Journal articles on the topic 'Glucocorticoid resistance in Asthma'
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Barnes, Peter J., Andrew P. Greening, and Graham K. Crompton. "Glucocorticoid Resistance in Asthma." American Journal of Respiratory and Critical Care Medicine 152, no. 6_pt_2 (December 1995): S125—S140. http://dx.doi.org/10.1164/ajrccm/152.6_pt_2.s125.
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Corrigan, Chris J., and Tak H. Lee. "Glucocorticoid Action and Resistance in Asthma." Allergology International 54, no. 2 (2005): 235–43. http://dx.doi.org/10.2332/allergolint.54.235.
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Keenan, Christine R., Michael J. Schuliga, and Alastair G. Stewart. "Pro-inflammatory mediators increase levels of the noncoding RNA GAS5 in airway smooth muscle and epithelial cells." Canadian Journal of Physiology and Pharmacology 93, no. 3 (March 2015): 203–6. http://dx.doi.org/10.1139/cjpp-2014-0391.
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The long noncoding RNA (lncRNA) GAS5 has been found to act as a decoy for the glucocorticoid receptor (GR), thus implicating GAS5 as a potential regulator of glucocorticoid sensitivity and resistance. Airway smooth muscle (ASM) cells and airway epithelial cells (AEC) play an important role in the pathogenesis and persistence of asthma and other chronic airways diseases. These airway structural cell types are also important cellular targets of the anti-inflammatory actions of glucocorticoids. In this study, we sought to examine the relevance of GAS5 to glucocorticoid sensitivity and resistance in ASM and AEC. We provide the first evidence that pro-inflammatory mediators up-regulate GAS5 levels in both airway epithelial and smooth muscle cells, and that decreasing GAS5 levels can enhance glucocorticoid action in AEC.
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Ito, Kazuhiro, Steve Getting, and Catherine Charron. "Mode of Glucocorticoid Actions in Airway Disease." Scientific World JOURNAL 6 (2006): 1750–69. http://dx.doi.org/10.1100/tsw.2006.274.
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Synthetic glucocorticoids are the most potent anti-inflammatory agents used to treat chronic inflammatory disease, such as asthma. However, a small number (<5%) of asthmatic patients and almost all patients with chronic obstructive pulmonary disease (COPD) do not respond well, or at all, to glucocorticoid therapy. If the molecular mechanism of glucocorticoid insensitivity is uncovered, it may in turn provide insight into the key mechanism of glucocorticoid action and allow a rational way to implement treatment regimens that restore glucocorticoid sensitivity. Glucocorticoids exert their effects by binding to a cytoplasmic glucocorticoid receptor (GR), which is subjected to post-translational modifications. Receptor phosphorylation, acetylation, nitrosylation, ubiquitinylation, and other modifications influence hormone binding, nuclear translocation, and protein half-life. Analysis of GR interactions to other molecules, such as coactivators or corepressors, may explain the genetic specificity of GR action. Priming with inflammatory cytokine or oxidative/nitrative stress is a mechanism for the glucocorticoid resistance observed in chronic inflammatory airway disease via reduction of corepressors or GR modification. Therapies targeting these aspects of the GR activation pathway may reverse glucocorticoid resistance in patients with glucocorticoid-insensitive airway disease and some patients with other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.
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Zein, Joe, Benjamin Gaston, Peter Bazeley, Mark D. DeBoer, Robert P. Igo, Eugene R. Bleecker, Deborah Meyers, et al. "HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma." Proceedings of the National Academy of Sciences 117, no. 4 (January 13, 2020): 2187–93. http://dx.doi.org/10.1073/pnas.1918819117.
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Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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Wang, Alberta L., Ronald Panganiban, Weiliang Qiu, Alvin T. Kho, Geoffrey Chupp, Deborah A. Meyers, Eugene R. Bleecker, Scott T. Weiss, Quan Lu, and Kelan G. Tantisira. "Drug Repurposing to Treat Glucocorticoid Resistance in Asthma." Journal of Personalized Medicine 11, no. 3 (March 3, 2021): 175. http://dx.doi.org/10.3390/jpm11030175.
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Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV1). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV1, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores < −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics.
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Ghiciuc, Cristina Mihaela, Andrei Gheorghe Vicovan, Celina Silvia Stafie, Sabina Antonela Antoniu, and Paraschiva Postolache. "Marine-Derived Compounds for the Potential Treatment of Glucocorticoid Resistance in Severe Asthma." Marine Drugs 19, no. 11 (October 20, 2021): 586. http://dx.doi.org/10.3390/md19110586.
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One of the challenges to the management of severe asthma is the poor therapeutic response to treatment with glucocorticosteroids. Compounds derived from marine sources have received increasing interest in recent years due to their prominent biologically active properties for biomedical applications, as well as their sustainability and safety for drug development. Based on the pathobiological features associated with glucocorticoid resistance in severe asthma, many studies have already described many glucocorticoid resistance mechanisms as potential therapeutic targets. On the other hand, in the last decade, many studies described the potentially anti-inflammatory effects of marine-derived biologically active compounds. Analyzing the underlying anti-inflammatory mechanisms of action for these marine-derived biologically active compounds, we observed some of the targeted pathogenic molecular mechanisms similar to those described in glucocorticoid (GC) resistant asthma. This article gathers the marine-derived compounds targeting pathogenic molecular mechanism involved in GC resistant asthma and provides a basis for the development of effective marine-derived drugs.
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Palumbo, María Laura, Andrés Prochnik, Miriam Ruth Wald, and Ana María Genaro. "Chronic Stress and Glucocorticoid Receptor Resistance in Asthma." Clinical Therapeutics 42, no. 6 (June 2020): 993–1006. http://dx.doi.org/10.1016/j.clinthera.2020.03.002.
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Matsumura, Yasuhiro. "Inflammation Induces Glucocorticoid Resistance in Patients with Bronchial Asthma." Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 8, no. 4 (December 1, 2009): 377–86. http://dx.doi.org/10.2174/187152309789839055.
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Adcock, I. M., S. J. Lane, C. R. Brown, M. J. Peters, T. H. Lee, and P. J. Barnes. "Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma." Journal of Immunology 154, no. 7 (April 1, 1995): 3500–3505. http://dx.doi.org/10.4049/jimmunol.154.7.3500.
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Abstract Although glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases, a small proportion of patients are resistant to their therapeutic effects. The molecular mechanism for this steroid resistance is unclear. Steroid resistance cannot be explained by pharmacokinetic mechanisms, by a defect in the binding of steroids to glucocorticoid receptors, nor by defective nuclear translocation of this receptor, thereby suggesting that the molecular abnormality lies distal to nuclear translocation. We examined the ability of nuclear translocated glucocorticoid receptors to bind to their DNA binding sites (GRE) using electrophoretic mobility shift assays in PBMC from patients with steroid-sensitive and steroid-resistant asthma. The binding of the glucocorticoid receptor to DNA in these patients was also studied using Scatchard analysis. Dexamethasone induced a significant rapid and sustained twofold increase in GRE binding in PBMCs from steroid-sensitive asthmatic patients and nonasthmatic individuals, but this was markedly reduced in steroid-resistant asthmatic patients. Scatchard analysis of glucocorticoid receptor-GRE binding showed no change in binding affinity but did show a reduced number of receptors available for DNA binding in the steroid-resistant patients. These results suggest that the ability of the glucocorticoid receptor to bind to GRE is impaired in steroid-resistant patients because of a reduced number of receptors available for binding to DNA.
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Adcock, I. M., S. J. Lane, C. R. Brown, T. H. Lee, and P. J. Barnes. "Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma." Journal of Experimental Medicine 182, no. 6 (December 1, 1995): 1951–58. http://dx.doi.org/10.1084/jem.182.6.1951.
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Glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases. However, a small proportion of patients is resistant to the therapeutic effects of glucocorticoids. Pharmacokinetic and ligand binding studies suggest that the molecular abnormality in steroid resistance lies distal to nuclear translocation. We have previously reported that there is a decreased ability of glucocorticoid receptors (GR) to bind to the DNA-binding site in peripheral blood mononuclear cells (PBMC) after dexamethasone treatment. This reduced DNA binding was due to a decrease in the number of receptors available rather than an alteration in affinity for DNA. To study this reduced DNA binding, we examined the ability of the nuclear translocated transcription factors activator protein 1 (AP-1), nuclear factor kappa B (NF-kappa B) and cyclic AMP response element-binding protein (CREB) to bind to their DNA-binding sites and to interact with GR in PBMC from patients with steroid-sensitive and steroid-resistant asthma. There was a significant reduction in the interaction between GR and AP-1 in these steroid-resistant patients, although interaction with other transcription factors activated in inflammation (NF-kappa B and CREB) was unaffected. An increase in the basal levels of AP-1 DNA binding was also detected in the nuclei from steroid-resistant asthmatic patients. There were no differences in the amount of messenger RNA detected for the components of AP-1, c-Fos and c-Jun, nor in the sequences of these messenger RNAs. These results suggest either that the ability of the GR to bind to glucocorticoid response elements and AP-1 is altered in steroid-resistant patients or that increased levels of AP-1 prevent GR DNA binding, and that this may be the molecular basis of resistance to the antiinflammatory effect of steroids in these cells.
