na modulação dos efeitos da poluição em animais com inflamação alérgica crônica. Objetivo: Estudar os efeitos do pó de ferro e da poluição em camundongos com inflamação pulmonar alérgica crônica e com modificação do receptor VAChT, avaliando a hiperresponsividade, remodelamento inflamatório e as respostas ao estresse oxidativo durante as estações de verão e inverno em dois locais de uma cidade do Brasil. Métodos: Foram utilizados um total de 108 animais, divididos em dezoito grupos (n = 6): WT (tipo selvagem), WT-Local1 (tipo selvagem exposto a pó metálico devido à pelotização de ferro em uma mineradora), WT-Local2 (tipo selvagem exposto a pó de metal 3,21mi em uma empresa de mineração), VAChT KD (animais geneticamente modificados com diminuição de VAChT); VAChT KD Local1 (exposto a pó de ferro devido da pelotização de minério de ferro em uma mineradora); VAChT KD-Local2 (exposto ao pó de ferro a 5 Km de uma mineradora), VAChT KDA (animais geneticamente modificados com diminuição de VAChT e sensibilizados com ovalbumina); VAChT KDA-Local1 (animais geneticamente modificados com diminuição de VAChT sensibilizados com ovalbumina e expostos ao Local1); VAChT KDA-Local2 (animais geneticamente modificados com diminuição de VAChT sensibilizados com ovalbumina e expostos ao Local2). Os animais foram expostos aos locais por 2 semanas durante as estações de verão e inverno. No 30º dia do protocolo, avaliamos hiperresponsividade, inflamação, remodelação, respostas ao estresse oxidativo e sistema colinérgico. Resultados: Quando analisamos os animais WT, os animais expostos ao Local 1 apresentaram aumento de %Rrs e %Raw em relação aos animais do grupo biotério, também houve aumento de %Rrs e células positivas para IL-17 no WT -Local2 animais em comparação com os animais WT. No verão, animais WT expostos ao Local 1 apresentaram aumento de %Rrs, Raw e IL-5 em relação aos animais expostos ao Local 2, e no inverno, animais expostos ao local 2 apresentaram aumento de células IL-17 positivas em relação aos animais expostos ao Local 1. Ao comparar animais VAChT KD com animais WT, houve aumento de %Rrs, NFkappaB, IL-5 e IL-13 e diminuição de -7 em animais VAChT KD. Os animais VAChT KDA apresentaram aumento da hiperresponsividade (%Rrs, %Raw, %Ers), de todos os marcadores inflamatórios avaliados, de remodelamento (MMP-9, TIMP-1, TGF-B, conteúdo de fibras de colágeno), de iNOS e de conteúdo de isoprostano em comparação aos animais do grupo VAChT KD. Animais VAChT KDA expostos ao Local 1 apresentaram aumento de %Rrs, %Htis, iNOS, eosinófilos, NF-Kappa B, IL-5 e IL-13 em relação aos animais que permaneceram no biotério. Os animais VAChT KDA expostos ao Local 2 apresentaram aumento de eosinófilos, IL-4, IL-5, IL-13, MMP-9, fibras colágenas e teor de isoprostano em relação aos animais que permaneceram no biotério. Conclusão: A redução da sinalização colinérgica aumenta a inflamação pulmonar em um modelo de inflamação pulmonar alérgica crônica e quando associada à poluição pode exacerbar algumas respostas relacionadas à inflamação, estresse oxidativo e remodelaçãoBackground: Exposure to ore dust in short periods, seasonally or in the long term, can produce harmful effects on the health of individuals with chronic allergic diseases, such as asthma. Little is known about the effects of the cholinergic anti-inflammatory pathway on the modulation of pollution effects in animals with chronic allergic inflammation. Objective: To study the effects of iron dust and pollution in mice with chronic allergic lung inflammation and with the modification of VAChT receptor by evaluating hyperresponsiveness, inflammatory remodeling and oxidative stress responses during the summer and winter stations in two locals in a city in Brazil. Methods: A total of one hundred and eight animals were used, were divided into eighteen groups (n = 6): WT (wild tipe), WT-Local1 (wild tipe exposed to metal powder due to pelletizing iron at a mining company), WT-Local2 (wild tipe exposed to metal powder 3.21mi at a mining company), KD VAChT (genetically modified animals with reduced VAChT); KD VAChT-Local1 (exposed to metal powder due to pelletizing iron ore at a mining company); KD VAChT-Local2 (exposed to metal powder 3.21mi at a mining company), KDA VAChT (genetically modified animals with reduced VAChT sensitized with ovalbumin); KDA VAChT-Local1 (genetically modified animals with reduced VAChT sensitized with ovalbumin and exposed to Local1); KDA VAChT-Local2 (genetically modified animals with reduced VAChT sensitized with ovalbumin and exposed to Local2). The animals were exposed to the locals for 2 weeks during the summer and winter stations. On 30th day of the protocol, we evaluated hyperresponsiveness, inflammation, remodeling, oxidative stress responses and cholinergic system. Results: When we analyzed the WT animals, the animals exposed to Local 1 showed an increase in %Rrs and %Raw compared to the animals in the vivarium group, there was also an increase in %Rrs and IL-17 positive cells in the WT-Local2 animals compared to the WT animals. In summer, WT animals exposed to Local 1 showed an increase in %Rrs, Raw and IL-5 compared to animals exposed to Local 2, and in winter, animals exposed to local 2 showed an increase in IL-17 positive cells compared to animals exposed to Local 1. When comparing VACht KD animals with WT animals, there was an increase in %Rrs, NFkappaB, IL-5 and IL-13 and a decrease in alpha-7 in VAChT KD animals. VAChT KDA animals showed increased hyperresponsiveness (%Rrs, %Raw, %Ers), of all inflammatory markers evaluated, of remodeling (MMP-9, TIMP-1, TGF-B, collagen fiber content), of iNOS and of isoprostane content compared to animals in the VAChT KD group. Animals VAChT KDA exposed to Local 1 showed an increase in %Rrs, %Htis, iNOS, eosinophils, NFKappa B, IL-5 and IL-13 compared to animals that remained in the vivarium. Animals VAChT KDA exposed to Local 2 showed an increase in eosinophils, IL-4, IL-5, IL-13, MMP-9, collagen fibers and isoprostane content compared to animals that remained in the vivarium. Conclusion: Reduced cholinergic signaling increases lung inflammation in a model of chronic allergic lung inflammation and that when associated with pollution it can exacerbate some responses related to inflammation, oxidative stress and remodelin

A Thin Film Approach to Engineering Functionality into Oxides

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65331/1/j.1551-2916.2008.02556.x.pd