Disfunções respiratórias felinas: caracterizando e diferenciando a asma e bronquite felinas / Feline respiratory dysfunctions: characterizing and differentiating feline asthma and bronchitis / Disfunciones respiratorias felinas: caracterización y diferenciación del asma y bronquitis felinas

As doenças respiratórias são consideradas doenças graves e potencialmente deletérias. Dentre elas, a asma e a bronquite crônica caracterizam-se como disfunções respiratórias que ameaçam constantemente o bem-estar dos gatos. Os pacientes apresentam mudanças na estrutura respiratória, reversíveis ou não, devido ao extenso quadro inflamatório, que obstrui o fluxo de ar, permite o acúmulo de muco e reduz o lúmen das vias aéreas. Os gatos acometidos apresentam tosses, respiração ruidosa, dispneia, e, em muitos casos, assumem posição ortopneica. O diagnóstico pode ser obtido através de exames de rotina, uso de radiografias torácicas, coleta e análise de fluidos broncoalveolares, e testes alergênicos. O manejo terapêutico baseia-se, combinado ou não, no uso de drogas como broncodilatadores, antiinflamatórios esteroidais, mucolíticos, antibióticos, agentes inalatórios e mudanças ambientais com objetivo de redução da exposição aos possíveis agentes alergênicos responsáveis pela incitação do quadro respiratório.

Respiratory diseases are considered serious and potentially harmful diseases. Among them, asthma and chronic bronchitis are characterized as respiratory disorders that constantly threaten the well-being of cats. The patients present changes in the respiratory structure, reversible or not, due to the extensive inflammatory condition, which obstructs the air flow, allows the accumulation of mucus and reduces the lumen of the airways. Affected cats have coughs, wheezing, dyspnoea, and in many cases assume an orthopneic position. The diagnosis can be obtained through routine exams, use of chest x-rays, collection and analysis of bronchoalveolar fluids, and allergen testing. Therapeutic management is based, combined or not, on the use of drugs such as bronchodilators, steroidal anti-inflammatory, mucolytics, antibiotics, inhalational agents and environmental changes in order to reduce exposure to possible allergenic agents responsible for the incitation of the respiratory condition.

Las enfermedades respiratorias son consideradas enfermedades graves y potencialmente dañinas. Entre ellos, el asma y la bronquitis crónica se caracterizan por ser trastornos respiratorios que amenazan constantemente el bienestar de los gatos. Los pacientes presentan cambios en la estructura respiratoria, reversibles o no debido al cuadro inflamatorio extenso, que obstruye el flujo de aire, permite la acumulación de moco y reduce la luz de las vías respiratorias. Los gatos afectados presentan tos, respiración ruidosa, disnea y, en muchos casos, adoptan una posición ortopneica. El diagnóstico se puede obtener mediante exámenes de rutina, uso de radiografías de tórax, recolección y análisis de líquidos broncoalveolares, y pruebas de alérgenos. El manejo terapéutico se basa, combinado o no, en el uso de fármacos como broncodilatadores, antiinflamatorios esteroides, mucolíticos, antibióticos, agentes inhalatorios y cambios ambientales con el objetivo de reducir la exposición a posibles agentes alergénicos responsables de incitar la afección respiratoria.

Role of SYVN1 in the control of airway remodeling in asthma protection by promoting SIRT2 ubiquitination and degradation.

BACKGROUND: Asthma is a heterogenous disease that characterized by airway remodeling. SYVN1 (Synoviolin 1) acts as an E3 ligase to mediate the suppression of endoplasmic reticulum (ER) stress through ubiquitination and degradation. However, the role of SYVN1 in the pathogenesis of asthma is unclear. RESULTS: In the present study, an ovalbumin (OVA)-induced murine model was used to evaluate the effect of SYVN1 on asthma. An increase in SYVN1 expression was observed in the lungs of mice after OVA induction. Overexpression of SYVN1 attenuated airway inflammation, goblet cell hyperplasia and collagen deposition induced by OVA. The increased ER stress-related proteins and altered epithelial-mesenchymal transition (EMT) markers were also inhibited by SYVN1 in vivo. Next, TGF-ß1-induced bronchial epithelial cells (BEAS-2B) were used to induce EMT process in vitro. Results showed that TGF-ß1 stimulation downregulated the expression of SYVN1, and SYVN1 overexpression prevented ER stress response and EMT process in TGF-ß1-induced cells. In addition, we identified that SYVN1 bound to SIRT2 and promoted its ubiquitination and degradation. SIRT2 overexpression abrogated the protection of SYVN1 on ER stress and EMT in vitro. CONCLUSIONS: These data suggest that SYVN1 suppresses ER stress through the ubiquitination and degradation of SIRT2 to block EMT process, thereby protecting against airway remodeling in asthma.