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Hong, Lingzi, Tomasz Herjan, Katarzyna Bulek, Jianxin Xiao, Suzy A. A. Comhair, Serpil C. Erzurum, Xiaoxia Li, and Caini Liu. "Mechanisms of Corticosteroid Resistance in Type 17 Asthma." Journal of Immunology 209, no. 10 (November 15, 2022): 1860–69. http://dx.doi.org/10.4049/jimmunol.2200288.
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Abstract IL-17A plays an important role in the pathogenesis of asthma, particularly the neutrophilic corticosteroid (CS)-resistant subtype of asthma. Clinical studies suggest that a subset of asthma patients, i.e., Th17/IL-17A–mediated (type 17) CS-resistant neutrophilic asthma, may improve with Th17/IL-17A pathway blockade. However, little is known about the mechanisms underlying type 17 asthma and CS response. In this article, we show that blood levels of lipocalin-2 (LCN2) and serum amyloid A (SAA) levels are positively correlated with IL-17A levels and are not inhibited by high-dose CS usage in asthma patients. In airway cell culture systems, IL-17A induces these two secreted proteins, and their induction is enhanced by CS. Furthermore, plasma LCN2 and SAA levels are increased in mice on a preclinical type 17 asthma model, correlated to IL-17A levels, and are not reduced by glucocorticoid (GC). In the mechanistic studies, we identify CEBPB as the critical transcription factor responsible for the synergistic induction of LCN2 and SAA by IL-17A and GC. IL-17A and GC collaboratively regulate CEBPB at both transcriptional and posttranscriptional levels. The posttranscriptional regulation of CEBPB is mediated in part by Act1, the adaptor and RNA binding protein in IL-17A signaling, which directly binds CEBPB mRNA and inhibits its degradation. Overall, our findings suggest that blood LCN2 and SAA levels may be associated with a type 17 asthma subtype and provide insight into the molecular mechanism of the IL-17A–Act1/CEBPB axis on these CS-resistant genes.
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Walsh, GM, DW Sexton, and MG Blaylock. "Corticosteroids, eosinophils and bronchial epithelial cells: new insights into the resolution of inflammation in asthma." Journal of Endocrinology 178, no. 1 (July 1, 2003): 37–43. http://dx.doi.org/10.1677/joe.0.1780037.
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Anti-inflammatory therapy in asthma is reliant on corticosteroids, particularly in their inhaled form. However, steroids are rather non-specific in their actions and they also raise concerns regarding compliance and side-effect Issues. Furthermore, a small proportion of patients with asthma fail to respond to oral glucocorticoids even at high doses. This Article will review the role that steroids and membrane receptor ligation play in the induction of eosinophil apoptosis together with the mechanisms by which corticosteroids enhance the disposal of apoptotic eosinophils by both professional and non-professional phagocytes. Eosinophils are thought to be the major pro-inflammatory effector cell in asthma and their persistence in the airways is probably enhanced by the presence of several asthma-relevant cytokines that prolong eosinophil survival by inhibition of apoptosis (interleukin (IL)-3, IL-5, granulocyte-macrophage colony-stimulating factor, IL-9, IL-13, IL-15). In contrast, a number of signals have been described that accelerate apoptosis in human eosinophils including corticosteroids or ligation of membrane receptors (CD95, CD45, CD69). Thus, the load of lung eosinophils in asthmatic disease is likely to be related to a balance in the tIssue microenvironment between pro- and anti-apoptotic signals. Furthermore, removal of apoptotic eosinophils by phagocytosis by alveolar macrophages or bronchial epithelial cells in a specific receptor-mediated way is as important as the process of apoptosis induction. Corticosteroids enhance the recognition and engulfment of apoptotic eosinophils by macrophages or bronchial epithelial cells. Caspases are key intracellular molecules in the control of apoptosis and defects in caspase-induced apoptosis in eosinophils from steroid-resistant individuals may contribute to the molecular mechanisms underlying glucocorticoid insensitivity in these cells. These findings point the way to new and more targeted anti-inflammatory therapy for asthma and may provide important clues for the development of alternative therapies for glucocorticoid resistance.
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Zuo, Xu, Xiaoping Guo, Yinuo Gu, Haoyu Zheng, Zhengjie Zhou, Xinlei Wang, Shengyu Jiang, Guoqiang Wang, Caina Xu, and Fang Wang. "Recent Advances in Nanomaterials for Asthma Treatment." International Journal of Molecular Sciences 23, no. 22 (November 20, 2022): 14427. http://dx.doi.org/10.3390/ijms232214427.
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Asthma is a chronic airway inflammatory disease with complex mechanisms, and these patients often encounter difficulties in their treatment course due to the heterogeneity of the disease. Currently, clinical treatments for asthma are mainly based on glucocorticoid-based combination drug therapy; however, glucocorticoid resistance and multiple side effects, as well as the occurrence of poor drug delivery, require the development of more promising treatments. Nanotechnology is an emerging technology that has been extensively researched in the medical field. Several studies have shown that drug delivery systems could significantly improve the targeting, reduce toxicity and improve the bioavailability of drugs. The use of multiple nanoparticle delivery strategies could improve the therapeutic efficacy of drugs compared to traditional delivery methods. Herein, the authors presented the mechanisms of asthma development and current therapeutic methods. Furthermore, the design and synthesis of different types of nanomaterials and micromaterials for asthma therapy are reviewed, including polymetric nanomaterials, solid lipid nanomaterials, cell membranes-based nanomaterials, and metal nanomaterials. Finally, the challenges and future perspectives of these nanomaterials are discussed to provide guidance for further research directions and hopefully promote the clinical application of nanotherapeutics in asthma treatment.
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Sousa, Ana R., Stephen J. Lane, John A. Cidlowski, Dontcho Z. Staynov, and Tak H. Lee. "Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor β-isoform." Journal of Allergy and Clinical Immunology 105, no. 5 (May 2000): 943–50. http://dx.doi.org/10.1067/mai.2000.106486.
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Corrigan, C. J., P. H. Brown, N. C. Barnes, S. J. Szefler, J. J. Tsai, A. J. Frew, and A. B. Kay. "Glucocorticoid Resistance in Chronic Asthma: Glucocorticoid Pharmacokinetics, Glucocorticoid Receptor Characteristics, and Inhibition of Peripheral Blood T Cell Proliferation by GlucocorticoidsIn Vitro." American Review of Respiratory Disease 144, no. 5 (November 1991): 1016–25. http://dx.doi.org/10.1164/ajrccm/144.5.1016.
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Stokes, Kindra N., Pryscilla Yoon, Michelle Makiya, Meheret Gebreegziabher, Nicole Holland-Thomas, Brandon Haugen, Konrad Pazdrak, Amy D. Klion, and Paneez Khoury. "Mechanisms of Glucocorticoid Resistance in Hypereosinophlic Syndromes." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 55.33. http://dx.doi.org/10.4049/jimmunol.198.supp.55.33.
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Abstract Glucocorticoids (GC) are anti-inflammatory agents commonly used to treat patients with hypereosinophilic syndrome (HES). GC promote eosinophil apoptosis and downregulation of Th2 cytokine production. Although abnormalities of GC receptor (GR) function and elevations in β-GR isoforms have been implicated in GC resistance in asthma, little is known about the mechanisms of GC resistance in HES. To explore the etiology of GC-resistance in HES, samples were analyzed from 19 subjects with HES enrolled on a prospective study of GC-responsiveness and 33 subjects with HES enrolled on a natural history study of eosinophilia for whom response to GC was known. GC responders were defined by a reduction in absolute eosinophil count (AEC) to <1000/mL after 0.5–1mg/kg of GC for ≥1 week. In the prospective trial, GM AEC was significantly decreased in the GC responders (n=14; GM 2430 to 245/mL, p<0.001) but not in GC non-responders (n=5; GM 12800 vs GM 9927, NS). In contrast, an expected rise in absolute neutrophil count was seen in 12/14 GC responders (GM 3.39 to 6.07, p<0.01) and 5/5 non-responders (GM 2.51 vs. 5.27, p<0.01), suggesting that GC resistance in HES is not a global phenomenon. Expression of GR isoforms (α, β, γ and P) was assessed by RT-PCR in RNA from purified eosinophils and showed no differences between responders (n=23) and non-responders (n=12). A panel of serum cytokine levels were measured in 37 subjects. Only IL-5 levels were significantly different between the groups (GM 86.2 pg/mL in non-responders vs. 15.3 in non-responders, p=0.019). IL-5, at levels comparable to those seen in GC non-responders, inhibited GC-induced eosinophil apoptosis in vitro (n=7). These data suggest that increased IL-5 may play a major role in GC resistance in HES.
