Exposure to Sodium Hypochlorite or Cigarette Smoke Induces Lung Injury and Mechanical Impairment in Wistar Rats.

Pulmonary irritants, such as cigarette smoke (CS) and sodium hypochlorite (NaClO), are associated to pulmonary diseases in cleaning workers. We examined whether their association affects lung mechanics and inflammation in Wistar rats. Exposure to these irritants alone induced alterations in the lung mechanics, inflammation, and remodeling. The CS increased airway cell infiltration, acid mucus production, MMP-12 expression, and alveolar enlargement. NaClO increased the number of eosinophils and macrophages in the bronchoalveolar lavage fluid, with cells expressing IL-13, MMP-12, MMP-9, TIMP-1, and iNOS in addition to increased IL-1ß and TNF-α levels. Co-exposure to both irritants increased epithelial and smooth muscle cell area, acid mucus production, and IL-13 expression in the airways, while it reduced the lung inflammation. In conclusion, the co-exposure of CS with NaClO reduced the pulmonary inflammation, but increased the acidity of mucus, which may protect lungs from more injury. A cross-resistance in people exposed to multiple lung irritants should also be considered.

Effects of intrauterine exposure to concentrated ambient particles on allergic sensitization in juvenile mice.

Intrauterine exposure to particulate matter (PM) has been associated with an increased risk of asthma development, which may differ by the age of asthma onset, sex, and pollutant concentration. To investigate the pulmonary effects of in utero exposure to concentrated urban ambient particles (CAPs) in response to house dust mite (HDM) sensitization in juvenile mice. Mice were exposed to CAPs (600 µg/m3 PM2.5) during the gestational period. Twenty-two-day postnatal mice were sensitized with HDM (100 µg, intranasally, 3 times per week). Airway responsiveness (AHR), serum immunoglobulin, and lung inflammation were assessed after 43 days of the postnatal period. Female (n = 47) and male (n = 43) mice were divided into four groups as follows: (1) FA: not exposed to CAPs; (2) CAPs: exposed to CAPs; (3) HDM: sensitized to HDM; and (4) CAPs+HDM: exposed to CAPs and HDM-sensitized. PM2.5 exposure did not worsen lung hyperresponsiveness or allergic inflammation in sensitized animals. The levels of the lung cytokines IL-4, TNF-α, and IL-2 were differentially altered in male and female animals. Males presented hyporesponsiveness and increased lung macrophagic inflammation. There were no epigenetic changes in the IL-4 gene. In conclusion, intrauterine exposure ambient PM2.5 did not worsened allergic pulmonary susceptibility but affected the pulmonary immune profile and lung function, which differed by sex.

[The development of autonomy among adolescents with Down syndrome based on the pedagogy of Paulo Freire]. / O desenvolvimento da autonomia em adolescentes com síndrome de Down a partir da pedagogia de Paulo Freire.

Autonomy is a process that enables us to understand and act on the environment and on ourselves. During adolescence, transformations result in the development of autonomy. Adolescents with Down syndrome (ADS) have perceptual-cognitive limitations and few opportunities to acquire autonomy. The development of autonomy in an occupational therapy group, with dyads of ADS and their main caregivers was analyzed. The evaluation of the materials produced in the therapeutic process pointed to four categories of analysis: self-perception, perception of the other, shared experience and change of attitude. The results show symbiotic relationships between the dyad, which hamper the individuation process and limit the opportunities to carry out activities independently. The therapeutic process based on Paulo Freire's pedagogy raised the level from an ingenuous to a critical awareness, resulting in changes in the attitudes of caregivers in relation to the identification of potential and acceptance of their own limitations and the ADS under care. This symbiosis complicates the individuation process and the access to experiences necessary for the development of autonomy. The therapeutic process can modify the attitudes of caregivers and foster continuity in development and autonomy.

A autonomia é um processo que nos capacita a compreender e agir sobre nós mesmos e sobre o ambiente. Na adolescência, transformações resultam no desenvolvimento da autonomia. Adolescentes com Síndrome de Down (ASD) têm limitações percepto-cognitivas e poucas oportunidades para aquisição de autonomia. Analisamos o desenvolvimento da autonomia em um grupo terapêutico de Terapia Ocupacional, com díades de ASD e seus principais cuidadores. A análise dos materiais documentais produzidos no processo terapêutico apontou quatro categorias de análise: autopercepção, percepção do outro, vivência compartilhada e mudança de atitude. Os resultados mostram relações simbióticas entre a díade, que dificultam o processo de individuação e limitam as oportunidades para realização das atividades de modo independente. O processo terapêutico baseado na pedagogia freiriana mobilizou de uma consciência ingênua para crítica, acarretando mudanças nas atitudes dos cuidadores em relação à identificação de potenciais e aceitação de limitações próprias e do ASD cuidado. Essa simbiose dificulta o processo de individuação e o acesso a experiências necessárias para o desenvolvimento de autonomia. O processo terapêutico pode modificar as atitudes dos cuidadores e propiciar continuidade do desenvolvimento e autonomia.

