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Two major chaperones, calreticulin (CRT) and binding immunoglobulin protein (GRP78/BiP) dependent on their location, have immunoregulatory or anti‐inflammatory functions respectively. CRT induces pro‐inflammatory cytokines, dendritic cell (DC) maturation and activates cytotoxic T cells against tumours. By contrast, GRP78/BiP induces anti‐inflammatory cytokines, inhibits DC maturation and heightens T‐regulatory cell responses. These latter functions rebalance immune homeostasis in inflammatory diseases, such as rheumatoid arthritis. Both chaperones are therapeutically relevant agents acting primarily on monocytes/DCs. Endogenous exposure of CRT on cancer cell surfaces acts as an 'eat‐me' signal and facilitates improved elimination of stressed and dying tumour cells by DCs. Therefore, therapeutics that promote endogenous CRT translocation to the cell surface can improve the removal of cancer cells. However, infused recombinant CRT dampens this cancer cell eradication by binding directly to the DCs. Low levels of endogenous BiP appear as a surface biomarker of endoplasmic reticulum (ER) stress in some types of tumour cells, a reflection of cells undergoing proliferation, in which resulting hypoxia and nutrient deprivation perturb ER homeostasis triggering the unfolded protein response, leading to increased expression of GRP78/BiP and altered cellular location. Conversely, infusion of an analogue of GRP78/BiP (IRL201805) can lead to long‐term immune resetting and restoration of immune homeostasis. The therapeutic potential of both chaperones relies on them being relocated from their intracellular ER environment. Ongoing clinical trials are employing therapeutic interventions to either enhance endogenous cell surface CRT or infuse IRL201805, thereby triggering several disease‐relevant immune responses leading to a beneficial clinical outcome. [ABSTRACT FROM AUTHOR]

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Short break trips in urban destinations are clearly increasing, and this fact has implications for destinations linked to the different length of stay segments. Thus, this paper analyses the duration of the stay in relation to motivation, satisfaction, image, repetition and recommendation of leisure tourists in an urban destination. The main contribution of this article is to highlight the differences and similarities between the behaviours of short and long breakers for the constructs mentioned, not developed until now. The theoretical model is validated using a structural equation modelling methodology. The sample size is 10,953 tourists visiting the city of Barcelona, relevant for its increasing tourism appeal. Results confirm that differences and similarities are found for those tourist segments. By way of example it is worth mentioning that the repeat visits have a negative effect on tourists' recommendation, in particular in the case of long break as compared with short break tourists. [ABSTRACT FROM AUTHOR]

Fibrotic lung diseases, such as idiopathic pulmonary fibrosis, are associated with spontaneous dry cough and hypersensitivity to tussive agents. Understanding the pathophysiology driving enhanced cough may help us to define better therapies for patients. We hypothesized that lung fibrosis induced by intratracheal bleomycin would exacerbate the cough reflex induced by tussive agents in guinea pigs. Disease progression in the lungs was characterized at days 1, 7, 14, 21 and 28 after bleomycin administration. Inflammatory and fibrotic markers, as well as neurotrophin levels, were assessed in bronchoalveolar lavage fluid and/or lung tissue. Cough sensitivity to citric acid, capsaicin and allylisothiocyanate was evaluated in conscious animals at days 14 and 21 after bleomycin administration. Pulmonary lesions evolved from an early inflammatory phase (from day 1 to day 7) to a fibrotic stage (between days 14 and 28). Fibrosis was related to increased levels of matrix metalloproteinase-2 in bronchoalveolar lavage fluid (day 21: saline, 0.26 ng/ml; bleomycin, 0.49 ng/ml). At day 14, we also observed increased cough reflexes to citric acid (163%), capsaicin (125%) and allylisothiocyanate (178%). Cough exacerbation persisted, but at a lower extent, by day 21 for capsaicin (100%) and allylisothiocyanate (54%). Moreover, bronchoalveolar lavage fluid concentrations of brain-derived neurotrophic factor, suggested to induce nerve remodelling in chronic cough, were also enhanced (day 1: saline, 14.21 pg/ml; bleomycin, 30.09 pg/ml). In summary, our model of bleomycin-induced cough exacerbation may be a valuable tool to investigate cough hypersensitivity and develop antitussive therapies for fibrotic lung diseases. [ABSTRACT FROM AUTHOR]

An abstract of the article "Strategies to improve lung absorption of intratracheally administered compounds in Drug Discovery," by Elena Calama and colleagues is presented.