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Demko, I. V., A. B. Salmina, A. V. Morgun, and N. A. Malinovskaya. "Expression of P-glycoprotein on blood lymphocytes and its role in development of steroid resistance in severe asthma." PULMONOLOGIYA, no. 3 (June 28, 2007): 41–46. http://dx.doi.org/10.18093/0869-0189-2007-0-3-41-46.
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P-glycoprotein (Pgp) is a membrane transporter of hydrophobic molecules providing efflux of xenobiotics from the cytosole outside the cell. In epithelial cells, Pgp is thought to be responsible for resistance to steroids. Severe bronchial asthma (SBA) is a heterogenous disease characterized by resistance to and dependence on steroids. The goal of this study was to assess expression of Pgp on peripheral blood lymphocytes in severe bronchial asthma and to evaluate the role of Pgp in developing the resistance to glucocorticoid therapy (GC). Assessment of Pgp expression revealed difference in response to GC treatment. All the patients were susceptible to GC, however, the time of therapeutic effect appearance and the number of Pgp-immunopositive cells differed significantly. Thus, more prolonged application of GC for reducing clinical manifestations was required in patients with aspirin induced or fatal bronchial asthma. The number of Pgp-immunopositive lymphocytes per one patients was significantly higher in patients with fatal bronchial asthma and in patients with steroid dependent bronchial asthma (6.8 ± 0.1 and 7.2 ± 0.2, respectively) comparing with patients with non stable bronchial asthma being therapeutically resistant (3.2±0.2 and 3.5±0.1, respectively). Thus, our findings suggest possible pathogenic role of Pgp in development of resistance to GC therapy in patients with bronchial asthma. Detection of Pgp expression on peripheral blood lymphocytes would allow optimizing the volume and duration of intensive anti inflammatory therapy and predicting the doses of basic drugs.
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Wang, Wen-Qian, Yu-Dong Xu, Long-Ping Cui, Lei-Miao Yin, Yu Wang, Yan-Yan Liu, and Yong-Qing Yang. "Acupuncture Has a Positive Effect on Asthmatic Rats in a Glucocorticoid-Independent Manner." Acupuncture in Medicine 34, no. 6 (December 2016): 433–40. http://dx.doi.org/10.1136/acupmed-2015-010934.
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Background There is some evidence to support the use of acupuncture as an alternative therapy for asthma. However, the mechanisms underlying its effects are not fully understood. We have reported previously that acupuncture has beneficial effects on asthma without changing the concentration of serum cortisol, although endogenous glucocorticoid (GC) plays an important role in regulating immune responses. Objective In this study, bilateral adrenalectomy (removal of both adrenal glands) was performed in rats before asthma model induction to investigate whether acupuncture influences asthma in a GC-dependent manner. Methods Adrenal-intact and adrenalectomised rats were injected with ovalbumin to induce asthma and then left untreated or treated with manual acupuncture (MA) at GV14, bilateral BL12 and bilateral BL13, or manual restraint without MA. Healthy and sham-adrenalectomised control groups were also included. Pulmonary resistance (RL), serum concentrations of corticosterone, and eosinophil counts were measured at the end of the experimental course. Sera from adrenal-intact and adrenalectomised asthmatic rats treated with acupuncture were injected into untreated adrenal-intact and adrenalectomised asthmatic rats to investigate further the potential role of GC in the effect of acupuncture. Results Acupuncture significantly decreased RL and eosinophil count in both adrenal-intact and adrenalectomised asthmatic rats. Moreover, administration of sera derived from acupuncture-treated adrenal-intact and adrenalectomised asthmatic rats attenuated the increase in RL and eosinophil count in both asthmatic models. Conclusions Results of this study suggest that endogenous GC is not a key contributor to the effects of acupuncture on asthma, and that acupuncture may have potentially therapeutic effects on asthma in a GC-independent manner.
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Ghonim, Mohamed Ahmed, Jeffrey Wang, Salome Valentina Ibba, Hanh Luu, and Hamid Boulares. "Poly(ADP)Ribose Polymerase inhibition by gene knockout or pharmacologically by olaparib restores steroid sensitivity in murine model of steroid-resistant Asthma." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 119.9. http://dx.doi.org/10.4049/jimmunol.202.supp.119.9.
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Abstract Background Asthma is a serious health issue worldwide and a common treatment for the disease is a combination of steroids with β2-agonist; however, many patients are refractory to steroid treatment. Individuals with steroid-resistant asthma have limited therapeutic options; some can die by status asthmaticus. steroid-resistant asthma is intimately associated with neutrophilic inflammation. Our laboratory has established a critical role for PARP-1 in asthma and neutrophile-based inflammation. Thus we hypothesize that PARP-1 may restores steroid sensitivity in murine model of steroid-resistant asthma. Objective To investigate whether PARP-1 inhibition could restore steroid sensitivity in steroid-resistant asthma model. Methods Murine model of steroid-resistant asthma and cell culture system were used. Results OVA challenge promotes eosinophilic-Th2 mediated response that is blocked by dexamethasone treatment. OVA priming with LPS/IFNγ results in class switching into neutrophile with developing resistance to the treatment with dexamethasone. PARP inhibition by gene knockout or by olaparib reversed the established steroid-resistant asthma manifestation in mice. This is attributed to marked reduction in the inflammatory cells infiltrating the airways and the significant reduction in the Th2 cytokines production, AHR, and the OVA-specific IgE secretion in both BALF and serum of the mice. The reversal of steroid resistance is explained by marked increase in the expression of Glucocorticoid Receptors (GR). Conclusion Our findings demonstrate a critical role for PARP-1 in steroid resistance and support the potential of PARP inhibition as a viable therapeutic strategy for treatment of steroid-resistant asthma.
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Quan-san, Zhang, Xu Xiaohong, Li ying, and Sun Zhaojia. "Role of Th17-cell related cytokines in geriatric asthma." Journal of International Medical Research 47, no. 2 (October 10, 2018): 580–90. http://dx.doi.org/10.1177/0300060518803828.
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Objective This study aimed to investigate the pathogenesis of geriatric asthma through immunoglobulin E (IgE), interleukin-17A (IL-17A), IL-17F, and glucocorticoid receptor-β (GR-β) expression. Methods We studied 51 geriatric male patients with asthma and 50 young male patients with asthma. We also included 21 normal geriatric males and 21 normal young males. All geriatric and young patients were divided into groups according to pulmonary function. Levels of cytokines, such as IgE, IL-17A, IL-17F, and GR-β, were measured. Pulmonary function was assessed. The results from patients were compared with those from the 42 healthy subjects. Results Serum IgE, IL-17A, IL-17F, and GR-β levels in geriatric patients with moderate or severe asthma were significantly higher than those in young patients with moderate asthma and in the normal population. Geriatric patients with asthma had higher asthma control test scores than did young patients with asthma. Conclusion Hormone resistance in geriatric male patients with asthma is more serious than that in young male patients with asthma. Airway inflammation and airway remodeling in geriatric male patients with asthma may be more serious than those in young male patients with asthma, even when there is similar pulmonary function.
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Matsumura, Yasuhiro. "Inflammatory Cellular Phenotypes and Molecular Mechanisms of Glucocorticoid Resistance in Patients with Bronchial Asthma." Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 12, no. 3 (July 1, 2013): 189–200. http://dx.doi.org/10.2174/18715230113129990010.
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Huizenga, Nannette A. T. M., Pieter de Lange, Jan W. Koper, Wouter W. de Herder, Roger Abs, Jan H. L. M. v. Kasteren, Frank H. de Jong, and Steven W. J. Lamberts. "Five Patients with Biochemical and/or Clinical Generalized Glucocorticoid Resistance without Alterations in the Glucocorticoid Receptor Gene*." Journal of Clinical Endocrinology & Metabolism 85, no. 5 (May 1, 2000): 2076–81. http://dx.doi.org/10.1210/jcem.85.5.6542.