Relationship between metacognitive awareness and motivation to learn in medical students.

BACKGROUND: In self-regulated learning, learning is defined as metacognitively guided, intrinsically motivated and strategic. In the context of medical education, the development of self-regulated learning can be associated with better academic and clinical performance. Hence, this report focuses on demonstrating the association between metacognitive awareness and motivation to learn among medical students in the clinical sciences portion of their education (3rd and 4th years of the medical programme) and characterizing medical students' motivational factors. METHODS: We performed a cross-sectional study with a qualitative and quantitative approach involving medical students from the University of Sao Paulo (USP) in Brazil. We have selected validated self-report questionnaires for the evaluation of metacognition (the Schraw and Dennison Metacognitive Awareness Inventory - MAI) and motivation to learn (the Baranik, Barron and Finney Achievement Goals for a Work Domain - AGWD). MAI has two domains: knowledge about cognition and regulation of cognition. AGWD divides achievement goals into mastery approach, mastery avoidance, performance approach and performance avoidance goal orientations. We also performed a qualitative analysis based on an open-ended question: "What motivates me the most in medical training?" RESULTS: One hundred eighty-five students completed the questionnaires: 103 (55.67%) were men, 110 (59.45%) were in their fourth year of the medical programme, and 152 (82.16%) were up to 24 years old. Only the knowledge about cognition domain of MAI was significantly associated with motivation to learn. We found that higher scores on the knowledge about cognition domain of MAI was associated with the mastery approach goal orientation (p = 0.003, median 0.71, IQR 0.23) and that lower scores on this same domain was associated with a mastery avoidance goal orientation (p = 0.034, median 0.65, IQR 0.14). The open-ended question showed that altruism, personal satisfaction, financial feedback, personal and supportive networks and graduating were motivational factors. CONCLUSIONS: Metacognitive awareness and motivation to learn are closely related. This association may represent a potential target for the educational process, as deans and faculty can adopt strategies focused on promoting self-regulated learning concerning students' motivational factors. This could enhance academic outcomes and promote more enjoyable learning.

Diphteria-tetanus-pertussis vaccine reduces specific IgE, inflammation and remodelling in an animal model of mite-induced respiratory allergy.

BACKGROUND: Adjuvants, such as bacterial lipopolysaccharides, have been studied to improve the efficacy of allergen-specific immunotherapy. The Bordetella pertussis (Pw) vaccine has been shown to have a protective role in ovalbumin-induced asthma models. However, its role in allergy to mites is unknown. We evaluated the effects of the diphtheria-tetanus-pertussis (DTPw) vaccine on a murine model of respiratory allergy induced by Dermatophagoides pteronyssinus (Derp). METHODS: In a 30-day protocol, BALB/c mice were immunized subcutaneously with saline or Derp, alone or in combination with diphtheria-tetanus (DT) or DTPw vaccines (days 0, 7 and 14). Subsequently, they underwent a daily intranasal challenge with saline or Derp (days 22-28) and were then sacrificed (day 29). We evaluated serum-specific immunoglobulins, bronchoalveolar lavage (BAL) cellularity, remodelling of the lower airways, density of polymorphonuclear leukocytes (PMNs) and acidic nasal mucus content. RESULTS: The animals sensitized with Derp produced high levels of specific immunoglobulins, increased density of PMNs and nasal mucus content, and elevated BAL cellularity and remodelling. Vaccines led to a reduction in IgE levels, with the Derp-DTPw group being similar to the saline groups. The vaccinated groups had reductions of BAL cellularity and remodelling, with more expressive results in the Derp-DTPw group compared to the Derp-DT group. The DT and DTPw vaccines inhibited the nasal PMN infiltrate, and DTPw modulated the production of acidic nasal mucus. CONCLUSIONS: The DTPw vaccine reduced serum specific IgE, nasal and pulmonary inflammation and remodelling of the lower airways.

Evaluation of the neuromuscular junction in a middle-aged mouse model of congenital myasthenic syndrome.

