Therapeutic Target In Asthma Research Articles

Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice

Lysophosphatidic acid (LPA), an intercellular lipid mediator, is increased in the bronchoalveolar fluids of patients with asthma after allergen exposure. LPA administration exaggerates allergic responses, and the type 2 LPA receptor (LPA2) has been reported as a therapeutic target for asthma. However, results with LPA2 agonist and antagonist along with LPA2 gene deficient mice have been controversial and contradictory. We compared the effects of LPA2 antagonist (H2L5186303) and agonist (GRI977143) in a single experimental protocol of ovalbumin (OVA)-induced allergic asthma by treating drugs before antigen sensitization or challenge. H2L5186303 showed strong suppressive efficacy when administered before OVA sensitization and challenge, such as suppression of airway hyper responsiveness, inflammatory cytokine levels, mucin production, and eosinophil numbers. However, GRI977143 showed significant suppression when administered before an OVA challenge. Increases in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid, Th2 cytokine levels, inflammatory scores, and mucin production were differentially ameliorated by the two drugs. The results demonstrate the multiple roles of LPA2 in asthmatic responses. We suggest that the development of LPA2 antagonists would achieve better therapeutic efficacy against asthma than agonists.

MicroRNA-21 promotes epithelial-mesenchymal transition and migration of human bronchial epithelial cells by targeting poly (ADP-ribose) polymerase-1 and activating PI3K/AKT signaling.

Epithelial-mesenchymal transition (EMT) is known to be involved in airway remodeling and fibrosis of bronchial asthma. However, the molecular mechanisms leading to EMT have yet to be fully clarified. The current study was designed to reveal the potential mechanism of microRNA-21 (miR-21) and poly (ADP-ribose) polymerase-1 (PARP-1) affecting EMT through the PI3K/AKT signaling pathway. Human bronchial epithelial cells (16HBE cells) were transfected with miR-21 mimics/inhibitors and PARP-1 plasmid/small interfering RNA (siRNA). A dual luciferase reporter assay and biotin-labeled RNA pull-down experiments were conducted to verify the targeting relationship between miR-21 mimics and PARP-1. The migration ability of 16HBE cells was evaluated by Transwell assay. Quantitative real-time polymerase chain reaction and Western blotting experiments were applied to determine the expression of Snail, ZEB1, E-cadherin, N-cadherin, Vimentin, and PARP-1. The effects of the PI3K inhibitor LY294002 on the migration of 16HBE cells and EMT were investigated. Overexpression of miR-21 mimics induced migration and EMT of 16HBE cells, which was significantly inhibited by overexpression of PARP-1. Our findings showed that PARP-1 was a direct target of miR-21, and that miR-21 targeted PARP-1 to promote migration and EMT of 16HBE cells through the PI3K/AKT signaling pathway. Using LY294002 to block PI3K/AKT signaling pathway resulted in a significant reduction in the migration and EMT of 16HBE cells. These results suggest that miR-21 promotes EMT and migration of HBE cells by targeting PARP-1. Additionally, the PI3K/AKT signaling pathway might be involved in this mechanism, which could indicate its usefulness as a therapeutic target for asthma.

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

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

Autocrine motility factor receptor as a therapeutic target for asthma: comments on 'AMFR drives allergic asthma development by promoting alveolar macrophage-derived GM-CSF production'.

Autocrine motility factor receptor as a therapeutic target for asthma: comments on 'AMFR drives allergic asthma development by promoting alveolar macrophage-derived GM-CSF production'.

Novel potential treatable traits in asthma: Where is the research taking us?

Asthma is a complex, heterogeneous disease in which the underlying mechanisms are not fully understood. Patients are often grouped into phenotypes (based on clinical, biologic, and physiologic characteristics) and endotypes (based on distinct genetic or molecular mechanisms). Recently, patients with asthma have been broadly split into 2 phenotypes based on their levels of type 2 inflammation: type 2 and non-type 2 asthma. However, this approach is likely oversimplified, and our understanding of the non-type 2 mechanisms in asthma remains extremely limited. Abetter understanding of asthma phenotypes and endotypes may assist in development of drugs for new therapeutic targets in asthma. One approach is to identify "treatable traits," which are specific patient characteristics related to phenotypes and endotypes that can be targeted by therapies. This review will focus on emerging treatable traits in asthma and aim to describe novel patient subgroups and endotypes that may represent the next step in the search for new therapeutic approaches.