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Abstract Cortisol resistance (CR) is a rare disease characterized by a generalized reduced sensitivity of end-organs to the actions of glucocorticoids (GCs). GC effects are mediated by the GC receptor (GR). The molecular alterations in CR described thus far were located in the hormone-binding domain of the GR gene. Recent reports of a considerable prevalence of abnormalities in the GR in patients attending the endocrine clinic prompted us to carry out further investigations with respect to GR protein and GR gene in patients attending the endocrine clinic for a broad spectrum of complaints and biochemical evidence suggesting a CR. In the present study, we describe five patients with biochemical and clinical CR. All patients showed a diurnal rhythm of serum cortisol concentrations (albeit at a high level), an insufficient suppression of serum cortisol concentration in reaction to 1 mg dexamethasone (DEX), and variable degrees of androgen overproduction, in the absence of clinical signs and symptoms of Cushing’s syndrome. Three of the four female patients presented with complaints of androgen overproduction, two of them in combination with fatigue. The other female patient had severe steroid-resistant asthma. The only male patient and his son were asymptomatic. In four patients, we investigated receptor protein characteristics on mononuclear leukocytes in a whole cell DEX binding assay and studied the ability of DEX to inhibit mitogen-induced cell proliferation in mononuclear leukocytes in vitro. In all patients investigated, we found alterations in receptor number or ligand affinity and/or the ability of DEX to inhibit mitogen-induced cell proliferation. To investigate the molecular defects leading to the clinical and biochemical pictures in these patients, we screened the GR gene using PCR/single-strand conformational polymorphism/sequence analysis. No GR gene alterations were found in these patients. In conclusion, the five patients described had clinical and biochemical evidence of CR, but no abnormalities were demonstrated in the GR gene. Probably, as yet undefined alterations somewhere in the cascade of events starting with ligand binding to the GR protein, and finally resulting in the regulation of the expression of GC responsive genes, or postreceptor defects or interactions with other nuclear factors form the pathophysiologic basis of CR in these patients.
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Roos, Abraham B., and Magnus Nord. "The emerging role of C/EBPs in glucocorticoid signaling: lessons from the lung." Journal of Endocrinology 212, no. 3 (November 1, 2011): 291–305. http://dx.doi.org/10.1530/joe-11-0369.
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Glucocorticoids (GCs) have been successfully used in the treatment of inflammatory diseases for decades. However, there is a relative GC resistance in several inflammatory lung disorders, such as chronic obstructive pulmonary disease (COPD), but still the mechanism(s) behind this unresponsiveness remains unknown. Interaction between transcription factors and the GC receptor contribute to GC effects but may also provide mechanisms explaining steroid resistance. CCAAT/enhancer-binding protein (C/EBP) transcription factors are important regulators of pulmonary gene expression and have been implicated in inflammatory lung diseases such as asthma, pulmonary fibrosis, cystic fibrosis, sarcoidosis, and COPD. In addition, several studies have indicated a role for C/EBPs in mediating GC effects. In this review, we discuss the different mechanisms of GC action as well as the function of the lung-enriched members of the C/EBP transcription factor family. We also summarize the current knowledge of the role of C/EBP transcription factors in mediating the effects of GCs, with emphasis on pulmonary effects, and their potential role in mediating GC resistance.
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Luo, Jingjing, Han Liu, Shucheng Hua, and Lei Song. "The Correlation of PM2.5 Exposure with Acute Attack and Steroid Sensitivity in Asthma." BioMed Research International 2022 (August 18, 2022): 1–8. http://dx.doi.org/10.1155/2022/2756147.
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Bronchial asthma is a common chronic inflammatory disease of the respiratory system. Asthma primarily manifests in reversible airflow limitation and airway inflammation, airway remodeling, and persistent airway hyperresponsiveness. PM2.5, also known as fine particulate matter, is the main component of air pollution and refers to particulate matter with an aerodynamic diameter of ≤2.5 μm. PM2.5 can be suspended in the air for an extensive time and, in addition, can contain or adsorb heavy metals, toxic gases, polycyclic aromatic hydrocarbons, bacterial viruses, and other harmful substances. Epidemiological studies have demonstrated that, in addition to increasing the incidence of asthma, PM2.5 exposure results in a significant increase in the incidence of hospital visits and deaths due to acute asthma attacks. Furthermore, PM2.5 was reported to induce glucocorticoid resistance in asthmatic individuals. Although various countries have implemented strict control measures, due to the wide range of PM2.5 sources, complex components, and unknown pathogenic mechanisms involving the atmosphere, environment, chemistry, and toxicology, PM2.5 damage to human health still cannot be effectively controlled. In this present review, we summarized the current knowledge base regarding the relationship between PM2.5 toxicity and the onset, acute attack prevalence, and steroid sensitivity in asthma.
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Ingawale, Deepa K., Satish K. Mandlik, and Snehal S. Patel. "An emphasis on molecular mechanisms of anti-inflammatory effects and glucocorticoid resistance." Journal of Complementary and Integrative Medicine 12, no. 1 (January 1, 2015): 1–13. http://dx.doi.org/10.1515/jcim-2014-0051.
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AbstractGlucocorticoids (GC) are universally accepted agents for the treatment of anti-inflammatory and immunosuppressive disorders. They are used in the treatment of rheumatic diseases and various inflammatory diseases such as allergy, asthma and sepsis. They bind with GC receptor (GR) and form GC–GR complex with the receptor and exert their actions. On activation the GC–GR complex up-regulates the expression of nucleus anti-inflammatory proteins called as transactivation and down-regulates the expression of cytoplasmic pro-inflammatory proteins called as transrepression. It has been observed that transactivation mechanisms are notorious for side effects and transrepressive mechanisms are identified for beneficial anti-inflammatory effects of GC therapy. GC hampers the function of numerous inflammatory mediators such as cytokines, chemokines, adhesion molecules, arachidonic acid metabolites, release of platelet-activating factor (PAF), inflammatory peptides and enzyme modulation involved in the process of inflammation. The GC resistance is a serious therapeutic problem and limits the therapeutic response of GC in chronic inflammatory patients. It has been observed that the GC resistance can be attributed to cellular microenvironment changes, as a consequence of chronic inflammation. Various other factors responsible for resistance have been identified, including alterations in both GR-dependent and GR-independent signaling pathways of cytokine action, hypoxia, oxidative stress, allergen exposure and serum-derived factors. The present review enumerates various aspects of inflammation such as use of GC for treatment of inflammation and its mechanism of action. Molecular mechanisms of anti-inflammatory action of GC and GC resistance, alternative anti-inflammatory treatments and new strategy for reversing the GC resistance have also been discussed.
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Contreras, Diana C., Jacqueline Cephus, Dawn Newcomb, and Jeffrey C. Rathmell. "Metabolic differences between Th2 and Th17 cells in airway inflammation." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 119.16. http://dx.doi.org/10.4049/jimmunol.202.supp.119.16.
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Abstract Asthma is an airway inflammatory disease that is mediated by T effector (Teff) cells, specifically Th2 and Th17 cells. As disease increases in severity, there is a shift towards a higher Th17 response. Treatment of asthmatic patients include the use of glucocorticoid (GC) steroids. These drugs are effective at controlling inflammation in mild cases but as disease severity increases towards neutrophilic disease there is resistance by Th17 cells to effects of the drugs. A key therapeutic objective is to identify either alternative treatments for asthma or targets that make Th17 cells more susceptible to GCs. Studies have shown cells which have increased glycolysis and oxidative phosphorylation are more resistant to the effects of GCs. In this study we show, that in the murine model of airway inflammation there are differences in the expression of metabolic proteins between Th2 and Th17 cells that are present in the lung. This has been seen in cells that have higher amounts glucose uptake. These results imply that the higher glucose utilization of Th17 cells and their metabolic flexibility may contribute to their resistance to the effects of GCs. We also show by CyTOF of PBMCs that individuals with asthma have increased expression of metabolic associated proteins compared to control individuals in their CD4 cells. These data support the metabolic shift observed in our in vitro studies.
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Corrigan, C. J., P. H. Brown, N. C. Barnes, J. J. Tsai, A. J. Frew, and A. B. Kay. "Glucocorticoid Resistance in Chronic Asthma: Peripheral Blood T Lymphocyte Activation and Comparison of the T Lymphocyte Inhibitory Effects of Glucocorticoids and Cyclosporin A." American Review of Respiratory Disease 144, no. 5 (November 1991): 1026–32. http://dx.doi.org/10.1164/ajrccm/144.5.page.