INTRODUCTION: Reduced expression of the vesicular acetylcholine transporter (VAChT) leads to changes in the distribution and shape of synaptic vesicles (SVs) at neuromuscular junctions (NMJs), suggesting vesicular acetylcholine (ACh) as a key component of synaptic structure and function. It is poorly understood how long-term changes in cholinergic transmission contribute to age- and disease-related degeneration in the motor system. METHODS: In this study we performed confocal imaging, electrophysiology, electron microscopy, and analyses of respiratory mechanics of the diaphragm NMJ components in 12-month-old wild-type (WT) and VAChTKDHOM mice. RESULTS: Diaphragms of NMJs of the VAChTKDHOM mice were similar to those in WT mice in number, colocalization, and fragmentation of pre-/postsynaptic components. However, they had increased spontaneous SV exocytosis, miniature endplate potential frequency, and diminished MEPP amplitude. No impairment in respiratory mechanics at rest was observed, probably due to the large neurotransmission safety factor of the diaphragm. DISCUSSION: The present findings help us to understand the consequences of reduced ACh release at the NMJs during aging.

Inflammatory and functional responses after (bio)diesel exhaust exposure in allergic sensitized mice. A comparison between diesel and biodiesel.

Many cities fail to meet air quality standards, which results in increased risk for pulmonary disorders, including asthma. Human and experimental studies have shown that diesel exhaust (DE) particles are associated with worsening of allergic asthma. Biodiesel (BD), a cleaner fuel from renewable sources, was introduced in the eighties. Because of the reduction in particulate matter (PM) emissions, BD was expected to cause fewer adverse pulmonary effects. However, only limited data on the effect of BD emissions in asthma are available. OBJECTIVE: Determine whether BD exhaust exposure in allergic sensitized mice leads to different effects on inflammatory and functional responses compared to DE exposure. METHODS: Balb/C mice were orotracheally sensitized with House Dust Mite (HDM) or a saline solution with 3 weekly instillations. From day 9 until day 17 after sensitization, they were exposed daily to filtered air (FA), DE and BD exhaust (concentration: 600 µg/m3 PM2.5). Lung function, bronchoalveolar lavage fluid (BALF) cell counts, cytokine levels (IL-2, IL-4, IL-5, IL-17, TNF-α, TSLP) in the BALF, peribronchiolar eosinophils and parenchymal macrophages were measured. RESULTS: HDM-sensitized animals presented increased lung elastance (p = 0.046), IgG1 serum levels (p = 0.029), peribronchiolar eosinophils (p = 0.028), BALF levels of total cells (p = 0.020), eosinophils (p = 0.028), IL-5 levels (p = 0.002) and TSLP levels (p = 0.046) in BALF. DE exposure alone increased lung elastance (p = 0.000) and BALF IL-4 levels (p = 0.045), whereas BD exposure alone increased BALF TSLP levels (p = 0.004). BD exposure did not influence any parameters after HDM challenge, while DE exposed animals presented increased BALF levels of total cells (p = 0.019), lymphocytes (p = 0.000), neutrophils (p = 0.040), macrophages (p = 0.034), BALF IL-4 levels (p = 0.028), and macrophagic inflammation in the lung tissue (p = 0.037), as well as decreased IgG1 (p = 0.046) and IgG2 (p = 0.043) levels when compared to the HDM group. CONCLUSION: The results indicate more adverse pulmonary effects of DE compared to BD exposure in allergic sensitized animals.

Physical Exercise Induces Immunoregulation of TREG, M2, and pDCs in a Lung Allergic Inflammation Model.

