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Interleukin 23 and the interleukin 23 receptor (IL-23-IL23R) are described as the major enhancing factors for Interleukin 17 (IL-17) in allergic airway inflammation. IL-17 is considered to induce neutrophilic inflammation in the lung, which is often observed in severe, steroid-resistant asthma-phenotypes. For that reason, understanding of IL-23 and IL-17 axis is very important for future therapy strategies, targeting neutrophil pathway of bronchial asthma.This study aimed to investigate the distribution and expression of IL-23R under physiological and inflammatory conditions. Therefore, a house dust mite (HDM) model of allergic airway inflammation was performed by treating mice with HDM intranasally. Immunofluorescence staining with panel of antibodies was performed in lung tissues to examine the macrophage, dendritic cell, and T cell subpopulations. The allergic airway inflammation was quantified by histopathological analysis, ELISA measurements, and airway function.HDM-treated mice exhibited a significant allergic airway inflammation including higher amounts of NE + cells in lung parenchyma. We found only a small amount of IL-23R positives, out of total CD3 + T cells, and no upregulation in HDM-treated animals. In contrast, the populations of F4/80 + macrophages and CD11c + F4/80 - dendritic cells (DCs) with IL-23R expression were found to be higher. But HDM treatment leads to a significant increase of IL-23R + macrophages, only. IL-23R was expressed by every examined macrophage subpopulation, whereas only Mϕ1 and hybrids between Mϕ1 and Mϕ2 phenotype and not Mϕ2 were found to upregulate IL-23R. Co-localization of IL-23R and IL-17 was only observed in F4/80 + macrophages, suggesting F4/80 + macrophages express IL-23R along with IL-17 in lung tissue.The study revealed that macrophages involving the IL-23 and IL-17 pathway may provide a potential interesting therapeutic target in neutrophilic bronchial asthma., (© 2022. The Author(s).)

Background: Titanium dioxide nanoparticles (TiO 2 NPs) have a wide range of applications in several industrial and biomedical domains. Based on the evidence, the workers exposed to inhaled nanosized TiO 2 powder are more susceptible to the risks of developing respiratory diseases. Accordingly, this issue has increasingly attracted the researchers' interest in understanding the consequences of TiO 2 NPs exposure. Regarding this, the present study was conducted to analyze the local effects of TiO 2 NPs on allergic airway inflammation and their uptake in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation., Methods: For the purpose of the study, female BALB/c mice with or without asthma were intranasally administered with TiO 2 NPs. The mice were subjected to histological assessment, lung function testing, scanning electron microscopy (SEM), inductively coupled plasma mass spectrometry (ICP-MS), and NP uptake measurement. In addition, T helper (Th) 1/Th2 cytokines were evaluated in the lung homogenate using the enzyme-linked immunosorbent assay., Results: According to the results, the mice receiving OVA alone or OVA plus TiO 2 NPs showed eosinophilic infiltrates and mucus overproduction in the lung tissues, compared to the controls. Furthermore, a significant elevation was observed in the circulating Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13 after NP exposure. The TiO 2 NPs were taken up by alveolar macrophages at different time points. As the results of the SEM and ICP-MS indicated, TiO 2 NPs were present in most of the organs in both asthmatic and non-asthmatic mice., Conclusion: Based on the findings of the current study, intranasally or inhalation exposure to high-dose nanosized TiO 2 particles appears to exacerbate the allergic airway inflammation and lead to systemic uptake in extrapulmonary organs. These results indicate the very important need to investigate the upper limit of intranasally or inhalation exposure to nanosized TiO 2 particles in occupational and environmental health policy.

