Diesel exhaust particulate induces pulmonary and systemic inflammation in rats without impairing endothelial function ex vivo or in vivo

Background

There is growing evidence that particulate air pollution derived from wood stoves causes acute inflammation in the respiratory system, increases the incidence of asthma and other allergic diseases, and increases respiratory morbidity and mortality. The objective of this study was to evaluate acute respiratory effects from short-term wood smoke exposure in humans. Twenty non-smoking atopic volunteers with normal lung function and without bronchial responsiveness were monitored during three different experimental exposure sessions, aiming at particle concentrations of about 200?μg/m³, 400?μg/m³, and clean air as control exposure. A balanced cross-over design was used and participants were randomly allocated to exposure orders. Particles were generated in a wood-burning facility and added to a full-scale climate chamber where the participants were exposed for 3 hours under controlled environmental conditions. Health effects were evaluated in relation to: peak expiratory flow (PEF), forced expiratory volume in the first second (FEV₁), and forced vital capacity (FVC). Furthermore, the effects were assessed in relation to changes in nasal patency and from markers of airway inflammation: fractional exhaled nitric oxide (FENO), exhaled breath condensate (EBC) and nasal lavage (NAL) samples were collected before, and at various intervals after exposure.

Results

No statistically significant effect of wood smoke exposure was found for lung function, for FENO, for NAL or for the nasal patency. Limited signs of airway inflammation were found in EBC.

Conclusion

In conclusion, short term exposure with wood smoke at a concentration normally found in a residential area with a high density of burning wood stoves causes only mild inflammatory response.     

Immunological Roles of NLR in Allergic Diseases and Its Underlying Mechanisms

Our understanding on the immunological roles of pathogen recognition in innate immunity has vastly increased over the past 20 years. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) are cytosolic pattern recognition receptors (PRR) that are responsible for sensing microbial motifs and endogenous damage signals in mammalian cytosol for immune surveillance and host defense. The accumulating discoveries on these NLR sensors in allergic diseases suggest that the pathogenesis of allergic diseases may not be confined to the adaptive immune response. Therapy targeting NLR in murine models also shields light on its potential in the treatment of allergies in man. In this review, we herein summarize the recent understanding of the role of NLR sensors and their molecular mechanisms involved in allergic inflammation, including atopic dermatitis and allergic asthma.     

The Multifaceted Mas-Related G Protein-Coupled Receptor Member X2 in Allergic Diseases and Beyond

Recent research on mast cell biology has turned its focus on MRGPRX2, a new member of the Mas-related G protein-coupled subfamily of receptors (Mrgprs), originally described in nociceptive neurons of the dorsal root ganglia. MRGPRX2, a member of this group, is present not only in neurons but also in mast cells (MCs), specifically, and potentially in other cells of the immune system, such as basophils and eosinophils. As emerging new functions for this receptor are studied, a variety of both natural and pharmacologic ligands are being uncovered, linked to the ability to induce receptor-mediated MC activation and degranulation. The diversity of these ligands, characterized in their human, mice, or rat homologues, seems to match that of the receptor’s interactions. Natural ligands include host defense peptides, basic molecules, and key neuropeptides such as substance P and vasointestinal peptide (known for their role in the transmission of pain and itch) as well as eosinophil granule-derived proteins. Exogenous ligands include MC secretagogues such as compound 48/80 and mastoparan, a component of bee wasp venom, and several peptidergic drugs, among which are members of the quinolone family, neuromuscular blocking agents, morphine, and vancomycin. These discoveries shed light on its capacity as a multifaceted participant in naturally occurring responses within immunity and neural stimulus perception, as in responses at the center of immune pathology. In host defense, the mice Mrgprb2 has been proven to aid mast cells in the detection of peptidic molecules from bacteria and in the release of peptides with antimicrobial activities and other immune mediators. There are several potential actions described for it in tissue homeostasis and repair. In the realm of pathologic response, there is evidence to suggest that this receptor is also involved in chronic inflammation. Furthermore, MRGPRX2 has been linked to the pathophysiology of non-IgE-mediated immediate hypersensitivity drug reactions. Different studies have shown its possible role in other allergic diseases as well, such as asthma, atopic dermatitis, contact dermatitis, and chronic spontaneous urticaria. In this review, we sought to cover its function in physiologic processes and responses, as well as in allergic and nonallergic immune disease.     