Small Proline-Rich Protein 3 Regulates IL-33/ILC2 Axis to Promote Allergic Airway Inflammation.

Small proline-rich proteins (SPRRs), components of cornified cell envelope precursors, have recently been found to participate in airway diseases. However, their role in allergic airway inflammatory conditions remains unknown. Here, we explored the expression of SPRR3 in house dust mite (HDM)-sensitized/challenged mice and attempted to elucidate the regulatory role of SPRR3 in allergic airway inflammation. SPRR3 was identified via bioinformatics analysis of Gene Expression Omnibus (GEO) databases and further confirmed to be upregulated in the lungs of asthmatic mice. Knockdown of SPRR3 via the intratracheal route significantly inhibited eosinophils in bronchoalveolar lavage fluid (BALF) and suppressed the expressions of type 2 cytokines (IL-4, IL-5, and IL-13) in BALF and lung tissues. Further, SPRR3 knockdown reduced the expression of IL-33 and further attenuated the activation of the PI3K/AKT/NF-κB signaling pathway in the recruitment of group 2 innate lymphoid cells (ILC2s) to inhibit allergic airway inflammation. In vitro, SPRR3 siRNA could alleviate HDM-induced inflammatory responses in BEAS-2B cells. This study reveals the regulatory role of SPRR3 in allergic airway inflammation, identifying this protein as a potential novel therapeutic target for asthma.

The TL1A-DR3 Axis in Asthma: Membrane-Bound and Secreted TL1A Co-Determined the Development of Airway Remodeling.

PurposeTumor necrosis factor-like ligand 1A (TL1A), especially its secreted form, has been shown to contribute to eosinophilic inflammation and mucus production, cardinal features of asthma, through its receptor, death receptor 3 (DR3). However, the role of the TL1A-DR3 axis in asthma, especially in terms of airway remodeling, has not yet been fully understood.MethodsThe present study investigated the expression and secretion of TL1A in the lung and human bronchial epithelial cells. DR3 small interfering RNA (siRNA), TL1A siRNA, and truncated plasmids were used respectively to identify the function of the TL1A-DR3 axis in vitro. To further validate the roles of the TL1A-DR3 axis in asthma, we collected airway biopsies and sputa from asthmatic patients and constructed a mouse model following rTL1A administration, DR3 knockdown, and TL1A knockout, the asthma-related inflammatory response and the pathological changes in airways were analyzed using various experimental methods. Associated signaling pathways downstream of TL1A knockout in the mouse model were analyzed using RNA sequencing.ResultsTL1A, especially its non-secreted form (nsTL1A) was involved in the remodeling process in asthmatics’ airways. Knockdown of TL1A or its receptor DR3 decreased the expression of fibrosis-associated protein in BEAS-2B cells. Reversely, overexpression of nsTL1A in airway epithelial cells facilitated the transforming growth factor-β-induced remodeling progress. In the asthma mouse model, activating the TL1A-DR3 axis contributes to airway inflammation, remodeling, and tissue destruction. Reciprocally, DR3 knockdown or TL1A knockout partly reverses airway remodeling in the asthma model induced by ovalbumin.ConclusionsOur results confirm differential TL1A expression (including its secreted and non-secreted form) in asthma, which modulates remodeling. The shared mechanism of action by which nsTL1A and secreted TL1A exert their effects on asthma development might be mediated via the nuclear factor-κB pathway. The TL1A-DR3 axis presents a promising therapeutic target in asthma.

Increased MMP12 mRNA expression in induced sputum was correlated with airway eosinophilic inflammation in asthma patients: Evidence from bioinformatic analysis and experiment verification.