IL-22 Is Deleterious along with IL-17 in Allergic Asthma but Is Not Detrimental in the Comorbidity Asthma and Acute Pneumonia.

There is evidence that IL-22 and IL-17 participate in the pathogenesis of allergic asthma. To investigate the role of IL-22, we used IL-22 deficient mice (IL-22 KO) sensitized and challenged with ovalbumin (OVA) and compared with wild type (WT) animals exposed to OVA. IL-22 KO animals exposed to OVA showed a decreased number and frequency of eosinophils, IL-5 and IL-13 in the airways, reduced mucus production and pulmonary inflammation. In addition, IL-22 KO animals exhibited a decreased percentage and number of lung CD11c+CD11b+ cells and increased apoptosis of eosinophils. Th17 cell transfer generated from IL-22 KO to animals previously sensitized and challenged with OVA caused a reduction in eosinophil frequency and number in the airways compared to animals transferred with Th17 cells generated from WT mice. Therefore, IL-22 is deleterious with concomitant secretion of IL-17. Our findings show a pro-inflammatory role for IL-22, confirmed in a model of allergen-free and allergen-specific immunotherapy. Moreover, during the comorbidity asthma and pneumonia that induces neutrophil inflammation, IL-22 was not detrimental. Our results show that targeting IL-22 would negatively affect the survival of eosinophils, reduce the expansion or migration of CD11c+CD11b+ cells, and negatively regulate allergic asthma.

Effects of Acylhydrazone Derivatives on Experimental Pulmonary Inflammation by Chemical Sensitization.

BACKGROUND: Chronic lung diseases are characterized by airway inflammation and remodelling of the lung parenchyma that triggers considerable impairment of respiratory function. OBJECTIVE: In this study, two compounds belonging to the N-acylhydrazone class were evaluated, aiming to identify new therapeutic agents for pulmonary inflammatory diseases. MATERIALS AND METHODS: The acute toxicity of 2-cyano-N'-(3-ethoxy-4-hydroxybenzylidene)- acetohydrazide (JR-12) and N'-benzylidene-2-cyano-3-phenylacrylohydrazide (JR09-Bz) was evaluated. Afterwards, they were tested in models of ovalbumin (OVA)-induced allergic asthma and pleurisy, bleomycin-induced pulmonary fibrosis, in addition to mucolytic activity. RESULTS AND DISCUSSION: The compounds did not show toxicity at the dose of 2,000 mg/kg, and no animal died. On OVA-induced pleurisy, animals treated with JR-12 or JR09-Bz at a dose of 10 mg/kg (orally) showed significant inhibition of the leukocyte infiltrate in the bronchoalveolar lavage by 62.5% and 61.5%, respectively, compared to the control group. The compounds JR-12 and JR09-Bz were also active in blocking the allergic asthmatic response triggered by OVA, reducing the leukocyte infiltrate by 73.1% and 69.8%, respectively. Histopathological changes and mast cell migration in treated animals with JR-12 or JR09-Bz were similar to treatment with the reference drugs dexamethasone and montelukast. JR-12 and JR09-Bz also reversed airway remodeling in animals on the bleomycin-induced fibrosis model compared to the control group. Furthermore, it was observed that N-arylhydrazone derivatives showed expectorant and mucolytic activities, increasing mucus secretion by 45.6% and 63.8% for JR-12 and JR09-Bz, respectively. CONCLUSION: Together, the results show that JR-12 and JR09-Bz showed promising activity against airway inflammation, as well as low toxicity.