The benefits of moderate aerobic physical exercise for allergic asthma are well-known, particularly that of the anti-inflammatory effect that occurs by reducing Th2 responses and lung remodeling. However, the mechanisms of this immunoregulation are still under investigation. In this study, we investigated the possible immunoregulatory mechanisms of lung inflammation induced by moderate aerobic exercise in an experimental asthma model. BALB/c mice were distributed into Control, Exercise (EX), OVA, and OEX groups. OVA and OEX groups were sensitized with ovalbumin (OVA) on days 0, 14, 21, 28, and 42 and were challenged with OVA aerosol three times a week from days 21 to 51. The EX and OEX groups underwent moderate aerobic physical exercise from days 21 to 51 (5 d/w, 1 h/d). The mice were euthanized on day 52. We evaluated pulmonary cytokine production, serum immunoglobulin levels, and the inflammatory cell profile in lung and mediastinal lymph nodes. OVA mice showed increased expression of IL-4, IL-6, IL-10, and TGF-ß and decreased macrophage type 2 (M2) recruitment. Physical exercise did not affect the increased antibody production of IgG2a, IgG1, or IgE induced by OVA. Of note, physical exercise alone markedly increased production of anti-inflammatory cytokines such as IL-10 and TGF-ß. Physical exercise in OVA-mice also increased the recruitment of M2 in the lungs, as well as the influx and activation of regulatory T cells (Tregs) and CD4 and CD8 lymphocytes. In the draining lymph nodes, it was also observed that physical exercise increased the activation of CD4 T cells, regardless of the presence of OVA. Notably, physical exercise decreased common dendritic cells' (cDCs; pro-inflammatory) expression of co-stimulatory molecules such as CD80, CD86, and ICOSL in the draining lymph nodes, as well as increased ICOSL in plasmacytoid dendritic cells (pDCs; anti-inflammatory). Together, these findings show that physical exercise modulates pulmonary allergic inflammation by increasing Treg and M2 recruitment, as well as pDCs activation, which leads to an increase in anti-inflammatory cytokines and a decrease in pro-inflammatory cells and mediators.

iNOS Inhibition Reduces Lung Mechanical Alterations and Remodeling Induced by Particulate Matter in Mice.

Background. The epidemiologic association between pulmonary exposure to ambient particulate matter (PM) and acute lung damage is well known. However, the mechanism involved in the effects of repeated exposures of PM in the lung injury is poorly documented. This study tested the hypotheses that chronic nasal instillation of residual oil fly ash (ROFA) induced not only distal lung and airway inflammation but also remodeling. In addition, we evaluated the effects of inducible nitric oxide inhibition in these responses. For this purpose, airway and lung parenchyma were evaluated by quantitative analysis of collagen and elastic fibers, immunohistochemistry for macrophages, neutrophils, inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), and alveolar septa 8-iso prostaglandin F2α (8-iso-PGF-2α) detection. Anesthetized in vivo (airway resistance, elastance, H, G, and Raw) respiratory mechanics were also analyzed. C57BL6 mice received daily 60ul of ROFA (intranasal) for five (ROFA-5d) or fifteen days (ROFA-15d). Controls have received saline (SAL). Part of the animals has received 1400W (SAL+1400W and ROFA-15d+1400W), an iNOS inhibitor, for four days before the end of the protocol. A marked neutrophil and macrophage infiltration and an increase in the iNOS, nNOS, and 8-iso-PGF2 α expression was observed in peribronchiolar and alveolar wall both in ROFA-5d and in ROFA-15d groups. There was an increment of the collagen and elastic fibers in alveolar and airway walls in ROFA-15d group. The iNOS inhibition reduced all alterations induced by ROFA, except for the 8-iso-PGF2 α expression. In conclusion, repeated particulate matter exposures induce extracellular matrix remodeling of airway and alveolar walls, which could contribute to the pulmonary mechanical changes observed. The mechanism involved is, at least, dependent on the inducible nitric oxide activation.

A plant proteinase inhibitor from Enterolobium contortisiliquum attenuates airway hyperresponsiveness, inflammation and remodeling in a mouse model of asthma.

INTRODUCTION: Proteinase inhibitors have been associated with anti-inflammatory and antioxidant activities and may represent a potential therapeutic treatment for asthma. PURPOSE: The aim of the present study was to evaluate the effects of Enterolobium contortisiliquum trypsin inhibitor (EcTI) on pulmonary mechanical function, eosinophilic recruitment, inflammatory cytokines, remodeling and oxidative stress in an experimental model of chronic allergic pulmonary inflammation. METHODS: BALB/c mice were divided into 4 groups: C (saline i.p and inhalations with saline), OVA (ovalbumin i.p and inhalations with ovalbumin); C+EC (saline i.p, inhalations with s aline and treatment with EcTI); OVA+EC (ovalbumin i.p, inhalations with ovalbumin and treatment with EcTI). On day 29, we performed the following tests: resistance (Rrs) and elastance (Ers) of the respiratory system; (b) quantify eosinophils, 8-ISO-PGF2α, collagen and elastic fiber volume fractions; (c) IFN-γ, IL-4, IL-5, IL-13, MMP-9, TIMP-1, TGF-ß, iNOS and p65-NFκB-positive cells in the airway and alveolar walls. RESULTS: In OVA+EC group, there was an attenuation of the Rrs and Ers, reduction of eosinophils, IL-4, IL-5, IL-13, IFN-γ, iNOS and p65-NFκB-positive cells compared to OVA group. The 8-ISO-PGF2α, elastic and collagen fibers volume fractions as well as the positive cells for MMP-9, TIMP-1 and TGF-ß positive cells were decreased in OVA+EC compared to the OVA group. CONCLUSION: EcTI attenuates bronchial hyperresponsiveness, inflammation, remodeling and oxidative stress activation in this experimental mouse model of asthma.