Asthma is a common chronic airway inflammatory disease worldwide. Studies on gene expression profiles in induced sputum may provide noninvasive diagnostic biomarkers and therapeutic targets for asthma. To investigate mRNA expression of MMP12 in induced sputum and its relationship with asthma airway eosinophilic inflammation. GSE76262 dataset was analyzed using R software, weighted gene coexpression network analysis (WGCNA), and protein-protein interaction (PPI) network construction. The top ten hub genes were screened with Cytoscape software (version 3.8.4). We then verified the mRNA expression of MMP12 in two other datasets (GSE137268 and GSE74075) via ROC curve estimates and our induced sputum samples using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Finally, we explored the correlation between MMP12 with asthmatic eosinophilic-related indicators. We obtained the top ten hub genes, namely, CCL17, CCL2, CSF1, CCL22, CCR3, CD69, FCGR2B, CD1C, CD1E, and MMP12 via expression profile screening and validation on the GSE76262 dataset. MMP12 was selected as the candidate gene through further validation on GSE137268 and GSE74075 datasets. Finally, we demonstrated that the mRNA expression of MMP12 is significantly upregulated in induced sputum of asthmatic patients (p<0.05) and significantly correlated with eosinophilic-related indicators (p<0.05). These findings indicated that MMP12 can act as a diagnostic biomarker for asthma. Our study successfully identified and demonstrated that MMP12 is a potential diagnostic biomarker for asthma due to its high expression and association with eosinophilic-related indicators. The results of this study can provide novel insights into asthmatic diagnosis and therapy in the future.

LncRNA NEAT1 regulates MMP-16 by targeting miR-200a/b to aggravate inflammation in asthma

Asthma is a common respiratory disease which is characterized by persistent airway inflammation. Abnormal expression of long non-coding RNAs (lncRNAs) is observed in asthma. However, whether lncRNA nuclear-enriched abundant transcript 1 (NEAT1) regulates asthmatic inflammation and its mechanism still needs to be further investigated. The expression levels of inflammatory factors (tumour necrosis factor (TNF)-α, interleukin (IL)-4, IL-13, and IL-10) were detected using reverse transcription quantitative real-time PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). MTT and flow cytometry assays were employed to determine cell proliferation and apoptosis, respectively. Dual luciferase reporter assay was performed to verify the relationship between miR-200a/b and MMP-16 or NEAT1. NEAT1 silencing markedly reduced TNF-α, IL-4, and IL-13 levels, while elevated IL-10 expression, suppressed cell proliferation, and promoted cell apoptosis. However, NEAT1 overexpression elicited the opposite effects on cell proliferation and inflammation cytokines secretion. What is more, NEAT1 negatively regulated miR-200a/b expression, and MMP16 was a target gene of miR-200a/b. miR-200a/b overexpression suppressed inflammation, cell proliferation, and enhanced cell apoptosis through regulation of MMP16. Moreover, MMP-16 overexpression or miR-200a/b inhibition abolished the regulatory effect of sh-NEAT1 on cell inflammation and apoptosis in BEAS-2B cells. NEAT1 acted as the role of sponge for miR-200a/b to regulate MMP-16 expression, thereby promoting asthma progression, suggesting that NEAT1 might have great potential as therapeutic target for asthma.

Eicosanoid receptors as therapeutic targets for asthma.

Eicosanoids comprise a group of oxidation products of arachidonic and 5,8,11,14,17-eicosapentaenoic acids formed by oxygenases and downstream enzymes. The two major pathways for eicosanoid formation are initiated by the actions of 5-lipoxygenase (5-LO), leading to leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and cyclooxygenase (COX), leading to prostaglandins (PGs) and thromboxane (TX). A third group (specialized pro-resolving mediators; SPMs), including lipoxin A4 (LXA4) and resolvins (Rvs), are formed by the combined actions of different oxygenases. The actions of the above eicosanoids are mediated by approximately 20 G protein-coupled receptors, resulting in a variety of both detrimental and beneficial effects on airway smooth muscle and inflammatory cells that are strongly implicated in asthma pathophysiology. Drugs targeting proinflammatory eicosanoid receptors, including CysLT1, the receptor for LTD4 (montelukast) and TP, the receptor for TXA2 (seratrodast) are currently in use, whereas antagonists of a number of other receptors, including DP2 (PGD2), BLT1 (LTB4), and OXE (5-oxo-ETE) are under investigation. Agonists targeting anti-inflammatory/pro-resolving eicosanoid receptors such as EP2/4 (PGE2), IP (PGI2), ALX/FPR2 (LXA4), and Chemerin1 (RvE1/2) are also being examined. This review summarizes the contributions of eicosanoid receptors to the pathophysiology of asthma and the potential therapeutic benefits of drugs that target these receptors. Because of the multifactorial nature of asthma and the diverse pathways affected by eicosanoid receptors, it will be important to identify subgroups of asthmatics that are likely to respond to any given therapy.