Clinical experience has shown that allergic and non-allergic respiratory, metabolic, mental, and cardiovascular disorders sometimes coexist with bronchial asthma. However, no study has been carried out that calculates the chance of manifestation of these disorders with bronchial asthma in Saarland and Rhineland-Palatinate, Germany. Using ICD10 diagnoses from health care institutions, the present study systematically analyzed the co-prevalence and odds ratios of comorbidities in the asthma population in Germany. The odds ratios were adjusted for age and sex for all comorbidities for patients with asthma vs. without asthma. Bronchial asthma was strongly associated with allergic and with a lesser extent to non-allergic comorbidities: OR 7.02 (95%CI:6.83-7.22) for allergic rhinitis; OR 4.98 (95%CI:4.67-5.32) allergic conjunctivitis; OR 2.41 (95%CI:2.33-2.52) atopic dermatitis; OR 2.47 (95%CI:2.16-2.82) food allergy, and OR 1.69 (95%CI:1.61-1.78) drug allergy. Interestingly, increased ORs were found for respiratory diseases: 2.06 (95%CI:1.64-2.58) vocal dysfunction; 1.83 (95%CI:1.74-1.92) pneumonia; 1.78 (95%CI:1.73-1.84) sinusitis; 1.71 (95%CI:1.65-1.78) rhinopharyngitis; 2.55 (95%CI:2.03-3.19) obstructive sleep apnea; 1.42 (95%CI:1.25-1.61) pulmonary embolism, and 3.75 (95%CI:1.64-8.53) bronchopulmonary aspergillosis. Asthmatics also suffer from psychiatric, metabolic, cardiac or other comorbidities. Myocardial infarction (OR 0.86, 95%CI:0.79-0.94) did not coexist with asthma. Based on the calculated chances of manifestation for these comorbidities, especially allergic and respiratory, to a lesser extent also metabolic, cardiovascular, and mental disorders should be taken into consideration in the diagnostic and treatment strategy of bronchial asthma., Bronchial Asthma: PREVALENCE OF CO-EXISTING DISEASES IN GERMANY: Patients in Germany with bronchial asthma are highly likely to suffer from co-existing diseases and their treatments should reflect this. Quoc Thai Dinh at Saarland University Hospital in Homburg, Germany, and co-workers conducted a large-scale study of patients presenting with bronchial asthma in the Saarland region between 2009 and 2012. Patients with asthma made up 5.4% of the region's total population, with a higher prevalence occurring in females. They found that bronchial asthma was strongly associated with allergic comorbidities such as rhinitis. Indeed, asthmatic patients had a seven times higher chance to suffer from allergic rhinitis than the rest of the population, and were at higher risk of respiratory diseases like pneumonia and obstructive sleep apnea syndrome. Further associations included cardiovascular, metabolic and mental disorders. Dinh's team call for asthma treatments to take such comorbidities into account.