An abstract of the article "Poly I:C causes exacerbation in a murine allergic inflammation model driven by house dust mite in Freund's complete adjuvant," by Jorge De Alba and colleagues is presented.

An abstract of the article "Effect of the circadian cycle in Late Asthmatic Response (LAR). Comparison between two allergic asthma models in rats and mice," by R. Otal and colleagues is presented.

Sedimentological and provenance (petrography, whole-rock geochemistry, zircon geochemistry, and ages documented by other authors) analysis carried out in San Felipe Formation and provenance (petrography and zircon geochemistry) analysis established for this unit and the Caracol Formation have allowed inferring the depositional environment for the San Felipe Formation, source area composition, and a possible relationship with the Laramide continental arc system during the Late Cretaceous in Northeast Mexico for both units. San Felipe Formation is constituted by two facies that are characterized by (a) intercalations of shales, tuffaceous sandstones that have Bouma sequence-like structures, ash tuffs and lapilli that develop supercritical and critical flow regime structures (e.g., low-angle parallel lamination), and (b) limestones with mudstone, wackestone, and packstone texture, that show Cruziana and Zoophycos ichnofacies. These features can be interpreted as a mixed ramp system in open sea conditions developed in the foredeep, forebulge, and back-bulge depozones. The San Felipe tuffaceous sandstones are lithic-feldspatho-quartzose to feldspatho-lithic-quartzose rocks (Q 54 F 22 L 24 ; n = 13; mean value), rich in microlithic and lathwork tuffaceous volcanic fragments (Lvf 40 LvMic + Lvlt 15 LvTob 45 ; felsitic volcanic grains-microlithic volcanic fragments + lathwork lithic fragment-tuffaceous fragments), with abundant volcanic glass. Tuffaceous sandstones from the Caracol Formation, a facial variant of the San Felipe unit, are lithic feldspatho-quartzose to feldspatho-lithic-quartzose rocks (Q 46 F 26 L 28 ; n = 12; mean value) rich in felsitic (Lvf 79 LvMic + Lvlt 4 LvTob 17) and plutonic lithics with subordinate metamorphic fragments and abundant volcanic glass. A predominance of felsitic tuffaceous volcanic lithics and plutonic fragments with low weathering degree (CIA = 41 ± 7; PIA = 38 ± 9) in the San Felipe volcaniclastic strata and magmatic zircons with chemistry linked mostly from continental arcs (log of U/Yb and Nb/Yb ratios) in both formations suggest that the volcaniclastic rocks of the San Felipe and the Caracol Formations have an origin related to the Cretaceous-Eocene Mexican Magmatic Arc. After a relatively fast transport, the volcanic tuffs were deposited in the foredeep, forebulge, and back-bulge depocenters distributed in Northeast Mexico. • Tuffaceous sand provence. • Whole-rock geochemistry. • Foredeep sedimentation. • Late Cretaceous Sonora Magmatic Arc Rocks. • Mexican orogen. [ABSTRACT FROM AUTHOR]