KCa3.1 differentially regulates trachea and bronchi epithelial gene expression in a chronic-asthma mouse model.

Ion channels are potentially exploitable as pharmacological targets to treat asthma. This study evaluated the role of KCa3.1 channels, encoded by Kcnn4, in regulating the gene expression of mouse airway epithelium and the development of asthma traits. We used the ovalbumin (OVA) challenge as an asthma model in wild-type and Kcnn4-/- mice, performed histological analysis, and measured serum IgE to evaluate asthma traits. We analyzed gene expression of isolated epithelial cells of trachea or bronchi using mRNA sequencing and gene ontology and performed Ussing chamber experiments in mouse trachea to evaluate anion secretion. Gene expression of epithelial cells from mouse airways differed between trachea and bronchi, indicating regional differences in the inflammatory and transepithelial transport properties of proximal and distal airways. We found that Kcnn4 silencing reduced mast cell numbers, mucus, and collagen in the airways, and reduced the amount of epithelial anion secretion in the OVA-challenged animals. In addition, gene expression was differentially modified in the trachea and bronchi, with Kcnn4 genetic silencing significantly altering the expression of genes involved in the TNF pathway, supporting the potential of KCa3.1 as a therapeutic target for asthma.

Functional and morphologic dysfunctions in the airways of rats submitted to an experimental model of obesity-exacerbated asthma.

The obesity-exacerbated asthma phenotype is characterized by more severe asthma symptoms and glucocorticoid resistance. The aim of this study was to standardize an obesity-exacerbated asthma model by a high glycemic level index (HGLI) diet and ovalbumin (OVA) sensitization and challenges in Wistar rats. Animals were divided into groups: control (Ctrl), obese (Ob), asthmatic (Asth), obese asthmatic (Ob + Asth) and obese asthmatic treated with dexamethasone (Ob + Asth + Dexa), and in vivo and in vitro functional and morphological parameters were measured. After HGLI consumption, there was an increase in body weight, fasting blood glucose, abdominal circumferences, body mass index and adiposity index. Respiratory function showed a reduction in pulmonary tidal volume and ventilation. In isolated tracheas, carbachol showed an increase in contractile efficacy in the Ob, Ob + Asth and Ob + Asth + Dexa, but mostly on Ob + Asth. Histological analysis of lungs showed peribronchovascular inflammation and smooth muscle hypertrophy and extracellular remodeling on Ob + Asth and Ob + Asth + Dexa. An obesity-exacerbated asthma model was successfully established. Therefore, this model allows further molecular investigations and the search for new therapies for the treatment and relief of symptoms of patients with obesity-induced resistant asthma.

Contribution of Kazal-Like Domains of the Serine Protease Inhibitor-1 from Toxoplasma gondii in Asthma Therapeutic Vaccination Effectiveness.

BACKGROUND: We have previously showed rTgPI-1 tolerogenic adjuvant properties in asthma treatment, turning it a promising candidate for allergen-specific immunotherapy. This therapy is an alternative treatment to control asthma that still presents several concerns related to its formulation. rTgPI-1 contains independent inhibitory domains able to inhibit trypsin and neutrophil elastase, both involved in asthma pathology. OBJECTIVES: In view of the need to design rational therapies, herein we investigated the contribution of the different inhibitory domains in rTgPI-1 therapeutic effectiveness. METHODS: BALB/c mice were rendered allergic by intraperitoneal OVA-alum sensitization and airway challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with OVA combined with the full-length recombinant protein rTgPI-1 or its truncated versions, Nt (containing trypsin-inhibitory domains) or Ct (containing neutrophil elastase-inhibitory domains). Afterward, mice were aerosol re-challenged. RESULTS: Asthmatic mice treated with the neutrophil elastase- or the trypsin-inhibitory domains separately failed to improve allergic lung inflammation. Only when all inhibitory domains were simultaneously administered, an improvement was achieved. Still, a better outcome was obtained when mice were treated with the full-length rTgPI-1. CONCLUSIONS: Adjuvant ability depends on the presence of all its inhibitory domains in a single entity, so it should be included in potential asthma treatment formulations as a full-length protein.