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Saif, Zarqa, Nicolette Hodyl, Eleanor Hobbs, Astrud Tuck, and Vicki Clifton. "Variation in glucocorticoid receptor isoforms expression and function: A possible force driving Glucocorticoid resistance among male fetal placental unit in pregnancies complicated with asthma." Placenta 34, no. 9 (September 2013): A26. http://dx.doi.org/10.1016/j.placenta.2013.06.079.
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Hagan, John B., Robert L. Taylor, and Ravinder J. Singh. "Assessment of Synthetic Glucocorticoids in Asthmatic Sputum." Allergy & Rhinology 2, no. 1 (January 2011): ar.2011.2.0002. http://dx.doi.org/10.2500/ar.2011.2.0002.
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Nonadherence with anti-inflammatory treatment is a frequent cause of continued symptoms in asthmatic patients. Clinical assessments including patient-reported medication administration may provide the asthma specialist incomplete information regarding actual adherence to anti-inflammatory medications. The objective of this report was to describe the first case where adherence to inhaled asthma therapy was assessed by direct analysis of glucocorticoids in induced sputum. The patient's blood, urine, and sputum were tested for synthetic corticosteroids using mass spectrometry. To evaluate a clinical suspicion of poor adherence, sputum, urine, and blood were used to assess for current compliance to medication use. We report a case where asthma specialists attributed poorly controlled asthma to nonadherence to medical therapy. After modification of the medical regimen, adherence with oral and inhaled steroids was assessed–via examination of the urine, blood, and sputum. Direct analysis of glucocorticoids in sputum is feasible and in theory could provide a novel tool to document current medication adherence. Concomitant assessment of glucocorticoids and eosinophils in the same induced sputum specimen could provide insight into possible steroid resistance in select referral patients with difficult asthma.
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Langenbach, Shenna Y., Ben J. Wheaton, Darren J. Fernandes, Catherine Jones, Tara E. Sutherland, Bronwyn C. Wraith, Trudi Harris, Michael J. Schuliga, Catriona McLean, and Alastair G. Stewart. "Resistance of fibrogenic responses to glucocorticoid and 2-methoxyestradiol in bleomycin-induced lung fibrosis in miceThis article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research." Canadian Journal of Physiology and Pharmacology 85, no. 7 (July 2007): 727–38. http://dx.doi.org/10.1139/y07-065.
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Bleomycin-induced lung fibrosis in mice reproduces some key features of pulmonary fibrosis in humans including alveolar inflammation, myofibroblast proliferation, and collagen deposition. Glucocorticoids have been used as first-line therapy for the treatment of lung fibrosis, although their clinical efficacy is equivocal. We examined the effect of the glucocorticoid, methylprednisolone (MP), and the estrogen metabolite, 2-methoxyestradiol (2MEO) on bleomycin-induced bronchoalveolar inflammation, fibrosis, and changes in lung function. The characterization of the time-course of the bleomycin-induced fibrosis indicated that lung dry mass and hydroxyproline content showed less variance than histopathological assessment of fibrosis. The bleomycin-induced increases in bronchoalveolar lavage (BAL) fluid cell number and protein levels were not significantly influenced by treatment with either MP (1 mg·(kg body mass)–1·day–1, i.p.) or 2MEO (50 mg·(kg body mass)–1·day–1, i.p.). Lung fibrosis, measured histopathologically or by hydroxyproline content, was not significantly influenced by either MP or 2MEO treatment, whereas the latter agent did reduce the increment in lung dry mass. The enlargement of alveolar airspaces and the decline in lung compliance were exacerbated by MP treatment. These data suggest that bleomycin-induced pulmonary fibrosis is resistant to inhibition by concurrent treatment with either glucocorticoids or 2MEO.
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Banuelos, Jesus, Soon Shin, and Nick Lu. "Distinct glucocorticoid sensitivity of Th17 cytokines in murine T hybridomas and primary cells (IRC11P.428)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 197.10. http://dx.doi.org/10.4049/jimmunol.194.supp.197.10.
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Abstract Cytokine suppression contributes to the anti-inflammatory actions of glucocorticoids (GCs). However, IL-17 has been reported to be resistant to GC regulation in asthma, nasal polyps, and Crohn’s disease. In contrast, a negative GC-response element has been identified in the promoter region of the IL-17 gene and IL-17 was sensitive to GC suppression in a murine asthma model. To clarify whether IL-17 and other Th17 cytokines are sensitive to GC regulation, we generated Th17 hybridoma cells by fusing in vitro differentiated murine (bl/6) Th17 cells with BW5147 thymoma. Two clones selectively expressing IL-17A, IL-17F, IL-22 and GM-CSF were stable for over 30 generations. Additional clones selectively expressing IFN-γ or IL-4, but not Th17 cytokines and BW5147 cells that produce little or no cytokines were used as controls. Dexamethasone, a potent GC, significantly inhibited anti-CD3 and anti-CD28-stimulated IFN-γ, IL-4, as well as IL-17A, IL-17F, and IL-22 in various clones. Interestingly, IL-17A and IL-17F, but not IL-22, were resistant to GC suppression in in vitro differentiated Th17 cells. Furthermore, hybridomas, but not in vitro differentiated Th17 cells underwent GC-induced apoptosis. IL-6 partially rescues hybridomas from GC-induced apoptosis, however it did not modulate IL-17 suppression by GCs. Our findings support that IL-17A and IL-17F are capable of being downregulated by GCs and Th17 cell microenvironment and cellular milleu engender GC resistance.
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Spahn, J. D., S. J. Szefler, W. Surs, D. E. Doherty, S. R. Nimmagadda, and D. Y. Leung. "A novel action of IL-13: induction of diminished monocyte glucocorticoid receptor-binding affinity." Journal of Immunology 157, no. 6 (September 15, 1996): 2654–59. http://dx.doi.org/10.4049/jimmunol.157.6.2654.
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Abstract We have recently demonstrated that the combination of IL-2 and IL-4 blunts T cell responses to glucocorticoids in steroid resistant (SR) asthma by reducing glucocorticoid receptor (GCR)-binding affinity. Since immune activation appears to be involved in the acquisition of steroid resistance, we sought to identify whether other cytokines could also induce diminished GCR-binding affinity. In the current report, utilizing a [3H]dexamethasone radioligand-binding assay and Scatchard analysis, we found that IL-13, a cytokine with similar actions as IL-4, could induce diminished GCR binding-affinity (GCR Kd = 34.4 +/- 2.3 nM with IL-13 vs Kd = 8.8 +/- 0.7 nM for unstimulated control cells; p < 0.001) in PBMC from normal subjects. In contrast, PBMC incubated with IL-1, IL-3, IL-5, IL-7, IL-8, IL-12, or granulocyte-macrophage-CSF had no effect on GCR-binding affinity; and no additive effect to the decreased GCR-binding affinity was noted when IL-13 was cocultured with IL-2 or IL-4. The cell target of IL-13-induced GCR effects was studied and found to reside in the non-T cell population; specifically, the monocyte fraction. To determine the functional significance of the decreased GCR-binding affinity, monocytes were pretreated with and without IL-1 3 prior to stimulation with LPS and hydrocortisone. IL-13 pretreatment of monocytes significantly diminished (p = 0.005) the suppressive effects of hydrocortisone on LPS-induced IL-6 production. IL-13, by virtue of its ability to induce diminished GCR-binding affinity, may contribute to impaired GC responsiveness during inflammatory illnesses.
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Schaaf, Marcel J. M., Danielle Champagne, Ivo H. C. van Laanen, Diane C. W. A. van Wijk, Annemarie H. Meijer, Onno C. Meijer, Herman P. Spaink, and Michael K. Richardson. "Discovery of a Functional Glucocorticoid Receptor β-Isoform in Zebrafish." Endocrinology 149, no. 4 (December 20, 2007): 1591–99. http://dx.doi.org/10.1210/en.2007-1364.
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In humans, two glucocorticoid receptor (GR) splice variants exist: GRα and GRβ, which are identical between amino acids 1–727 and then diverge. Whereas GRα (the canonical GR) acts as a ligand-activated transcription factor, GRβ does not bind traditional glucocorticoid agonists, lacks GRα’s transactivational activity, and acts as a dominant-negative inhibitor of GRα. It has been suggested that this receptor isoform is involved in the induction of glucocorticoid resistance in asthma patients. Unfortunately, a GR β-isoform has been detected in only humans, and therefore, an animal model for studies on this isoform is lacking. In the present study, we demonstrate that in zebrafish a GR isoform exists that diverges from the canonical zebrafish GR at the same position as human GRβ from human GRα. The zebrafish GR β-isoform acts as a dominant-negative inhibitor in reporter assays, and the extent of inhibition and the effective GRα/GRβ ratio is similar to studies performed with the human GR isoforms. In addition, the subcellular localization of zebrafish GRβ is similar to its human equivalent. Finally, expression levels of GRα and GRβ were determined in adult zebrafish tissues and at several developmental stages. Both receptor isoforms were detected throughout the body, and GRβ mRNA levels were relatively low compared with GRα mRNA levels, as in humans. Thus, for the first time, a GR β-isoform has been identified in a nonhuman animal species, shedding new light on the relevance of this GR splice variant and providing a versatile animal model for studies on the GR system.