Nanotechnology is showing promise in many medical applications such as drug delivery and hyperthermia. Nanoparticles administered to the respiratory tract cause local reactions and cross the blood-air barrier, thereby providing a means for easy systemic administration but also a potential source of toxicity. Little is known about how these effects are influenced by preexisting airway diseases such as asthma. Here, BALB/c mice are treated according to the ovalbumin (OVA) asthma protocol to promote allergic airway inflammation. Dispersions of polyethylene-glycol-coated (PEGylated) and citrate/tannic-acid-coated (citrated) 5 nm gold nanoparticles are applied intranasally to asthma and control groups, and (i) airway resistance and (ii) local tissue effects are measured as primary endpoints. Further, nanoparticle uptake into extrapulmonary organs is quantified by inductively coupled plasma mass spectrometry. The asthmatic precondition increases nanoparticle uptake. Moreover, systemic uptake is higher for PEGylated gold nanoparticles compared to citrated nanoparticles. Nanoparticles inhibit both inflammatory infiltrates and airway hyperreactivity, especially citrated gold nanoparticles. Although the antiinflammatory effects of gold nanoparticles might be of therapeutic benefit, systemic uptake and consequent adverse effects must be considered when designing and testing nanoparticle-based asthma therapies., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: The chemokine CXCL12 interacting with the CXC receptor 4 (CXCR4) has been reported to play a role in the development and progression of bronchial asthma, but its mechanism of action is still unknown. The objective of this study was to assess the effect of the CXCL12 neutraligand chalcone 4 on the migration of dendritic cells (DCs) in a murine model of allergic airway inflammation., Methods: A 21-day ovalbumin (OVA)-induced allergic-airway TH2 inflammation model in BALB/c mice was used. Four groups were sensitized with OVA adsorbed on alum and challenged either with OVA or saline for 4 days. Mice were treated intranasally with chalcone 4 (300 nmol/kg body weight) or solvent 2 h before each OVA or saline challenge; 24 h after the last challenge, CD11c+F4/80- DCs were counted in the bronchoalveolar lavage. Jugular-nodose ganglion complex (JNC) sections were sampled, and for immunofluorescence staining, cryocut sections were prepared. MHC II+F4/80- DCs as well as calcitonin gene-related peptide (CGRP)- and substance P (SP)-positive neuronal cell bodies were analyzed., Results: In OVA-challenged mice, chalcone 4 caused a significantly decreased DC/neuron ratio in the JNC from 51.7% in solvent-treated to 32.6% in chalcone 4-treated mice. In parallel, chalcone 4 also decreased the DC population in BALF from 11.5 × 103 cells in solvent to 4.5 × 103 cells in chalcone 4-treated mice. By contrast, chalcone 4 had no effect on the expression of the neuropeptides CGRP and SP in JNC., Conclusion: This study reported the CXCL12 neutraligand chalcone 4 to affect DC infiltration into the airways and airway ganglia as well as to decrease airway eosinophilic inflammation and, therefore, validated CXCL12 as a new target in allergic disease models of asthma., (© 2018 S. Karger AG, Basel.)

Bronchial asthma is a heterogeneous, complex, chronic inflammatory and obstructive pulmonary disease driven by various pathways to present with different phenotypes. A small proportion of asthmatics (5-10%) suffer from severe asthma with symptoms that cannot be controlled by guideline therapy with high doses of inhaled steroids plus a second controller, such as long-acting β2 agonists (LABA) or leukotriene receptor antagonists, or even systemic steroids. The discovery and characterization of the pathways that drive different asthma phenotypes have opened up new therapeutic avenues for asthma treatment. The approval of the humanized anti-IgE antibody omalizumab for the treatment of severe allergic asthma has paved the way for other cytokine-targeting therapies, particularly those targeting interleukin (IL)-4, IL-5, IL-9, IL-13, IL-17, and IL-23 and the epithelium-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin. Knowledge of the molecular basis of asthma phenotypes has helped, and continues to help, the development of novel biologicals that target a diverse array of phenotype-specific molecular targets in patients suffering from severe asthma. This review summarizes potential therapeutic approaches that are likely to show clinical efficacy in the near future, focusing on biologicals as promising novel therapies for severe asthma., (© 2016 S. Karger AG, Basel.)