Asymmetric Dimethylarginine in Chronic Obstructive Pulmonary Disease (ADMA in COPD)

l-Arginine metabolism including the nitric oxide (NO) synthase and arginase pathways is important in the maintenance of airways function. We have previously reported that accumulation of asymmetric dimethylarginine (ADMA) in airways, resulting in changes in l-arginine metabolism, contributes to airways obstruction in asthma and cystic fibrosis. Herein, we assessed l-arginine metabolism in airways of patients with chronic obstructive pulmonary disease (COPD). Lung function testing, measurement of fractional exhaled NO (FeNO) and sputum NO metabolites, as well as quantification of l-arginine metabolites (l-arginine, l-ornithine, l-citrulline, ADMA and symmetric dimethylarginine) using liquid chromatography-mass spectrometry (LC-MS) were performed. Concentrations of l-ornithine, the product of arginase activity, correlated directly with l-arginine and ADMA sputum concentrations. FeNO correlated directly with pre- and post-bronchodilator forced expiratory volume in one second (FEV₁). Sputum arginase activity correlated inversely with total NO metabolite (NO_x) and nitrite concentrations in sputum, and with pre- and post-bronchodilator FEV₁. These findings suggest that ADMA in COPD airways results in a functionally relevant shift of l-arginine breakdown by the NO synthases towards the arginase pathway, which contributes to airway obstruction in these patients.     

Vitamin D and Microbiota: Is There a Link with Allergies?

There is increasing recognition of the importance of both the microbiome and vitamin D in states of health and disease. Microbiome studies have already demonstrated unique microbial patterns in systemic autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus. Dysbiosis also seems to be associated with allergies, in particular asthma, atopic dermatitis, and food allergy. Even though the effect of vitamin D supplementation on these pathologies is still unknown, vitamin D deficiency deeply influences the microbiome by altering the microbiome composition and the integrity of the gut epithelial barrier. It also influences the immune system mainly through the vitamin D receptor (VDR). In this review, we summarize the influence of the microbiome and vitamin D on the immune system with a particular focus on allergic diseases and we discuss the necessity of further studies on the use of probiotics and of a correct intake of vitamin D.     

Oxidative Stress Mediated-Alterations of the MicroRNA Expression Profile in Mouse Hippocampal Neurons

Oxidative stress plays a critical role in the etiology and pathogenesis of neurodegenerative disorders, and the molecular mechanisms that control the neuron response to ROS have been extensively studied. However, the oxidative stress-effect on miRNA expression in hippocampal neurons has not been investigated, and little is known on the effect of ROS-modulated miRNAs on cell function. In this study, H₂O₂ was used to stimulate the mouse primary hippocampal neurons to develop an oxidative stress cell model. The alterations of miRNAs expression were detected by microarray analysis and five miRNAs were validated by real-time RT-PCR. The bioinformatic analysis of deregulated miRNAs was performed to determine their potential roles in the pathogenesis of neurological disorders. We found that H₂O₂ mediated a total of 101 deregulated miRNAs, which mainly took part in the regulation of the MAPK pathway. Among them, miR-135b and miR-708 were up-regulated significantly and their targets were predicted to be involved in DNA recombination, protein ubiquitination, protein autophosphorylation and development of neurons. These results demonstrated that oxidative stress alters the miRNA expression profile of hippocampal neurons, and the deregulated miRNAs might play a potential role in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD).     

鼻吸入布地奈德对支气管哮喘的影响

目的研究鼻局部吸入布地奈德治疗过敏性鼻炎对哮喘发作的影响。探讨患者用布地奈德治疗过敏性鼻炎对哮喘症状及肺功能变化的影响。方法采用临床试验方法研究门诊63例支气管哮喘合并过敏性鼻炎患者。随机分为布地奈德组(30例)和对照组(33例)。所有患者均规律经口吸入哮喘常规药物,布地奈德组规律加用鼻吸布地奈德。随访12周后再次进行研究,比较患者哮喘症状以及肺功能变化。结果布地奈德组在经过鼻吸布地奈德12周后与对照组ACT记分和肺功能比较有统计学意义(P<0.01)。2组在治疗前的差异无统计学意义(P>0.05)。结论过敏性鼻炎是哮喘发病的危险因素,鼻局部吸入布地奈德治疗伴有轻、中度哮喘的过敏性鼻炎患者,当鼻炎症状改善的同时,哮喘症状亦获得缓解,气道反应性降低。     

Antagonism of microRNA function in zebrafish embryos by using locked nucleic acid enzymes (LNAzymes)

MicroRNAs (miRNAs) have crucial functions in many cellular processes, such as differentiation, proliferation and apoptosis; aberrant expression of miRNAs has been linked to human diseases, including cancer. Tools that allow specific and efficient knockdown of miRNAs would be of immense importance for exploring miRNA function. Zebrafish serves as an excellent vertebrate model system to understand the functions of miRNAs involved in a variety of biological processes. We designed and employed a strategy based on locked nucleic acid enzymes (LNAzymes) for in vivo knockdown of miRNA in zebrafish embryos. We demonstrate that LNAzyme can efficiently knockdown miRNAs with minimal toxicity to the zebrafish embryos.     