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Manni, Michelle, Sivanarayana Mandalapu, Kevin McHugh, and John Alcorn. "The IL-17-independent role of IL-23 in severe asthma (HYP7P.300)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 119.15. http://dx.doi.org/10.4049/jimmunol.192.supp.119.15.
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Abstract Asthma is a common respiratory disease affecting approximately 300 million people worldwide with no current preventions or cures. Th17 cells are known to be influential in asthma pathogenesis, especially in asthmatics with severe disease that fail to respond to glucocorticoid therapy. Interleukin-23 is critical for the maintenance and full acquisition of Th17 cells, but very little is known about its direct effects outside of IL-17 signaling. This study seeks to investigate novel mechanisms by which IL-23 regulates allergic airway disease. To do this, BALB/c SCID and Rag2-/-γc-/- mice were treated with adenoviral IL-23 or control and airway disease was assessed 3 days later. Preliminary data show that exogenous IL-23 induced airway neutrophilia and pulmonary expression of genes related to asthma pathogenesis and Th17-related cytokines and chemokines, while it increased airway resistance in response to methacholine and decreased lung compliance in BALB/c SCID mice. Further, IL-23 induced airspace inflammation and production of Th17-related cytokines and chemokines, while not impacting lung function in Rag2-/-γc-/- mice. This work suggests a novel role for IL-23 in airway disease as IL-23 itself could induce inflammation, which was predominately neutrophilic, in mice regardless of immune status. More significantly, IL-23 was also shown to modulate pulmonary expression of extracellular matrix-related proteins in these mice, which is currently under investigation.
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Kamada, Alan K., Donald Y. M. Leung, Melanie C. Gleason, Malcolm R. Hill, and Stanley J. Szefler. "High-dose systemic glucocorticoid therapy in the treatment of severe asthma: A case of resistance and patterns of response." Journal of Allergy and Clinical Immunology 90, no. 4 (October 1992): 685–87. http://dx.doi.org/10.1016/0091-6749(92)90144-q.
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Yuan, Jia-ying, Zhi-ying Tong, Yu-chao Dong, Jia-yi Zhao, and Yan Shang. "Research progress of icariin, an extract of traditional Chinese medicine, in the treatment of asthma." Allergologia et Immunopathologia 50, no. 1 (January 1, 2022): 9–16. http://dx.doi.org/10.15586/aei.v50i1.490.
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Bronchial asthma is a common chronic airway disease, and long-term management of asthma is the focus and difficulty of clinical treatment. Glucocorticoids are often used as the first choice for the treatment of asthma. However, the occurrence of hormone dependence, hormone resistance, local and systemic adverse reactions caused by hormone application also brings problems for the treatment of asthma. Finding safe and effective new therapeutic drugs is an important research direction at present. Icariin is the effective ingredient of traditional Chinese medicine Epimedium. It has various biological activities such as anti-inflammatory, anti-oxidative stress, and immune regulation. It has high safety and has a wide range of clinical applications. Icariin has the characteristics of multi-target intervention in the treatment of asthma. This article reviews recent studies in order to provide new research directions for further therapeutic drug development.
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Britt, Rodney D., Michael A. Thompson, Sarah Sasse, Christina M. Pabelick, Anthony N. Gerber, and Y. S. Prakash. "Th1 cytokines TNF-α and IFN-γ promote corticosteroid resistance in developing human airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 316, no. 1 (January 1, 2019): L71—L81. http://dx.doi.org/10.1152/ajplung.00547.2017.
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Corticosteroids (CSs) are commonly used to manage wheezing and asthma in pediatric populations. Although corticosteroids are effective in alleviating airway diseases, some children with more moderate-severe asthma phenotypes show CS resistance and exhibit significant airflow obstruction, persistent inflammation, and more frequent exacerbations. Previous studies have demonstrated that Th1 cytokines, such as TNF-α and IFN-γ, promote CS resistance in adult human airway smooth muscle (ASM). In the present study, using a human fetal ASM cell model, we tested the hypothesis that TNF-α/IFN-γ induces CS resistance. In contrast to TNF-α or IFN-γ alone, the combination of TNF-α/IFN-γ blunted the ability of fluticasone propionate (FP) to reduce expression of the chemokines CCL5 and CXCL10 despite expression of key anti-inflammatory glucocorticoid receptor target genes being largely unaffected by TNF-α/IFN-γ. Expression of the NF-κB subunit p65 and phosphorylation of Stat1 were elevated in cells treated with TNF-α/IFN-γ, an effect that remained in the presence of FP. siRNA knockdown studies demonstrated the effects of TNF-α/IFN-γ on increased p65 are mediated by Stat1, a transcription factor activated by IFN-γ. Expression of TNFAIP3, a negative regulator of NF-κB activity, was not altered by TNF-α/IFN-γ. However, the effects of TNF-α/IFN-γ were partially reduced by overexpression of TNFAIP3 but did not influence p65 expression. Together, these data suggest that IFN-γ augments the effects of TNF-α on chemokines by enhancing expression of key inflammatory pathways in the presence of CS. Interactions between TNF-α- and IFN-γ-mediated pathways may promote inflammation in asthmatic children resistant to CSs.
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Wang, Chien-Neng. "The Role of Myristoylated, Alanine-rich C-kinase Substrate (MARCKS) in a Murine Model of Chronic Airway Inflammation." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 44.8. http://dx.doi.org/10.4049/jimmunol.200.supp.44.8.
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Abstract Severe asthma, a complicate chronic lung inflammation. Several chronic inflammatory cells that involved in the inflammatory responses, such as macrophages, neutrophils, and eosinophils, produce large amounts of ROS, the excess level of ROS would increase lung inflammation and lung injury. In fact, this inflammation is well controlled by steroid, but some subset of patients these glucocorticoids are less effective. Neutrophil recruitment is a prominent feature of acute exacerbations of chronic asthma. In patients with difficult-to-control asthma, neutrophilic inflammation rather than eosinophils often predominate. Myristoylated alanine-rich C kinase substrate (MARCKS), is a protein kinase C (PKC) substrate. MARCKS also plays a crucial role that phosphorylation of MARCKS by PKC leads its release from plasma membrane into the cytosol, participating in regulating cell migration such as macrophage and neutrophil. We found that increase of airway MARCKS phosphorylation in asthmatic patients and murine model of chronic steroid-resistance allergic asthma. In this report, our observations indicate that 1) targeting of MARCKS phosphorylation inhibited chronic asthmatic symptoms, such as eosinophil and neutrophil infiltrate into lung. MPS peptide inhibits mucus production, collagen deposition and airway hyperresponsiveness rather than steroid-resistance group; 2) targeting of MARCKS phosphorylation decreased IFN-r, IL-4, IL-17A, IL-33, eotaxin and KC production. MPS peptide also inhibit NADPH oxidase DUOX-1, 2 protein expression and end product 3-nitrotyrosine production; We found that MPS peptide shows a therapeutic potential for steroid-resistance allergic asthma.
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Jiang, Yanping, Allison K. Farrell, Erin T. Tobin, Henriette E. Mair-Meijers, Derek E. Wildman, Francesca Luca, Richard B. Slatcher, and Samuele Zilioli. "Socioeconomic status, financial stress, and glucocorticoid resistance among youth with asthma: Testing the moderation effects of maternal involvement and warmth." Brain, Behavior, and Immunity 96 (August 2021): 92–99. http://dx.doi.org/10.1016/j.bbi.2021.05.014.
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Zhou, J., ZM Kang, QM Xie, C. Liu, SJ Lou, YZ Chen, and CL Jiang. "Rapid nongenomic effects of glucocorticoids on allergic asthma reaction in the guinea pig." Journal of Endocrinology 177, no. 1 (April 1, 2003): R1—R4. http://dx.doi.org/10.1677/joe.0.177r001.