Protective effects of Surfacen® in allergen-induced asthma mice model.

Airway obstruction with increased airway resistance in asthma, commonly caused by smooth muscle constriction, mucosal edema and fluid secretion into the airway lumen, may partly be due to a poor function of pulmonary surfactant. Surfacen®, a clinical pulmonary surfactant, has anti-inflammatory action, but its effect on asthma has not been studied. This work aimed to evaluate the effect of Surfacen® in a murine allergen-induced acute asthma model, using house dust mite allergens. In a therapeutic experimental setting, mice were first sensitized by being administered with two doses (sc) of Dermatophagoides siboney allergen in aluminum hydroxide followed by one intranasal administration of the allergen. Then, sensitized mice were administered with aerosol of hypertonic 3% NaCl, Salbutamol 0.15 mg/kg, or Surfacen® 16 mg in a whole-body chamber on days 22, 23, and 24. Further, mice were subjected to aerosol allergen challenge on day 25. Surfacen® showed bronchial dilation and inhibition of Th2 inflammation (lower levels of IL-5 and IL-13 in broncoalveolar lavage) which increased IFN-γ and unchanged IL-10 in BAL. Moreover, Sufacen® administration was associated with a marked inhibition of the serum specific IgE burst upon allergen exposure, as well as, IgG2a antibody increase, suggesting potential anti-allergy effects with inclination towards Th1. These results support also the effectiveness of the aerosol administration method to deliver the drug into lungs. Surfacen® induced a favorable pharmacological effect, with a bronchodilator outcome comparable to Salbutamol, consistent with its action as a lung surfactant, and with an advantageous anti-inflammatory and anti-allergic immunomodulatory effect.

Beyond eosinophilia: inflammatory patterns in patients with asthma.

Background: Recently, inflammatory cell ratios have gained importance as useful indicators in the categorization of asthma.Objective: We compared the concentration of white blood cells in peripheral blood, as well as their respective inflammatory cell ratios, between patients with asthma and a healthy control group.Methods: We performed cross-sectional analyses of the data obtained from 53 adult patients with asthma and 109 adult controls. In our study, we estimated and compared the following inflammatory cell ratios: Neutrophil-Lymphocyte Ratio (NLR), Eosinophil-Lymphocyte Ratio (ELR), Eosinophil-Neutrophil Ratio (ENR), Eosinophil-Monocyte Ratio (EMR), and Platelet-Lymphocyte Ratio (PLR). The magnitude of association was quantified with the odds ratio.Results: In both groups, the average age was 33 years. In asthmatic patients, we obtained the following results: eosinophils ≥ 400 cells/µl, accounted for 37.7%; basophils ≥ 110 cells/µl, comprised 37.7%; and monocytes < 320 cells/µl, reached 11.3%. In the control group, the results were as follows: 4.6%, 9.2% and 0.9%, respectively. When compared to the control group, asthmatic patients had higher odds of eosinophils ≥ 400 cells/µl (OR = 12.61, p < 0.0001); higher odds of basophils ≥ 110 cells/µl (OR = 6.00, p < 0.0001); and increased odds of monocytes < 320 cells/µl (OR = 13.79, p = 0.017). NLR did not differ between our two groups; however, ELR, ENR, EMR and PLR were significantly higher in the asthma group.Conclusions: Overall, patients with asthma have a higher concentration of eosinophils and basophils, fewer monocytes in their blood, and higher ratios of increased chronic inflammation.

Translation, cross-cultural adaptation and psychometric evaluation of the Brazilian version of the Cystic Fibrosis Knowledge Scale (CFKS).