In this study, we track the evolution of a clastic shoreline before carbonate deposition takes over. The Late Jurassic to Early Cretaceous La Casita Formation in northeastern Mexico serves as an excellent example for such a shoreline. The work includes a re-interpretation of the tectono-sedimentary environment. The La Casita Formation includes nine facies associations related to river, wave, storm, and tidal processes along a deltaic coastline. Systems influenced by rivers develop more muddy successions with sedimentary structures characteristic of these systems (e.g., normal gradation, parallel lamination, and ripples). In comparison, the systems influenced by waves/storms and tides develop more sandy successions with the development of structures generated by oscillatory flows (ripples and hummocky cross-stratification) and bidirectional ripples and dunes with mud-drapes on their stoss side, respectively. The distribution of sub-environments (e.g., interdistributary bay and shoreface) was controlled by waves and tides. Paleocurrent directions indicate that the coastline was oriented NNW-SSE. The wave- and storm-dominated sedimentary environments contain a large diversity of trace fossils (BI ∼4) related to colonizing organisms in well-oxygenized environments with abundant food, normal salinity, and high temperature. The river- and tide-influenced settings are governed by a low trace fossil diversity (BI ∼2), indicating highly stressful conditions generated by the incursions of hypopycnal plumes. Allocyclic processes were associated with the reactivation of basement faults that controlled the exposure and distribution area of the basement rocks (e.g., the nearby Coahuila block and Tamaulipas Arch). In conclusion, the revision of the environmental evolution of the La Casita Formation has implications for the marine incursion of the Gulf of Mexico and its relationship with the pacific margin and the strike-slip basin development. • Wave governed deltaic coast. • Tidal governed deltaic coast. • Monterrey trough. • Allocyclical process. • Autocyclical process. [ABSTRACT FROM AUTHOR]

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

AZD8871 is a novel muscarinic antagonist and β 2 -adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M 3 receptor (pIC 50 in binding assays: 9.5) and shows kinetic selectivity for the M 3 (half-life: 4.97 hours) over the M 2 receptor (half-life: 0.46 hour). It is selective for the β 2 -adrenoceptor over the β 1 and β 3 subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and β 2 -adrenoceptor functional activity in isolated guinea pig tissue (pIC 50 in electrically stimulated trachea: 8.6; pEC 50 in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2- and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchoconstriction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M 3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

RNA viruses are a major cause of respiratory infections and are known to exacerbate asthma and other respiratory diseases. Our aim was to test the ability of poly(I:C) (polyinosinic:polycytidylic acid), a viral surrogate, to elicit exacerbation in a model of severe asthma driven by HDM (house dust mite) in FCA (Freund's complete adjuvant). Poly(I:C) was administered intranasally around the HDM challenge in FCA-HDM-sensitized animals. Changes in AHR (airway hyperresponsiveness), BALF (bronchoalveolar lavage fluid) inflammatory infiltrate, HDM-specific immunoglobulins and cytokine/chemokine release were evaluated at different points after the challenge. The effect of oral dexamethasone was also assessed. Exacerbation was achieved when poly(I:C) was administered 24 h before the HDM challenge and was characterized by enhanced AHR and an increase in the numbers of neutrophils, macrophages and lymphocytes in the BALF. Th1, Th2 and Th17 cytokines were also elevated at different time points after the challenge. Peribronchial and alveolar inflammation in lung tissue were also augmented. AHR and inflammatory infiltration showed reduced sensitivity to dexamethasone treatment. We have set up a model that mimics key aspects of viral exacerbation in a corticosteroid-refractory asthmatic phenotype which could be used to evaluate new therapies for this condition., (© 2015 Authors; published by Portland Press Limited.)

Abediterol is a novel potent, long-acting inhaled β(2)-adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human β(2)-adrenoceptor and a functional selectivity over β(1)-adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human β(2)-adrenoceptor (E(max) = 91 ± 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC(50) = 1.9 ± 0.4 nM; t½ onset = 7-10 min) is not significantly different from that of formoterol, but its duration of action (t½ ∼ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t½ = 36 h) than salmeterol (t½ = 6 h) and formoterol (t½ = 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile.