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Glucocorticoids (GCs) are routinely believed to work solely through genomic mechanisms. Recent evidence indicates that GCs can act at the membrane to exert rapid nongenomic effects on various tissues and cells. To ascertain whether nongenomic effects of GCs exist on the allergic asthma reaction, Hartley guinea pigs were sensitized with ovalbumin and challenged with the same antigen given by aerosol. Some animals received inhaled budesonide (3 mg/ml suspended in Hydroxypropyl methylcellulose vehicle) for 5 minutes before ovalbumin challenge; Other animals received saline or blank vehicle as control. We measured the changes of lung resistance and dynamic lung compliance, the pulmonary function used to evaluate allergic asthma severity. Inhaled budesonide inhibited allergic reaction within 10 minutes, which would preclude genomic-mediated responses that normally takes several hours to occur. This study infers for the first time that rapid nongenomic effect of GCs exists on allergic asthma reaction, and provides a new way to investigate nongenomic mechanism of GCs. Further study would raise the possibility of new therapeutic strategies for allergic disease including asthma.
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Alsaffar, Sura F., Haider A. Rasheed, Jabbar H. Yenzeel, and Haider F. Ghazi. "The association of FKBP5 polymorphism with asthma susceptibility in asthmatic patients." Journal of Basic and Clinical Physiology and Pharmacology 32, no. 4 (June 25, 2021): 479–84. http://dx.doi.org/10.1515/jbcpp-2020-0450.
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Abstract Objectives Inhaled corticosteroids are the most effective controllers of asthma, although asthmatics vary in their response. FKBP51 is a major component of the glucocorticoid receptor which regulates its responses to corticosteroids. Therefore, the present study aims to identify the role of FKBP5 gene polymorphism in asthma susceptibility and corticosteroid resistance. Methods DNA was extracted from the blood of 68 asthmatic and 40 control subjects. FKBP5 gene fragments were amplified by PCR and sequenced by the Sanger method. The sequencing results were aligned by mapping on the reference sequences of National center of Biotechnology Information (NCBI) and single nucleotide polymorphisms (SNPs) which were checked. Finally, the genotype, allele frequency and odds ratio (OR) were calculated. Results The FKBP5 fragment sequencing revealed the presence of rs1360780 and one novel SNP found in 17 samples taken from asthmatic patients as compared to db SNP data in the NCBI database. The FKBP5 variant (rs1360780) indicated that the allele frequency of risk allele T was 41.18% in patients and 20% in control group members p<0.001 and OR=2.8 when compared to a wild C allele frequency of 58.82% in patients and 64% in the control group members. The novel SNP FKBP5 was compared to the SNP database in the NCBI database in which wild T allele was substituted with G. The novel SNP was submitted to the ClinVar Submission Portal at NCBI with accession number: rs1581842283 and confirmed an asthma susceptibility risk factor with allele G frequency of 11.76% in asthmatics and 2.5% in the control group members (OR=5.2, p<0.05), as compared to a wild T allele frequency of 88.24% in asthmatics and 97.5% in the control group members. Conclusions The risk allele T of rs1360780 and the novel SNP rs1581842283 risk allele G predict asthma susceptibility but show no association with corticosteroid resistant.
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Mori, Akio, Satoshi Kouyama, Miyako Yamaguchi, Arisa Kinoshita, Yosuke Kamide, Hiroaki Hayashi, Kentaro Watai, et al. "Blocking CD28 signal in steroid resistant asthma." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 192.7. http://dx.doi.org/10.4049/jimmunol.196.supp.192.7.
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Abstract To investigate the mechanism of steroid resistance in severe asthma, effect of CD28 signal blockade on T cell activation and asthma model was analyzed. PBMC obtained from mild (steroid sensitive, SS), steroid dependent (SD), and steroid resistant (SR) asthmatics were stimulated with mitogens. Der f 2-specific Th clones were established and effects of glucocorticoids (GCs) on the proliferation and cytokine synthesis were analyzed. Steroid responsiveness of murine Th clones reactive to ovalbumin were analyzed. Unprimed BALB/c mice were transferred with these clones and then antigen challenged. Effect of GC on BALF eosinophilia was evaluated. CTLA4-Ig was administered through nasal inhalation or venous injection. IL-5 production by PBMC of SS asthmatics was significantly reduced after ICS administration, but that of SD asthma remained high. IC50 values for the suppression of cytokine synthesis and proliferation responses by dexamethasone was not different among SS, SD, or SR asthmatics. Addition of CD28 signal induced steroid resistance in IL-2 and PI-3 kinase dependent manner. Murine SS and SR Th clones were selected based on the steroid sensitivity of their proliferation responses in vitro. Airway infiltration of eosinophils and lymphocytes of mice transferred with SS clones were effectively inhibited by GC. In contrast, those of mice transferred with SR clones were not significantly inhibited. Administration of CTLA4-Ig significantly suppressed the proliferation of GC-treated SR clones in vitro, and the BALF eosinophilia of mice transferred with SR clones in vivo. Costimulatory signal mediated through CD28 seems crucial for the induction of steroid resistance and might be a target for therapeutic intervention.
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A. Sahib, Adel, and Abdul Wahab A.Al-Shaikely. "Evaluation of the Role of Interleukein-2 and Interleukein-4 in the Immunopathogenesis of Steroid Therapy Resistance in Iraqi Asthmatic Patients." Iraqi Journal of Pharmaceutical Sciences ( P-ISSN: 1683 - 3597 , E-ISSN : 2521 - 3512) 17, no. 1 (March 30, 2017): 47–54. http://dx.doi.org/10.31351/vol17iss1pp47-54.
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Interleukins (IL-2 and IL-4) are increased in asthmatics and were reported to induce resistance to steroid therapy in some patients who fail to get benefit from glucocorticoids when used in full dose and for long period of time. In this context, the present study was conducted on Iraqi patients to provide additional laboratory mean, beside the clinical diagnosis, for the decision whether the asthma is steroid sensitive or resistant by monitoring the level of immunoglobulins, complement proteins and interleukins among asthmatic patients (steroid sensitive or resistant) and the possible contribution of other factors like age, sex and environments in the development of steroid resistance. A total number of 55 asthmatics and 28 normal subjects were enrolled in the study. Patients were diagnosed clinically as steroid sensitive (SSA) and steroid resistant (SRA) and blood samples were taken from all subjects included in the study for the measurement of immunoglobulins (IgA, IgG, IgM and IgE), complement proteins (C3 and C4), interleukins (Il-2 and Il-4), and total and differential WBC counts.The results showed no age, sex and residence dependency of acquired steroid resistance, while smoking habit (and may be the atopic allergy) constitute marked predisposing factors. The level of IgA and IgE were high in both SRA and SSA, while IgG level was low in SRA. Complement proteins (C3 and C4) were not differ in asthmatic patients in comparison with control group. The interesting results were those concerning interleukins. The levels of IL-2 and IL-4 were very high in SRA than in SSA. These are parallel with high lymphocyte and neutrophil counts in blood samples of those patients.In conclusion, beside clinical diagnostic features concerning the dose and duration of therapy with glucocorticoids, monitoring the levels of IL-2 and IL-4 could provide additional laboratory diagnostic measures for the convincing decision that asthma is steroid resistant.
Key words: steroid resistant asthma, steroid sensitive asthma, IL-2, IL-4
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Victoni, Tatiana, Emiliano Barreto, Vincent Lagente, and Vinicius F. Carvalho. "Oxidative Imbalance as a Crucial Factor in Inflammatory Lung Diseases: Could Antioxidant Treatment Constitute a New Therapeutic Strategy?" Oxidative Medicine and Cellular Longevity 2021 (February 9, 2021): 1–11. http://dx.doi.org/10.1155/2021/6646923.
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Inflammatory lung disease results in a high global burden of death and disability. There are no effective treatments for the most severe forms of many inflammatory lung diseases, such as chronic obstructive pulmonary disease, emphysema, corticosteroid-resistant asthma, and coronavirus disease 2019; hence, new treatment options are required. Here, we review the role of oxidative imbalance in the development of difficult-to-treat inflammatory lung diseases. The inflammation-induced overproduction of reactive oxygen species (ROS) means that endogenous antioxidants may not be sufficient to prevent oxidative damage, resulting in an oxidative imbalance in the lung. In turn, intracellular signaling events trigger the production of proinflammatory mediators that perpetuate and aggravate the inflammatory response and may lead to tissue damage. The production of high levels of ROS in inflammatory lung diseases can induce the phosphorylation of mitogen-activated protein kinases, the inactivation of phosphoinositide 3-kinase (PI3K) signaling and histone deacetylase 2, a decrease in glucocorticoid binding to its receptor, and thus resistance to glucocorticoid treatment. Hence, antioxidant treatment might be a therapeutic option for inflammatory lung diseases. Preclinical studies have shown that antioxidants (alone or combined with anti-inflammatory drugs) are effective in the treatment of inflammatory lung diseases, although the clinical evidence of efficacy is weaker. Despite the high level of evidence for the efficacy of antioxidants in the treatment of inflammatory lung diseases, the discovery and clinical investigation of safer, more efficacious compounds are now a priority.