Dietary fish oil n-3 fatty acids increase regulatory cytokine production and exert anti-inflammatory effects in two murine models of inflammation

The higher incidence of inflammatory diseases in Western countries might be related, in part, to a high consumption of saturated fatty acids and n−6 polyunsaturated fatty acids (PUFA) and an insufficient intake of n−3 fatty acids. The purpose of this study was to examine the effects of dietary n−3 fatty acids on innate and specific immune response and their anti-inflammatory action in models of contact and atopic dermatitis. Balb/C mice were fed for 3 wk either n−6 or n−3 PUFA-fortified diets. After inducing a contact or an atopic dermatitis, immunological parameters were analyzed to evaluate the anti-inflammatory potential of these n−3 PUFA. n−3 PUFA reduced innate and specific immune responses through inhibition of T_H1 and T_H2 responses, increase of immunomodulatory cytokines such as IL-10, and regulation of gene expression. The inhibition of both kinds of responses was confirmed by the anti-inflammatory effect observed in contact and atopic dermatitis. Reduction in weight, edema, thickness, leukocyte infiltration, and enhancement of antioxidant defenses in the inflamed ears of mice from both models along with the prevention of delayed-type hypersensitivity induced in atopic dermatitis proved n−3 PUFA efficacy. Our data suggest that dietary fish oil-derived n−3 fatty acids have immunomodulatory effects and could be useful in inflammatory disorders.     

Altered arachidonic acid content in polymorphonuclear and mononuclear cells from patients with allergic rhinitis and/or asthma

We previously have found that monocytes from patients with allergic rhinitis and/or asthma produce less PGE₂ than cells from normal subjects in response to a histamine-induced lymphokine. In order to investigate this observation further, we measured the fatty acid content in the total phospholipids derived from the plasma, red cells, buffy coat cells, neutrophils, monocytes and lymphocytes of 27 allergic patients and 21 normal controls. There were no substantial differences between atopics and normals in the fatty acid analyses carried out for plasma and red cells. However, linoleic acid (18∶2n−6) levels were elevated significantly in the buffy coat fraction, while arachidonic acid (20∶4n−6) levels were reduced. Measurement of fatty acid levels after fractionation of the buffy coat population into neutrophils and monocytes yielded similar elevations in 18∶2n−6 and reduced 20∶4n−6. In contrast, lymphocytes appeared to have the reverse pattern, i.e., significantly reduced 18∶2n−6 and elevated 20∶4n−6 levels. These data suggest that atopic leukocytes may have altered essential fatty acid metabolism.     

Could the Epigenetics of Eosinophils in Asthma and Allergy Solve Parts of the Puzzle?

Epigenetics is a field of study investigating changes in gene expression that do not alter the DNA sequence. These changes are often influenced by environmental or social factors and are reversible. Epigenetic mechanisms include DNA methylation, histone modification, and noncoding RNA. Understanding the role of these epigenetic mechanisms in human diseases provides useful information with regard to disease severity and development. Several studies have searched for the epigenetic mechanisms that regulate allergies and asthma; however, only few studies have used samples of eosinophil, a proinflammatory cell type known to be largely recruited during allergic or asthmatic inflammation. Such studies would enable us to better understand the factors that influence the massive recruitment of eosinophils during allergic and asthmatic symptoms. In this review, we sought to summarize different studies that aimed to discover differential patterns of histone modifications, DNA methylation, and noncoding RNAs in eosinophil samples of individuals with certain diseases, with a particular focus on those with asthma or allergic diseases.     