The liver X receptors (LXRalpha/beta) are orphan nuclear receptors that are expressed in a large number of cell types and have been shown to have anti-inflammatory properties. Nuclear receptors have previously proved to be amenable targets for small molecular mass pharmacological agents in asthma, and so the effect of an LXR ligand was assessed in models of allergic airway inflammation. LXR agonist, GW 3965, was profiled in rat and mouse models of allergic asthma. In the Brown Norway rats, GW 3965 (3-30 mg/kg) was unable to reduce the bronchoalveolar lavage eosinophilia associated with this model and had no impact on inflammatory biomarkers (eotaxin and IL-1beta). The compound did significantly stimulate ABCA-1 (ATP-binding cassette A1) mRNA expression, indicating that there was adequate exposure/LXR activation. In the mouse model, the LXR ligand surprisingly increased airway reactivity, an effect that was apparent in both the Ag and nonchallenged groups. This increase was not associated with a change in lung tissue inflammation or number of mucus-containing cells. There was, however, a marked increase in airway smooth muscle thickness in both treated groups. We demonstrated an increase in contractile response to exogenous methacholine in isolated airways taken from LXR agonist-treated animals compared with the relevant control tissue. We corroborated these findings in a human system by demonstrating increased proliferation of cultured airway smooth muscle. This phenomenon, if evidenced in man, would indicate that LXR ligands may directly increase airway reactivity, which could be detrimental, especially in patients with existing respiratory disease and with already compromised lung function.

Estrogen receptor (ER) beta agonists have been demonstrated to possess anti-inflammatory properties in inflammatory disease models. The objective of this study was to determine whether ERbeta agonists affect in vitro and in vivo preclinical models of asthma. mRNA expression assays were validated in human and rodent tissue panels. These assays were then used to measure expression in human cells and our characterized rat model of allergic asthma. ERB-041 [7-ethenyl-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol], an ERbeta agonist, was profiled on cytokine release from interleukin-1beta-stimulated human airway smooth muscle (HASM) cells and in the rodent asthma model. Although ERbeta expression was demonstrated at the gene and protein level in HASM cells, the agonist failed to have an impact on the inflammatory response. Similarly, in vivo, we observed temporal modulation of ERbeta expression after antigen challenge. However, the agonist failed to have an impact on the model endpoints such as airway inflammation, even though plasma levels reflected linear compound exposure and was associated with an increase in receptor activation after drug administration. In these modeling systems of airway inflammation, an ERbeta agonist was ineffective. Although ERbeta agonists are anti-inflammatory in certain models, this novel study would suggest that they would not be clinically useful in the treatment of asthma.

Since the discovery of the first matrix metalloproteinase (MMP), this ever-growing family of proteinases has been the subject of intense research. Although it was initially believed that MMPs were solely involved in matrix turnover and degradation, there are now data suggesting MMPs are actively involved in the inflammatory process. In previous studies, we have demonstrated an increase in MMP expression in human cell-based assays and in preclinical rat models of airway inflammation. Therefore, the aim of this study was to characterize the role of MMPs in these models by profiling the impact of a broad-spectrum MMP inhibitor. In lipopolysaccharide (LPS)-stimulated THP-1 cells and primary human lung tissue macrophages, the MMP inhibitor had no significant effect on the release of tumor necrosis factor-alpha, interleukin (IL)-8, IL-1 beta, growth-regulated oncogene-alpha, macrophage inflammatory protein-1 alpha, or IL-6 whereas dexamethasone has a significant impact on all cytokines from both cell types. Similarly, in the more biologically complex LPS-driven rat model of airway inflammation, the MMP inhibitor did not have an impact on mediator release and cellular burden. The compound did, however, significantly reduce levels of lung MMP-9. Furthermore, in a "disease" model, the compound did not affect cellular inflammation but did significantly reduce elastase-induced experimental emphysema. In summary, these data demonstrate for the first time that MMPs do not play a role in the increase in inflammatory mediators or cellular burden observed in these preclinical models. However, they do appear to be involved in the elastase-driven breakdown of airway structure, which is not due to a direct effect of the stimulus.