BACKGROUND: Information on the level of knowledge about cystic fibrosis (CF) among affected people and their families is still scarce. OBJECTIVE: This study aimed to translate, cross-culturally adapt and analyze the psychometric properties of the Brazilian version of Cystic Fibrosis Knowledge Scale (CFKS). MATERIALS AND METHODS: The translation and cross-cultural adaptation involved the stages of translation, synthesis of translations, reverse translation, synthesis of reverse translations, review by a multi-professional committee of experts and pre-testing. The reliability, viability, construct, predictive, concurrent and discriminant validity were investigated. RESULTS: The sample consisted of 40 individuals with cystic CF, 47 individuals with asthma, 242 healthcare workers and 81 students from the health area. The Brazilian version of the CFKS presented high internal consistency (α = 0.91), moderate floor and ceiling effects, without differences in the test-retest scores. An analysis of factorial exploration identified three dimensions. Confirmatory factor analysis led to an acceptable data-model fit. There was good predictive validity, with a difference in the scores among all the evaluated groups (p <0.001), as well as good discriminant validity since individuals with asthma had greater knowledge of asthma compared to CF (r = 0.401, p = 0.005; r2 = 0.162). However, there was no difference between the diagnosis time and knowledge about CF (r = -0.25, p = 0.11; r2 = 0.06), either between treatment adherence and knowledge about CF (r = -0.04, p = 0.77; r2 = 0.002). CONCLUSION: The Brazilian version of the CFKS indicated that the scale is able to provide valid, reliable and reproducible measures for evaluating the knowledge about CF.

Blocking ATP-releasing channels prevents high extracellular ATP levels and airway hyperreactivity in an asthmatic mouse model.

Allergic asthma is a chronic airway inflammatory response to different triggers like inhaled allergens. Excessive ATP in fluids from patients with asthma is considered an inflammatory signal and an important autocrine/paracrine modulator of airway physiology. Here, we investigated the deleterious effect of increased extracellular ATP (eATP) concentration on the mucociliary clearance (MCC) effectiveness and determined the role of ATP releasing channels during airway inflammation in an ovalbumin (OVA)-sensitized mouse model. Our allergic mouse model exhibited high levels of eATP measured in the tracheal fluid with a luciferin-luciferase assay and reduced MCC velocity determined by microspheres tracking in the trachea ex vivo. Addition of ATP had a dual effect on MCC, where lower ATP concentration (µM) increased microspheres velocity, whereas higher concentration (mM) transiently stopped microspheres movement. Also, an augmented ethidium bromide uptake by the allergic tracheal airway epithelium suggests an increase in ATP release channel functionality during inflammatory conditions. The use of carbenoxolone, a nonspecific inhibitor of connexin and pannexin1 channels reduced the eATP concentration in the allergic mouse tracheal fluid and dye uptake by the airway epithelium, providing evidence that these ATP release channels are facilitating the net flux of ATP to the lumen during airway inflammation. However, only the specific inhibition of pannexin1 with 10Panx peptide significantly reduced eATP in bronchoalveolar lavage and decreased airway hyperresponsiveness in OVA-allergic mouse model. These data provide evidence that blocking eATP may be a pharmacological alternative to be explored in rescue therapy during episodes of airflow restriction in patients with asthma.

Testosterone-to-estradiol ratio and lung function in a prospective study of Puerto Rican youth.

BACKGROUND: Age- and sex-related differences in asthma may be due to changes in sex hormone levels. OBJECTIVE: To evaluate whether a change in free testosterone or free testosterone-to-estradiol ratio is associated with changes in lung function and eosinophils in the Puerto Rican youth. METHODS: We tested for the association between the change in sex hormone levels and change in lung function or change in eosinophils in a prospective study of 317 children (with and without asthma) followed up from ages 6 to 14 years to ages 10 to 20 years (146 females, 171 males) in San Juan, Puerto Rico. Serum levels of testosterone, estradiol, sex hormone-binding globulin, and progesterone were measured at 2 study visits, approximately 4.9 years apart. Using testosterone and sex hormone-binding globulin levels, we derived free testosterone and the free testosterone-to-estradiol ratio. Multivariable linear regression was used for the analysis of change in lung function and eosinophils, conducted separately by sex. RESULTS: In girls, each quartile increment in the free testosterone-to-estradiol ratio was associated with a 2.03% increment in percent predicted forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) between study visits. In males, each quartile increment in the free testosterone-to-estradiol ratio was associated with a 3.27% increment in percent predicted FEV1 and a 1.81% increment in percent predicted FEV1/FVC between study visits. In girls with asthma, an increased free testosterone-to-estradiol ratio was significantly associated with decreased eosinophils between visits (P=0.03). CONCLUSION: In Puerto Rican youth, increased free testosterone-to-estradiol ratio over time was associated with an increased FEV1/FVC in both sexes, and with an increased FEV1 in males.