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Shabani, Driton, Lirim Mustafa, Pellumb Islami, Ali Iljazi, Arta Dauti, and Hilmi Islami. "Effect of Glucocorticoids Following Application of Adenosine Receptor Blockers in Patients with Chronic Obstructive Bronchitis and Bronchial Asthma." Open Access Macedonian Journal of Medical Sciences 8, B (July 15, 2020): 597–601. http://dx.doi.org/10.3889/oamjms.2020.3894.
Full textAbstract:
AIM: The effects of the glucocorticoids (GR) fluticasone and budesonide and a blocker of the adenosine receptor in the treatment of patients with chronic obstructive pulmonary disease (COPD) and bronchial asthma were studied in this work.
METHODS: The parameters of lung function were determined with body plethysmography. Airway resistance (Raw) was registered and measured and the intrathoracic gas volume and specific resistance (SRaw) of the airways were also calculated.
RESULTS: The results of this study of patients with COPD and bronchial asthma used doxofylline as a blocker of the adenosine receptor. Doxofylline was given orally on 7 consecutive days at home with a dose of 2 × 400 mg orally. Raw and IGTV were then measured, and SRaw was calculated. The results indicated a significant decrease in the airway specific resistance (p < 0.05). On the 8th day, the same patients were given two inhalations with spray fluticasone and budesonide (budesonide, 2 inh × 2 mg; Pulmicort 2 inh × 125 mcg). After the inhalations were given, Raw and IGTV were measured after 5, 15, 30, 60, and 120 min, SRaw was then calculated.
CONCLUSION: After the preliminary application of doxofylline, the GRs fluticasone and budesonide have a significant effect (p < 0.01) on the decrease of the airway SRaw. This effect suggests that the blocking effect of the adenosine receptor (p < 0.05) emphasizes the bronchodilation effect of GRs (p < 0.01).
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Earl, Chris S., Teh Wooi Keong, Shi‐qi An, Sarah Murdoch, Yvonne McCarthy, Junkal Garmendia, Joseph Ward, et al. "Retracted:Haemophilus influenzaeresponds to glucocorticoids used in asthma therapy by modulation of biofilm formation and antibiotic resistance." EMBO Molecular Medicine 7, no. 8 (May 20, 2015): 1018–33. http://dx.doi.org/10.15252/emmm.201505088.
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Титова, О. Н., N. A. Kuzubova, and D. B. Sklyarova. "A patient with severe bronchial asthma: biological therapy vs systemic corticosteroids." Russian Medical Inquiry 6, no. 7 (2022): 393–98. http://dx.doi.org/10.32364/2587-6821-2022-6-7-393-398.
Full textAbstract:
Severe bronchial asthma (SBA) is associated with a significantly lower quality of life and increased mortality. The prevalence of SBA is 3–10% of all patients with asthma. The diagnosis of SBA means that patients require high doses of inhaled corticosteroids/long-acting beta agonists (ICS/LABA) or a fixed dose combination of ICS/LABA and long-acting anticholinergics (ICS/LABA/LAAC). If the above therapy is not effective, systemic glucocorticoids (GCs) are commonly prescribed to treat patients with SBA. However, their use increases the risk of such adverse events as fractures, disorders of carbohydrate metabolism, gastrointestinal bleeding, infections, and visual disturbances. In most cases the SBA development is linked to T2-high inflammation which is manifested by elevated eosinophil level in the peripheral blood. In turn, eosinophilia is associated with an increased rate of asthma exacerbations and resistance to the standard anti-inflammatory therapy. Suppression of eosinophil activity is a promising approach to pathogenetic therapy of SBA. The up-to-date biological therapy with monoclonal antibodies helps to improve asthma control, reduce the number of exacerbations and to reduce systemic GCs or even to avoid them. Currently, targeted therapy for SBA includes medicines to circulating IL-5 (mepolizumab, reslizumab), its receptor alpha-subunit, IL-5RA (benralizumab), or IL-4 receptor alpha-subunit (dupilumab). Benralizumab induces potent eosinophil apoptosis, resulting in rapid and nearly complete depletion of eosinophils in the blood and target tissues. KEYWORDS: severe bronchial asthma, biological therapy, benralizumab, interleukin-5, eosinophilic inflammation, systemic corticosteroids. FOR CITATION: Titova O.N., Kuzubova N.A., Sklyarova D.B. A patient with severe bronchial asthma: biological therapy vs systemic corticosteroids. Russian Medical Inquiry. 2022;6(7):393–398 (in Russ.). DOI: 10.32364/2587-6821-2022-6-7-393-398.
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Jankauskaitė, Lina, Valdonė Misevičienė, Laimutė Vaidelienė, and Rimantas Kėvalas. "Lower Airway Virology in Health and Disease—From Invaders to Symbionts." Medicina 54, no. 5 (October 13, 2018): 72. http://dx.doi.org/10.3390/medicina54050072.
Full textAbstract:
Studies of human airway virome are relatively recent and still very limited. Culture-independent microbial techniques showed growing evidence of numerous viral communities in the respiratory microbial ecosystem. The significance of different acute respiratory viruses is already known in the pathogenesis of chronic conditions, such as asthma, cystic fibrosis (CF), or chronic obstructive lung disease (COPD), and their exacerbations. Viral pathogens, such as influenza, metapneumovirus, parainfluenza, respiratory syncytial virus, or rhinovirus, have been associated with impaired immune response, acute exacerbations, and decrease in lung function in chronic lung diseases. However, more data have attributed a role to Herpes family viruses or the newly identified Anelloviridae family of viruses in chronic diseases, such as asthma, idiopathic pulmonary fibrosis (IPF), or CF. Impaired antiviral immunity, bacterial colonization, or used medication, such as glucocorticoids or antibiotics, contribute to the imbalance of airway microbiome and may shape the local viral ecosystem. A specific part of virome, bacteriophages, frames lung microbial communities through direct contact with its host, the specific bacteria known as Pseudomonas aeruginosa or their biofilm formation. Moreover, antibiotic resistance is induced through phages via horizontal transfer and leads to more severe exacerbations of chronic airway conditions. Morbidity and mortality of asthma, COPD, CF, and IPF remains high, despite an increased understanding and knowledge about the impact of respiratory virome in the pathogenesis of these conditions. Thus, more studies focus on new prophylactic methods or therapeutic agents directed toward viral–host interaction, microbial metabolic function, or lung microbial composition rearrangement.
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Sternberg, EM. "Neuroendocrine regulation of autoimmune/inflammatory disease." Journal of Endocrinology 169, no. 3 (June 1, 2001): 429–35. http://dx.doi.org/10.1677/joe.0.1690429.
Full textAbstract:
Interactions between the immune and nervous systems play an important role in modulating host susceptibility and resistance to inflammatory disease. Neuroendocrine regulation of inflammatory and immune responses and disease occurs at multiple levels: systemically, through the anti-inflammatory action of glucocorticoids released via hypothalamic-pituitary-adrenal axis stimulation; regionally, through production of glucocorticoids within and sympathetic innervation of immune organs such as the thymus; locally, at sites of inflammation. Estrogens also play an important role in immune modulation, and contribute to the approximately 2- to 10-fold higher incidence of autoimmune/inflammatory diseases seen in females of all mammalian species. During inflammation, cytokines from the periphery activate the central nervous system through multiple routes. This results in stimulation of the hypothalamic-pituitary-adrenal axis which, in turn through the immunosuppressive effects of the glucocorticoids, generally inhibits inflammation. Recent studies indicate that physiological levels of glucocorticoids are immunomodulatory rather than solely immunosuppressive, causing a shift in patterns of cytokine production from a TH1- to a TH2-type pattern. Interruptions of this loop at any level and through multiple mechanisms, whether genetic, or through surgical or pharmacological interventions, can render an inflammatory resistant host susceptible to inflammatory disease. Over-activation of this axis, as occurs during stress, can also affect severity of infectious disease through the immunosuppressive effects of the glucocorticoids. These interactions have been clearly demonstrated in many animal models, across species, strains and diseases, and are also relevant to human inflammatory, autoimmune and allergic illnesses, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, allergic asthma and atopic skin disease. While many genes and environmental factors contribute to susceptibility and resistance to autoimmune/inflammatory diseases, a full understanding of the molecular effects on immune responses of combinations of neuropeptides, neurohormones and neurotransmitters at all levels has opened up new therapeutic approaches and are essential for the design of future therapies based on such principles.