Airway nerves have the capacity to control airway functions via neuronal reflexes and through neuromediators and neuropeptides. Neuronal mechanisms are known to play a key role in the initiation and modulation of airway hyperresponsiveness and inflammation. Therefore, the nerve fibres may contribute to airway narrowing in asthma and COPD. In addition to the traditional transmitters such as norepinephrine in postganglionic sympathetic nerve fibres and acetylcholine in parasympathetic nerve fibres, a large number of neuropeptides have been identified to have different pharmacological effects on the muscle tone of the vessels and bronchi, mucus secretion and immune cells. Meanwhile, a broad range of stimuli including capsaicin, bradykinin, hyperosmolar saline, tobacco smoke, allergens, ozone, inflammatory mediators and even cold, dry air have been shown to activate sensory nerve fibres to release neuropeptides such as the tachykinins substance P (SP) and neurokinin A (NKA) to mediate neurogenic inflammation. Different aspects of the neurogenic inflammation have been well studied in animal models of chronic airway inflammation and anticholinergic agents such as ipratropium bromide (Atrovent (®)) and tiotropium bromide (Spiriva (®)) have been proved to be important when used as bronchodilators for the treatment of obstructive airway diseases such as COPD. However, little is known about the role of neurogenic airway inflammation in human diseases. In this review, we address the current knowledge of the airway sensory nerves in human asthma and COPD., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The two obstructive airway diseases bronchial asthma and chronic obstructive pulmonary disease (COPD) represent major global causes of disability and death. Whereas COPD research was largely underfunded in the 1980s and 1990s, increased funding activities have been initiated since the year 2000. However, detailed scientometric data on the development of research for asthma and COPD have not been generated so far., Methods: The present scientometric study was conducted to establish a database of research quantity and quality in the 20-year period between 1987 and 2006 using the Web of Science information system and the United Kingdom and Germany for comparison of research activities., Results: The information database Web of Science was screened and during the period from 1987 to 2006 a number of 8,874 items related to asthma was published by UK affiliations. Of these, 1,824 were published in cooperation with a total of 86 other countries. This is a ratio of 20.55%. In the same period, 3,341 items were published by German institutions (923 in cooperation with 56 other countries, ratio of 27.63%). Citation analysis demonstrated an average citation of 24.48 per UK article and 17.62 per German article. For COPD, 2,179 items were published by UK affiliations and 689 items by German institutions. Of the UK COPD publications, 570 were published in cooperations with 47 countries (ratio of 22.95 %). By contrast, 218 of the 689 German COPD articles were published with 29 other countries (ratio of 25.49%). When citation analysis was performed, average citation ratios of 18.93 for the UK and 10.61 for German were found., Conclusion: Summarizing this first country-specific comparative benchmarking analysis for obstructive pulmonary diseases it can be concluded that (1) asthma research dominated in the past 20 years; (2) COPD research gained importance in the field since the end of the 1990s; (3) there are large differences present in the research output between the two high-income countries examined.

The airway nerve has gained importance in the field of respiratory research as it is known to have the capacity to release numerous mediators which can cause pulmonary effects in the airways. Meanwhile, a broad range of stimuli including capsaicin, bradykinin, hyperosmolar saline, tobacco smoke, allergens, ozone, inflammatory mediators and cold dry air have been shown to activate sensory nerve fibres to release neuropeptides such as the tachykinins substance P (SP) and neurokinin A (NKA) to mediate neurogenic inflammation. SP is synthesized in cell bodies of airway neurons of the trigeminal, jugulare and nodose ganglia. Following their release, tachykinins are degraded by neutral endopeptidase (NEP) and an angiotensin-converting enzyme. Tachykinins have been proposed to play an important role in human respiratory diseases such as bronchial asthma und chronic obstructive diseases (COPD) as they have been shown to have potent effects on the tone of airway smooth muscle, airway secretions, bronchial circulation and on inflammatory and immune cells by activation of the neurokinin-1 (NK-1) and neurokinin-2 (NK-2) receptors. Recently, new tachykinins such as virokinin and hemokinin were identified and characterised. Different aspects of the neurogenic inflammation have been well studied in animal models of allergic airway inflammation, but only little is known about the role of neurogenic airway inflammation in human diseases. To address the precise role of tachykinins and airway sensory nerves in human asthma und COPD, experiments on sensory nerve sensitisation and neuro-immune interaction have to be carried out in future studies.

Background: Exposure to environmental tobacco smoke (ETS) has been shown to increase symptoms of allergic bronchial asthma, but direct effects on the expression of inflammatory markers have not been demonstrated thus far., Objective: The aim of this study was to assess the correlation of ETS exposure with the expression of proinflammatory mediators in airway secretions, including IFN-gamma and IL-12, as well as IL-5 and IL-13, in allergic asthmatic schoolchildren and healthy control subjects., Methods: By using the nasopharyngeal aspiration technique, airway secretions were collected from 24 atopic children with asthma (age, 6-16 years) and 26 healthy control subjects, and the concentration of cytokines was measured with immunoenzymatic methods., Results: IL-13 levels were highly increased in patients with asthma (P < .005), and parental tobacco smoke resulted in a significant increase in airway IL-13 secretion in these children compared with that seen in nonexposed children and healthy control subjects (median, 860 pg/mL vs 242 pg/mL and 125 pg/mL, respectively). Furthermore, a positive correlation between IL-13 levels and serum IgE concentrations (r(s) = 0.55) was found in children with allergic asthma., Conclusions: These results indicate that ETS augments the expression and secretion of IL-13 in allergic asthma and that nasopharyngeal aspiration is a suitable method to assess cytokine measurements in airways in children. Measurements of IL-13 in secretions might be taken into account as a noninvasive marker of airway inflammation and to assess the detrimental effects of ETS.