Author Correction: Low dose of chlorine exposure exacerbates nasal and pulmonary allergic inflammation in mice.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Gender differences in the perception of quality of life during internal medicine training: a qualitative and quantitative analysis.

BACKGROUND: The higher level of participation by women in medicine may impact this profession's evolution due to gender differences perceived during medical school, after graduation and during residency. Gender differences regarding quality of life are associated with higher states of anxiety and depression among female physicians. We aimed to assess gender differences in the perception of quality of life with quantitative methods and to understand further, from the female residents´ point of view, the reasons that may influence the perception of quality of life using qualitative method. Resilience, empathy and daytime sleepiness were also scored. METHODS: We performed a cross-sectional study with first-year internal medicine residents to evaluate self-reported quality of life factors specific to medical residents (VERAS-Q), including empathy (Jefferson Scale of Empathy), resilience (Wagnild and Young Brief Resilience Scale) and daytime sleepiness (Epworth Scale). We explored, from the female residents´ view which factors may influence the perception of quality of life using a focus group method. RESULTS: In our study, one hundred and nine residents completed the survey: 31 (28.4%) were female and 78 (71.6%) were male. Female residents exhibited significantly lower scores than those of male residents for quality of life in the domains of time management (30.3, females vs 41.1, males; p < 0.001), psychology (48.1, females vs 56.7, males; p < 0.01) and physical health (42.8, females vs 53.6, males; p < 0.05). Female residents also scored higher for daytime sleepiness (13.0, females vs 9.0, males; p < 0.001), with pathological scores for daytime sleepiness. No significant gender differences were found in the resilience or empathy scores. The focus group assessment revealed difficulty in concentration and knowledge acquisition, insecurity, feelings of loss, greater critical perception, self-doubt and difficulty in creating effective bonds to support the training period as the main factors involved in the lower perception of quality of life among the women. CONCLUSIONS: In conclusion, female residents had lower scores for quality of life and higher scores for daytime sleepiness. Measures to improve quality of life among female residents during this critical period of medical training might include investing in mentoring to help them better manage their time and encouraging activities that facilitate relationship development.

The Plant Proteinase Inhibitor CrataBL Plays a Role in Controlling Asthma Response in Mice.

Background. CrataBL is a protein isolated from Crataeva tapia bark. It has been shown to exhibit several biological properties, including anti-inflammatory, analgesic, antitumor, and insecticidal activities. There are no studies evaluating the role of CrataBL in experimental asthma models. Aim. To evaluate the effects of CrataBL on lung mechanics, inflammation, remodeling, and oxidative stress activation of mice with allergic pulmonary inflammation. Materials and Methods. BALB/c mice (6-7 weeks old, 25-30g) were divided into four groups: nonsensitized and nontreated mice (C group, n=8); ovalbumin- (OVA-) sensitized and nontreated mice (OVA group, n=8); nonsensitized and CrataBL-treated mice (C+CR group, n=8); OVA-sensitized and CrataBL-treated mice (OVA+CR group, n=8). We evaluated hyperresponsiveness to methacholine, bronchoalveolar lavage fluid (BALF), pulmonary inflammation, extracellular matrix remodeling, and oxidative stress markers. Results. CrataBL treatment in OVA-sensitized mice (OVA+CR group) attenuated the following variables compared to OVA-sensitized mice without treatment (OVA group) (all p<0.05): (1) respiratory system resistance (Rrs) and elastance (Ers) after methacholine challenge; (2) total cells, macrophages, polymorphonuclear cells, and lymphocytes in BALF; (3) eosinophils and volume fraction of collagen and elastic fibers in the airway and alveolar wall according to histopathological and morphometry analysis; (4) IL-4-, IL-5-, IL-13-, IL-17-, IFN-γ-, MMP-9-, TIMP-1-, TGF-ß-, iNOS-, and NF-kB-positive cells and volume of 8-iso-PGF2α in airway and alveolar septa according to immunohistochemistry; and (5) IL-4, IL-5, and IFN-γ according to an ELISA. Conclusion. CrataBL contributes to the control of hyperresponsiveness, pulmonary inflammation, extracellular matrix remodeling, and oxidative stress responses in an animal model of chronic allergic pulmonary inflammation.