Therapeutic Effects of an Anti-sialyl Lewis X Antibody in a Murine Model of Allergic Asthma

Asthma is an allergic disease that causes severe infiltration of leukocytes into the lungs. Leukocyte infiltration is mediated by the binding of sialyl Lewis X (sLe^x) glycans present on the leukocytes to E-and P-selectins present on the endothelial cells at the sites of inflammation. Here, we found that mouse eosinophils express sLe^x glycans, and their infiltration into the lungs and proliferation in the bone marrow were significantly suppressed by an anti-sLe^x monoclonal antibody (mAb) F2 in a murine model of ovalbumin-induced asthma. The percentage of eosinophils in the bronchoalveolar lavage fluid and bone marrow and serum IgE levels decreased significantly in the F2-administered mice. Levels of T helper type 2 (Th2) cytokines and chemokines, involved in IgE class switching and eosinophil proliferation and recruitment, were also decreased in the F2-administered mice. An ex vivo cell rolling assay revealed that sLe^x glycans mediate the rolling of mouse eosinophils on P-selectin-expressing cells. These results indicate that the mAb F2 exerts therapeutic effects in a murine model of allergen-induced asthma, suggesting that sLe^x carbohydrate antigen could serve as a novel therapeutic target for allergic asthma.     

Circulating Organ-Specific MicroRNAs Serve as Biomarkers in Organ-Specific Diseases: Implications for Organ Allo- and Xeno-Transplantation

Different cell types possess different miRNA expression profiles, and cell/tissue/organ-specific miRNAs (or profiles) indicate different diseases. Circulating miRNA is either actively secreted by living cells or passively released during cell death. Circulating cell/tissue/organ-specific miRNA may serve as a non-invasive biomarker for allo- or xeno-transplantation to monitor organ survival and immune rejection. In this review, we summarize the proof of concept that circulating organ-specific miRNAs serve as non-invasive biomarkers for a wide spectrum of clinical organ-specific manifestations such as liver-related disease, heart-related disease, kidney-related disease, and lung-related disease. Furthermore, we summarize how circulating organ-specific miRNAs may have advantages over conventional methods for monitoring immune rejection in organ transplantation. Finally, we discuss the implications and challenges of applying miRNA to monitor organ survival and immune rejection in allo- or xeno-transplantation.     

Effect of Nanoparticles Exposure on Fractional Exhaled Nitric Oxide (FENO) in Workers Exposed to Nanomaterials

Fractional exhaled nitric oxide (FENO) measurement is a useful diagnostic test of airway inflammation. However, there have been few studies of FENO in workers exposed to nanomaterials. The purpose of this study was to examine the effect of nanoparticle (NP) exposure on FENO and to assess whether the FENO is increased in workers exposed to nanomaterials (NM). In this study, both exposed workers and non-exposed controls were recruited from NM handling plants in Taiwan. A total of 437 subjects (exposed group = 241, non-exposed group = 196) completed the FENO and spirometric measurements from 2009–2011. The authors used a control-banding (CB) matrix to categorize the risk level of each participant. In a multivariate linear regression analysis, this study found a significant association between risk level 2 of NP exposure and FENO. Furthermore, asthma, allergic rhinitis, peak expiratory flow rate (PEFR), and NF-κB were also significantly associated with FENO. When the multivariate logistic regression model was adjusted for confounders, nano-TiO₂ in all of the NM exposed categories had a significantly increased risk in FENO > 35 ppb. This study found associations between the risk level of NP exposure and FENO (particularly noteworthy for Nano-TiO₂). Monitoring FENO in the lung could open up a window into the role nitric oxide (NO) may play in pathogenesis.     

Analysis of Results of Specific IgE in 100 Atopic Dermatitis Patients with the Use of Multiplex Examination ALEX2—Allergy Explorer