Background: Recent studies have shown that the neurotrophins NGF and BDNF are produced by eosinophils. The influence of neurotrophins in allergic diseases including asthma has been described. The regulation by pharmacological substance remains unclear., Objectives: The aim of this study was to assess whether approved pharmacological substances in the treatment of asthma such as corticosteroids or theophylline regulate neurotrophins on a cellular level., Methods: Eosinophils were purified by negative immunoselection from allergics and non-allergic donors. Eosinophils were incubated with dexamethasone and theophylline and supernatants were collected for measurement of neurotrophic factors. The content of neurotrophins in eosinophil lysates was determined by ELISA. Regulation of stored NGF and BDNF was demonstrated by Western-blotting and flow cytometry while influence on transcription level was demonstrated by RT-PCR., Results: Eosinophils produce and release the neurotrophins NGF and BDNF at different levels in allergics and non-allergics. Dexamethason lead to a significant downregulation of NGF in eosinophils of allergics. The levels of BDNF were not significantly reduced. Theophylline did not influence the levels of NGF nor BDNF significantly., Conclusions: The production of the neurotrophin NGF was downregulated by an established substance such as dexamethasone. This might further contribute to the pharmacological potential of corticosteroids in allergic asthma.

Background: A wealth of clinical observation has suggested that stress and asthma morbidity are associated. We have previously established a mouse model of stress-exacerbated allergic airway inflammation, which reflects major clinical findings., Objective: The aim of the current study was to investigate the role of the neurokinin- (NK-)1 receptor in the mediation of stress effects in allergic airway inflammation., Methods: BALB/c mice were systemically sensitized with ovalbumin (OVA) on assay days 1, 14, and 21 and repeatedly challenged with OVA aerosol on days 26 and 27. Sound stress was applied to the animals for 24 hours, starting with the first airway challenge. Additionally, one group of stressed and one group of nonstressed mice received the highly specific NK-1 receptor antagonist RP 67580. Bronchoalveolar lavage fluid was obtained, and cell numbers and differentiation were determined. Airway hyperreactivity was measured in vitro by electrical field stimulation of tracheal smooth-muscle elements., Results: Application of stress in sensitized and challenged animals resulted in a significant increase in leukocyte number in the bronchoalveolar lavage fluid. Furthermore, stressed animals showed enhanced airway reactivity. The increase of inflammatory cells and airway reactivity was blocked by treatment of animals with the NK-1 receptor antagonist., Conclusion: These data indicate that the NK-1 receptor plays an important role in mediating stress effects in allergen-induced airway inflammation.

Bronchial asthma represents a severe chronic inflammatory disease with increasing prevalence. The pathogenesis is characterized by complex neuroimmune dysregulation. Although the immunopathogenesis of the disease has been extensively studied, the nature of neuronal dysfunction still remains poorly understood. Recent data indicate that neurotrophins contribute to airway inflammation, broncho-obstruction and airway hyperresponsiveness. Using an established murine model of allergic bronchial asthma, the contribution of the pan-neurotrophin receptor p75(NTR) was defined. This receptor is expressed both in normal and asthmatic lungs and airways. Analysis of p75(NTR-/-) mice, as well as in vivo blocking of p75(NTR), revealed that airway inflammation is to a large extent dependent upon functional receptor expression. Furthermore, neuronal hyperreactivity depends entirely on this receptor. Based on these data, a novel molecular pathway in the neuroimmune pathogenesis of bronchial asthma could be defined.