Low dose of chlorine exposure exacerbates nasal and pulmonary allergic inflammation in mice.

Work-exacerbated asthma (WEA) is defined as preexisting asthma that worsens with exposure to irritants [e.g., chlorine (Cl2) derivatives] in the workplace. The maximum allowable concentration in the workplace of Cl2 exposure is 3 mg/ m3 (described in OSHA). We investigated in an experimental asthma model in mice the effects of a single exposure to a sodium hypochlorite dose with this allowed chlorine concentration and a tenfold higher dose. Acute chlorine exposure at 3.3 mg/m3 in the OVA-sensitized group increased eosinophils in the peribronquial infiltrate, cytokine production, nasal mucus production and the number of iNOS positive cells in the distal lung compared to only sensitized mice. The exposure to a higher dose of 33.3 mg/m3 in the OVA-sensitized group resulted in an increase in respiratory system elastance, in the total and differential numbers of inflammatory cells in bronchoalveolar lavage fluid, IL-4, IL-5, and IL-17 in the lungs, eosinophils in peribronquial infiltrate and mucus content in nasal compared to non-exposed and sensitized animals. In this asthma model, chorine exposures at an allowable dose, contributed to the potentiation of Th2 responses. The functional alterations were associated with increased iNOS and ROCK-2 activation in the distal lung.

Aerobic exercise inhibits obesity-induced respiratory phenotype.

PURPOSE: Obesity results in decreased lung function and increased inflammation. Moderate aerobic exercise (AE) reduced lung inflammation and remodeling in a variety of respiratory disease models. Therefore, this study investigated whether AE can attenuate a diet-induced obesity respiratory phenotype; including airway hyper-responsiveness (AHR), remodeling and inflammation. METHODS: Sixty C57Bl/6 male mice were distributed into four groups: control lean (CL), exercise lean (EL), obese (O) and obese exercise (OE) groups (2 sets of 7 and 8 mice per group; n = 15). A classical model of diet-induced obesity (DIO) over 12 weeks was used. AE was performed 60 min/day, 5 days/week for 5 weeks. Airway hyperresponsiveness (AHR), lung inflammation and remodeling, adipokines and cytokines in bronchoalveolar lavage (BAL) was determined. RESULTS: A high fat diet over 18 weeks significantly increased body weight (p < .0001). Five weeks of AE significantly reduced both AHR and pulmonary inflammation. AHR in obese mice that exercised was reduced at the basal level (p < .05), vehicle (PBS) (p < .05), 6.25 MCh mg/mL (p < .05), 12.5 MCh mg/mL (p < .01), 25 MCh mg/mL (p < .01) and 50 MCh mg/mL (p < .05). Collagen (p < .001) and elastic (p < .001) fiber deposition in airway wall and also smooth muscle thickness (p < .001) were reduced. The number of neutrophils (p < .001), macrophages (p < .001) and lymphocytes (p < .01) were reduced in the peribronchial space as well as in the BAL: lymphocytes (p < .01), macrophages (p < .01), neutrophils (p < .001). AE reduced obesity markers leptin (p < .001), IGF-1 (p < .01) and VEGF (p < .001), while increased adiponectin (p < .01) in BAL. AE also reduced pro-inflammatory cytokines in the BAL: IL-1ß (p < .001), IL-12p40 (p < .001), IL-13 (p < .01), IL-17 (p < .001, IL-23 (p < .05) and TNF-alpha (p < .05), and increased anti-inflammatory cytokine IL-10 (p < .05). CONCLUSIONS: Aerobic exercise reduces high fat diet-induced obese lung phenotype (AHR, pulmonary remodeling and inflammation), involving anti-inflammatory cytokine IL-10 and adiponectin.

Animal models of asthma: utility and limitations.

Clinical studies in asthma are not able to clear up all aspects of disease pathophysiology. Animal models have been developed to better understand these mechanisms and to evaluate both safety and efficacy of therapies before starting clinical trials. Several species of animals have been used in experimental models of asthma, such as Drosophila, rats, guinea pigs, cats, dogs, pigs, primates and equines. However, the most common species studied in the last two decades is mice, particularly BALB/c. Animal models of asthma try to mimic the pathophysiology of human disease. They classically include two phases: sensitization and challenge. Sensitization is traditionally performed by intraperitoneal and subcutaneous routes, but intranasal instillation of allergens has been increasingly used because human asthma is induced by inhalation of allergens. Challenges with allergens are performed through aerosol, intranasal or intratracheal instillation. However, few studies have compared different routes of sensitization and challenge. The causative allergen is another important issue in developing a good animal model. Despite being more traditional and leading to intense inflammation, ovalbumin has been replaced by aeroallergens, such as house dust mites, to use the allergens that cause human disease. Finally, researchers should define outcomes to be evaluated, such as serum-specific antibodies, airway hyperresponsiveness, inflammation and remodeling. The present review analyzes the animal models of asthma, assessing differences between species, allergens and routes of allergen administration.