Uncovering the Role of Oxidative Imbalance in the Development and Progression of Bronchial Asthma.

Asthma is a chronic inflammatory disease of the airways related to epithelial damage, bronchial hyperresponsiveness to contractile agents, tissue remodeling, and luminal narrowing. Currently, there are many data about the pathophysiology of asthma; however, a new aspect has emerged related to the influence of reactive oxygen and nitrogen species (ROS and RNS) on the origin of this disease. Several studies have shown that an imbalance between the production of ROS and RNS and the antioxidant enzymatic and nonenzymatic systems plays an important role in the pathogenesis of this disease. Considering this aspect, this study is aimed at gathering data from the scientific literature on the role of oxidative distress in the development of inflammatory airway and lung diseases, especially bronchial asthma. For that, articles related to these themes were selected from scientific databases, including human and animal studies. The main findings of this work showed that the respiratory system works as a highly propitious place for the formation of ROS and RNS, especially superoxide anion, hydrogen peroxide, and peroxynitrite, and the epithelial damage is reflected in an important loss of antioxidant defenses that, in turn, culminates in an imbalance and formation of inflammatory and contractile mediators, such as isoprostanes, changes in the activity of protein kinases, and activation of cell proliferation signalling pathways, such as the MAP kinase pathway. Thus, the oxidative imbalance appears as a promising path for future investigations as a therapeutic target for the treatment of asthmatic patients, especially those resistant to currently available therapies.

The impact of maternal periodontitis in the development of asthma in the offspring.

Clinical and experimental studies show an association between maternal periodontitis and adverse outcomes during gestation. On the other hand, there were no studies evaluating the impact of maternal periodontitis on the offspring. Thus, our objective was to investigate the repercussion of maternal periodontitis on the development of asthma in the offspring. Pregnant rats were submitted or not to periodontitis by ligature technique. Thirty days after birth, the puppies were sensitized and challenged with ovalbumin (OVA) in order to induce asthmatic response. Our results showed that maternal periodontitis reduced cellular infiltrate in the parenchyma of offspring, tracheal responsiveness, lung edema, and anti-OVA antibodies, without alter mucus as well as cytokines production. We concluded that periodontitis has relevant impact on the offspring's immune system, blunting the response to allergic and inflammatory stimulus. This study shows the important role of oral health during pregnancy and opens possibilities for future studies in order to explain the effects of periodontitis during pregnancy in the offspring.

Low-dose chlorine exposure impairs lung function, inflammation and oxidative stress in mice.

AIM: To explore the different consequences of acute and chronic exposure to chlorine gas (Cl2) on the functional and histological parameters of health mice. MAIN METHODS: Firstly, male BALB/c mice were acute exposed to 3.3 or 33.3 or 70.5 mg/m3 Cl2. We analyzed the lung function, the inflammatory cells in the bronchoalveolar lavage, cell influx in the peribrochoalveolar space and mucus production. In a second phase, mice were chronic exposed to 70.5 mg/m3 Cl2. Besides the first phase analyses, we also evaluated the epithelial cells thickness, collagen deposition in the airways, immunohistochemistry stain for IL-1ß, iNOS, IL-17 and ROCK-2 and the levels of IL-5, IL-13, IL-17, IL-1ß and TNF-α in lung homogenate. KEY FINDINGS: Acute exposure to chlorine impaired the lung function, increased the number of inflammatory cells in the BALF and in the airways, also increased the mucus production. Furthermore, when chlorine was exposed chronically, increased the airway remodeling with collagen deposition and epithelial cells thickness, positive cells for IL-1ß, iNOS, IL-17 in the airways and in the alveolar walls and ROCK-2 in the alveolar walls, lung inflammation with increased levels of IL-5, IL-13, IL-1ß and TNF-α in the lung homogenate, and also, induced the acid mucus production by the nasal epithelium. SIGNIFICANCE: Acute and chronic exposure to low dose of chlorine gas worsens lung function, induces oxidative stress activation and mucus production and contributes to augmenting inflammation in health mice.