Background and aim: Progress in laboratory diagnostics of IgE-mediated allergy is the use of component-resolved diagnosis. Our study analyses the results of specific IgE to 295 allergen reagents (117 allergenic extracts and 178 molecular components) in patients suffering from atopic dermatitis (AD) with the use of ALEX2 Allergy Explorer. Method: The complete dermatological and allergological examination, including the examination of the sensitization to molecular components with ALEX2 Allergy Explorer testing, was performed. The statistical analysis of results was performed with these methods: TURF (total unduplicated reach and frequency), best reach and frequency by group size, two-sided tests, Fisher’s exact test, and chi-square test (at an expected minimum frequency of at least 5). Results: Altogether, 100 atopic dermatitis patients were examined: 48 men, 52 women, the average age 40.9 years, min. age 14 years, max. age 67 years. The high and very high level of specific IgE was reached in 75.0% of patients to 18 molecular components: from PR-10 proteins (Aln g 1, Bet v 1, Cor a1.0103, Cor a1.0401, Fag s 1), lipocalin (Can f 1), NPC2 family (Der f 2, Der p 2), uteroglobin (Fel d 1), from Alternaria alternata (Alt a 1), Beta expansin (Lol p 1, Phl p 1), molecular components from Timothy, cultivated rye (Secc pollen) and peritrophin-like protein domain Der p 23. The high and very high level of specific IgE to other lipocalins (Fel d 7, Can f 4), to arginine kinase (Bla g 9, German cockroach), and to allergen extracts Art v (mugwort), and Cyn d (Bermuda grass) reached 52.0% of patients. The severity of AD is in significant relation to the sensitization to molecular components of storage mites (Gly d 2, Lep d 2—NPC2 family), lipocalins (Can f 1, Can f 2, Can f 4, and Can f 6), arginine kinase (Asp f 6, Bla g 9, Der p 20, Pen m 2), uteroglobin (Fel d 1, Ory c 3), Mn superoxide dismutase (Mala s 11), PR-10 proteins (Fag s 1, Mal d 1, Cor a 1.0401, Cor a 1.0103), molecular components of the peritrophin-like domain (Der p 21, Der p 23), and to Secc pollen. In the subgroup of patients suffering from bronchial asthma, the significant role play molecular components from house dust mites and storage mites (Lep d 2, Der p 2, Der f 2—NPC2 family), cysteine protease (Der p 1), peritrophin-like protein domain (Der p 21, Der p 23), enolase from Alternaria alternata (Alt a 6), and Beta expansin Phl p 1. Conclusion: The results of our study demonstrate the detailed profile of sensitization to allergens reagents (allergen extract and molecular components) in patients with atopic dermatitis. We show the significance of disturbed epidermal barrier, resulting in increased penetration of allergens. We confirmed the significant relationship between the severity of AD, the occurrence of bronchial asthma and allergic rhinitis, and high levels of specific IgE to allergen reagents. Our results may be important for regime measures and immunotherapy; Der p 23 shall be considered as an essential component for the diagnosis and specific immunotherapy of house dust mite allergy.     

Changes in Serum MicroRNAs after Anti-IL-5 Biological Treatment of Severe Asthma

There is currently enough evidence to think that miRNAs play a role in several key points in asthma, including diagnosis, severity of the disease, and response to treatment. Cells release different types of lipid double-membrane vesicles into the extracellular microenvironment, including exosomes, which function as very important elements in intercellular communication. They are capable of distributing genetic material, mRNA, mitochondrial DNA, and microRNAs (miRNAs). Serum miRNA screening was performed in order to analyze possible changes in serum miRNAs in 10 patients treated with reslizumab and 6 patients with mepolizumab after 8 weeks of treatment. The expression of miR-338-3p was altered after treatment (p < 0.05), although no significant differences between reslizumab and mepolizumab were found. Bioinformatic analysis showed that miR-338-3p regulates important pathways in asthma, such as the MAPK and TGF-β signaling pathways and the biosynthesis/degradation of glucans (p < 0.05). However, it did not correlate with an improvement in lung function. MiRNA-338-3p could be used as a biomarker of early response to reslizumab and mepolizumab in severe eosinophilic asthmatic patients. In fact, this miRNA could be involved in airway remodeling, targeting genes related to MAPK and TGF-β signaling pathways.     

MicroRNAs,Parkinson’s Disease,and Diabetes Mellitus

Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the population over the age of 60. Diabetes Mellitus (DM) is a metabolic disorder that affects approximately 25% of adults over the age of 60. Recent studies showed that DM increases the risk of developing PD. The link between DM and PD has been discussed in the literature in relation to different mechanisms including mitochondrial dysfunction, oxidative stress, and protein aggregation. In this paper, we review the common microRNA (miRNA) biomarkers of both diseases. miRNAs play an important role in cell differentiation, development, the regulation of the cell cycle, and apoptosis. They are also involved in the pathology of many diseases. miRNAs can mediate the insulin pathway and glucose absorption. miRNAs can also regulate PD-related genes. Therefore, exploring the common miRNA biomarkers of both PD and DM can shed a light on how these two diseases are correlated, and targeting miRNAs is a potential therapeutic opportunity for both diseases.     

The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut

Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H₁R) antagonists, which are used to control allergic inflammation, antagonists at H₂R, which therapeutically decrease gastric acid release, and an antagonist at H₃R, which is indicated to treat narcolepsy. Ligands at H₄R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H₄R ligands so far. Nevertheless, pre-clinically, H₄R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H₁R, H₂R, and H₃R do not provide an effect on inflammation, supporting the idea that H₄R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H₄R in inflammatory and inflammation-associated diseases of the gut.