Cigarette Smoke Increases CD8α+ Dendritic Cells in an Ovalbumin-Induced Airway Inflammation.

Asthma is an allergic lung disease and, when associated to cigarette smoke exposition, some patients show controversial signs about lung function and other inflammatory mediators. Epidemiologic and experimental studies have shown both increasing and decreasing inflammation in lungs of subjects with asthma and exposed to cigarette smoke. Therefore, in this study, we analyzed how cigarette smoke affects pro-inflammatory and anti-inflammatory mediators in a murine model of allergic pulmonary inflammation. We sensitized Balb/c mice to ovalbumin (OVA) with two intraperitoneal injections. After sensitization, the animals were exposed to cigarette smoke twice a day, 30 min per exposition, for 12 consecutive days. In order to drive the cell to the lungs, four aerosol challenges were performed every 48 h with the same allergen of sensitization. OVA sensitization and challenge developed pulmonary Th2 characteristic response with increased airway responsiveness, remodeling, increased levels of IgE, interleukin (IL)-4, and IL-13. Cigarette smoke, unexpectedly, reduced the levels of IL-4 and IL-13 and simultaneously decreased anti-inflammatory cytokines as IL-10 and transforming growth factor (TGF)-ß in sensitized and challenged animals. OVA combined with cigarette smoke exposition decreased the number of eosinophils in bronchoalveolar lavage and increased the number of neutrophils in lung. The combination of cigarette smoke and lung allergy increased recruitment of lymphoid dendritic cells (DCs) into lymph nodes, which may be the leading cause to an increase in number and activation of CD8+ T cells in lungs. In addition, lung allergy and cigarette smoke exposure decreased an important regulatory subtype of DC such as plasmacytoid DC as well as its activation by expression of CD86, PDL2, and ICOSL, and it was sufficient to decrease T regs influx and anti-inflammatory cytokines release such as IL-10 and TGF-ß but not enough to diminish the structural changes. In conclusion, we observed, in this model, that OVA sensitization and challenge combined with cigarette smoke exposure leads to mischaracterization of the Th2 response of asthma by decreasing the number of eosinophils, IL-4, and IL-13 and increasing number of neutrophils, which is related to the increased number of CD8ɑ+ DCs and CD8+ T cells as well as reduction of the regulatory cells and its released cytokines.

Vacina de Bordetella pertussis reduz IgE específica, inflamação e remodelamento num modelo animal de alergia respiratória induzida por ácaro / Bordetella pertussis vaccine reduces specific IgE, inflammation, and remodeling in an animal model of respiratory allergy caused by house dust mites

Objetivo: Adjuvantes, como lipopolissacárides bacterianos, vêm sendo estudados para melhorar a eficácia da imunoterapia alérgeno-específica. A vacina de Bordetella pertussis (Pw) mostrou ter papel protetor em modelos de asma induzida por ovalbumina. Porém, seu papel na alergia a ácaros é desconhecido. Avaliamos os efeitos da vacina difteria-tétano-coqueluche (DTPw) em um modelo murino de alergia respiratória induzida por Dermatophagoides pteronyssinus (Derp). Métodos: Num protocolo de 30 dias, camundongos BALB/c foram imunizados por via subcutânea com salina ou Derp, isoladamente ou associados às vacinas de difteria-tétano (DT) ou DTPw (dias 0, 7 e 14). Posteriormente, os animais sofreram desafio intranasal diariamente com salina ou Derp (dias 22 a 28) e foram sacrificados (dia 29). Avaliamos imunoglobulinas séricas específicas, celularidade no lavado bronco-alveolar (BAL), remodelamento das vias aéreas inferiores, densidade de leucócitos polimorfonucleares (PMN) e área de muco ácido no epitélio nasal. Resultados: Os animais sensibilizados com Derp produziram altos níveis de imunoglobulinas específicas, apresentaram aumento da densidade de PMN e da área de muco ácido nasal, elevação da celularidade no BAL e remodelamento. As vacinas levaram à redução dos níveis de IgE, sendo o grupo Derp-DTPw similar aos grupos salina. Os grupos vacinados tiveram redução da celularidade no BAL e do remodelamento, com resultados mais expressivos no grupo Derp-DTPw em relação ao Derp-DT. As vacinas DT e DTPw inibiram o infiltrado PMN nasal e DTPw modulou a produção do muco ácido. Conclusões: A vacina DTPw diminuiu a IgE específica sérica, inflamação nasal e pulmonar e o remodelamento das vias respiratórias inferiores.