Lactococcus lactis NZ9000 Prevents Asthmatic Airway Inflammation and Remodelling in Rats through the Improvement of Intestinal Barrier Function and Systemic TGF-ß Production.

INTRODUCTION: The use of probiotics has been broadly popularized due to positive effects in the attenuation of aberrant immune responses such as asthma. Allergic asthma is a chronic respiratory disease characterized by airway inflammation and remodelling. OBJECTIVE: This study was aimed to evaluate the effect of oral administration of Lactococcus lactis NZ9000 on asthmatic airway inflammation and lung tissue remodelling in rats and its relation to the maintenance of an adequate intestinal barrier. METHODS: Wistar rats were ovalbumin (OVA) sensitized and challenged and orally treated with L. lactis. Lung inflammatory infiltrates and cytokines were measured, and remodelling was evaluated. Serum OVA-specific immunoglobulin (Ig) E levels were assessed. We also evaluated changes on intestinal environment and on systemic immune response. RESULTS: L. lactis diminished the infiltration of proinflammatory leucocytes, mainly eosinophils, in the bronchoalveolar compartment, decreased lung IL-4 and IL-5 expression, and reduced the level of serum allergen-specific IgE. Furthermore, L. lactis prevented eosinophil influx, collagen deposition, and goblet cell hyperplasia in lung tissue. In the intestine, L. lactis-treated asthmatic rats increased Peyer's patch and goblet cell quantity and mRNA expression of IgA, MUC-2, and claudin. Additionally, intestinal morphological alterations were normalized by L. lactis administration. Splenocyte proliferative response to OVA was abolished, and serum levels of transforming growth factor (TGF)-ß were increased by L. lactis treatment. CONCLUSIONS: These findings suggest that L. lactis is a potential candidate for asthma prevention, and the effect is mediated by the improvement of intestinal barrier function and systemic TGF-ß production.

4-Carvomenthenol ameliorates the murine combined allergic rhinitis and asthma syndrome by inhibiting IL-13 and mucus production via p38MAPK/NF-κB signaling pathway axis.

The aim of this study was to analyze the 4-carvomenthenol (carvo) oral treatment on the experimental model of the combined allergic rhinitis and asthma syndrome (CARAS). BALB/c mice were OVA-sensitized on day zero and 7th (50 µg/mL OVA in 10 mg/mL Al (OH)3) and OVA-challenged (5 mg/mL, 20 µL/animal) for three weeks. In the last week, the animals were dally challenged with aerosol of OVA and the carvo treatment (12.5, 25 or 50 mg/kg) occurred one hour before each OVA-challenge. Data were analyzed and p < 0.05 was considered significant. Carvo (12.5-50 mg/kg) decreased significantly the eosinophil migration into the nasal (NALF) and bronchoalveolar (BALF) cavities as well as on the nasal and lung tissues of sick animals. The treatment also decreased mucus production on both tissue sections stained with PAS (periodic acid-Schiff satin). In addition, the histological analyzes demonstrated that sick mice presented hyperplasia and hypertrophy of the lung smooth muscle layer followed by increasing of extracellular matrix and carvo (50 mg/kg) inhibited these asthmatic parameters. We analyzed the allergic rhinitis signals as nasal frictions and sneezing and observed that carvo decreased these two signals as well as serum OVA-specific IgE titer, type 2 cytokine synthesis, mainly IL-13, with increasing of IL-10 production. Decreasing of IL-13 production corroborated with decreasing of mucus production and these effects were dependent on p38MAPK/NF-κB(p65) signaling pathway inhibition. Therefore, these data demonstrated that a monoterpene of essential oils presents anti-allergic property on an experimental model of CARAS suggesting a new drug prototype to treat this allergic syndrome.

The paradox does not fit all: Racial disparities in asthma among Mexican Americans in the U.S.