Objective: Adjuvant therapies, such as the use of bacterial lipopolysaccharides, have been evaluated as tools to improve the effectiveness of allergen-specific immunotherapy. Bordetella pertussis vaccine (Pw) has been shown to have a protective role in asthma models induced by ovalbumin. Conversely, its role in allergy to dust mites is unknown. We evaluated the effects of diphtheria-tetanus-pertussis vaccine (DTPw) in a murine model of respiratory allergy induced by Dermatophagoides pteronyssinus (Derp). Methods: Over a 30-day protocol, BALB/c mice were immunized subcutaneously with saline or Derp, alone or combined with diphtheria-tetanus vaccine (DT) or DTPw (days 0, 7, and 14). Then, they were subjected to intranasal challenge with saline or Derp daily (days 22 to 28), and sacrificed on day 29. We evaluated serum specific immunoglobulins, bronchoalveolar lavage (BAL) cellularity, lower airway remodeling, density of polymorphonuclear leukocytes (PMN), and acidic mucus area in the nasal epithelium. Results: Animals sensitized to Derp produced high levels of specific immunoglobulins, showed increased PMN density and acidic mucus in the nasal mucosa, and elevated BAL cellularity and remodeling. Vaccines led to the reduction of IgE levels, with the Derp-DTPw group showing similar results to those of the saline groups. Vaccinated groups showed reduced BAL cellularity and airway remodeling, with more expressive results in the Derp-DTPw group compared to Derp-DT. DT and DTPw vaccines inhibited PMN infiltration in nasal mucosa, and DTPw modulated the production of acidic nasal mucus. Conclusions: DTPw vaccine decreased serum specific IgE, nasal and pulmonary inflammation, and lower airway remodeling.

Aerobic Exercise Reduces Asthma Phenotype by Modulation of the Leukotriene Pathway.

INTRODUCTION: Leukotrienes (LTs) play a central role in asthma. Low- to moderate-intensity aerobic exercise (AE) reduces asthmatic inflammation in clinical studies and in experimental models. This study investigated whether AE attenuates LT pathway activation in an ovalbumin (OVA) model of asthma. METHODS: Sixty-four male, BALB/c mice were distributed into Control, Exercise (Exe), OVA, and OVA + Exe groups. Treadmill training was performed at moderate intensity, 5×/week, 1 h/session for 4 weeks. Quantification of bronchoalveolar lavage (BAL) cellularity, leukocytes, airway remodeling, interleukin (IL)-5, IL-13, cysteinyl leukotriene (CysLT), and leukotriene B4 (LTB4) in BAL was performed. In addition, quantitative analyses on peribronchial leukocytes and airway epithelium for LT pathway agents: 5-lypoxygenase (5-LO), LTA4 hydrolase (LTA4H), CysLT1 receptor, CysLT2 receptor, LTC4 synthase, and LTB4 receptor 2 (BLT2) were performed. Airway hyperresponsiveness (AHR) to methacholine (MCh) was assessed via whole body plethysmography. RESULTS: AE decreased eosinophils (p < 0.001), neutrophils (p > 0.001), lymphocytes (p < 0.001), and macrophages (p < 0.01) in BAL, as well as eosinophils (p < 0.01), lymphocytes (p < 0.001), and macrophages (p > 0.001) in airway walls. Collagen (p < 0.01), elastic fibers (p < 0.01), mucus production (p < 0.01), and smooth muscle thickness (p < 0.01), as well as IL-5 (p < 0.01), IL-13 (p < 0.01), CysLT (p < 0.01), and LTB4 (p < 0.01) in BAL were reduced. 5-LO (p < 0.05), LTA4H (p < 0.05), CysLT1 receptor (p < 0.001), CysLT2 receptor (p < 0.001), LTC4 synthase (p < 0.001), and BLT2 (p < 0.01) expression by peribronchial leukocytes and airway epithelium were reduced. Lastly, AHR to MCh 25 mg/mL (p < 0.05) and 50 mg/mL (p < 0.01) was reduced. CONCLUSION: Moderate-intensity AE attenuated asthma phenotype and LT production in both pulmonary leukocytes and airway epithelium of OVA-treated mice.