Mexican Americans have a lower prevalence of asthma than White Americans, Black Americans, and Other Hispanics. This is concordant with the Hispanic Paradox, which posits that Hispanics have good health and lower mortality than White Americans despite their relative socioeconomic disadvantages. However, the research is limited in relation to the effects of race on health, independent of ethnicity, among this population. In this study, the author disaggregated Mexican Americans, foreign-born and U.S.-born into two categories, White and Black Mexicans, in order to assess their likelihood of having an asthma diagnosis, compared to White Americans and to each other. This study used harmonized data from the National Health Interview Survey from 2000-2018 with a final analytic sample of N = 1,094,516. The analysis was conducted using binary logistic regression, controlling for acculturation and health behavior-related variables, as well as sociodemographic characteristics. In the results, Black Mexicans had a significant disadvantage in relation to their White counterparts and White Americans. The findings suggest there is an intra-ethnic racial disparity in asthma and the Hispanic paradox is not applicable across racial lines for Mexican Americans. These findings also suggest Black Mexicans' poor asthma outcomes are the byproduct of various mechanisms of racial inequality.

The Novel H4R Antagonist 1-[(5-Chloro-2,3-Dihydro-1-Benzofuran-2-Yl)Methyl]-4-Methyl-Piperazine (LINS01007) Attenuates Several Symptoms in Murine Allergic Asthma.

BACKGROUND/AIMS: Histamine is an important chemical transmitter involved in inflammatory processes, including asthma and other chronic inflammatory diseases. Its inflammatory effects involve mainly the histamine H4 receptor (H4R), whose role in several studies has already been demonstrated. Our group have explored the effects of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines as antagonists of H4R, and herein the compounds LINS01005 and LINS01007 were studied with more details, considering the different affinity profile on H4R and the anti-inflammatory potential of both compounds. METHODS: We carried out a more focused evaluation of the modulatory effects of LINS01005 and LINS01007 in a murine asthma model. The compounds were given i.p. (1-7 mg/kg) to ovalbumin sensitized BALB/c male mice (12 weeks old) 30 min before the antigen challenging, and after 24 h the cell analysis from the bronchoalveolar lavage fluid (BALF) was performed. The lung tissue was used for evaluation by western blot (COX-2, 5-LO, NF-κB and STAT3 expressions) and histological analysis. RESULTS: Treatment with the more potent H4R antagonist LINS01007 significantly decreased the total cell count and eosinophils in BALF at lower doses when compared to LINS01005. The expression of COX-2, 5-LO, NF-κB and STAT3 in lung tissue was significantly reduced after treatment with LINS01007. Morphophysiological changes such as mucus and collagen production and airway wall thickening were significantly reduced after treatment with LINS01007. CONCLUSION: These results show important down regulatory effect of novel H4R antagonist (LINS01007) on allergic lung inflammation.

CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice.

Rationale: Increased IL-8 levels and neutrophil accumulation in the airways are common features found in patients affected by pulmonary diseases such as Asthma, Idiopathic Pulmonary Fibrosis, Influenza-A infection and COPD. Chronic neutrophilic inflammation is usually corticosteroid insensitive and may be relevant in the progression of those diseases. Objective: To explore the role of Ladarixin, a dual CXCR1/2 antagonist, in several mouse models of airway inflammation with a significant neutrophilic component. Findings: Ladarixin was able to reduce the acute and chronic neutrophilic influx, also attenuating the Th2 eosinophil-dominated airway inflammation, tissue remodeling and airway hyperresponsiveness. Correspondingly, Ladarixin decreased bleomycin-induced neutrophilic inflammation and collagen deposition, as well as attenuated the corticosteroid resistant Th17 neutrophil-dominated airway inflammation and hyperresponsiveness, restoring corticosteroid sensitivity. Finally, Ladarixin reduced neutrophilic airway inflammation during cigarette smoke-induced corticosteroid resistant exacerbation of Influenza-A infection, improving lung function and mice survival. Conclusion: CXCR1/2 antagonist Ladarixin offers a new strategy for therapeutic treatment of acute and chronic neutrophilic airway inflammation, even in the context of corticosteroid-insensitivity.