Transcriptomic Analysis Exploring the Molecular Mechanisms of Hanchuan Zupa Granules in Alleviating Asthma in Rat.

Objective To investigate the molecular mechanisms of HCZP treatment of asthma. Materials and Methods Thirty Sprague Dawley (SD) rats were divided into normal, asthma, and HCZP groups (n = 10). The asthma model was sensitized by 1 mg ovalbumin (OVA)/aluminum hydroxide Al(OH)3mixture and then challenged with 1% aerosolized OVA for four weeks. Rats in the HCZP group received 10.08 g/kg/d HCZP for four weeks during OVA challenge. Then, lung tissues of rats in each group were collected for RNA sequencing. Moreover, the expression level of some core genes was detected by using western blotting and immunohistochemistry. Results Inflammatory cell infiltration and pathological damage of the lungs improved in the HCZP group. Compared with the asthma group (0.049 ± 0.002 mm2/mm; 0.036 ± 0.006 mm2/mm; and 0.014 ± 0.001 mm2/mm), total wall thickness (0.042 ± 0.001 mm2/mm), inner wall thickness (0.013 ± 0.001 mm2/mm), and smooth muscle layer thickness (0.012 ± 0.001 mm2/mm) significantly decreased in the HCZP group. Bioinformatics analysis showed that hub genes such as bradykinin receptor B2 (Bdkrb2) and CD4 molecule (Cd4) had different expression patterns between model and HCZP groups. Two transcription factors, forkhead box Q1 (Foxq1) and nuclear factor of activated T cells 2 (Nfatc2), served important regulatory roles in asthma. Compared with the model group, Bdkrb2 protein expression increased and Nfatc2 protein expression decreased in the HCZP group. Discussion and Conclusion. HCZP could alleviate asthma via regulating the expression of several hub genes, which might serve as therapeutic targets for asthma. However, the mechanism of these genes will be studied in the future.

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

To identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (PGWAS < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (PTWAS = 1.42E-54). Other TWAS genes include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). We demonstrate that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants is in the blood. We map 485 blood eQTL-regulated genes associated with asthma and 50 of them are causal by Mendelian randomization. Prioritization of druggable genes reveals known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.

Fructose-1,6-bisphosphatase aggravates oxidative stress-induced apoptosis in asthma by suppressing the Nrf2 pathway.

Asthma is a chronic airway disease that causes excessive inflammation, oxidative stress, mucus production and bronchial epithelial cell apoptosis. Fructose‐1,6‐bisphosphatase (Fbp1) is one of the rate‐limiting enzymes in gluconeogenesis and plays a critical role in several cancers. However, its role in inflammatory diseases, such as asthma, is unclear. Here, we examined the expression, function and mechanism of action of Fbp1 in asthma. Gene Expression Omnibus (GEO) data sets revealed that Fbp1 was overexpressed in a murine model of asthma and in interleukin (IL)‐4‐ or IL‐13‐stimulated bronchial epithelial cells. We confirmed the findings in an animal model as well as Beas‐2B and 16HBE cells. In vitro investigations revealed that silencing of Fbp1 reduced apoptosis and the proportion of cells in the G2/M phase, whereas overexpression led to increases. Fbp1 knock‐down inhibited oxidative stress by activating the nuclear factor erythroid 2‐related factor 2 (Nrf2) pathway, whereas Fbp1 overexpression aggravated oxidative stress by suppressingthe Nrf2 pathway. Moreover, the Nrf2 pathway inhibitor ML385 reversed the changes caused by Fbp1 inhibition in Beas‐2B and 16HBE cells. Collectively, our data indicate that Fbp1 aggravates oxidative stress‐induced apoptosis by suppressing Nrf2 signalling, substantiating its potential as a novel therapeutic target in asthma.

Th17/Treg cell imbalance plays an important role in respiratory syncytial virus infection compromising asthma tolerance in mice

Mucosal tolerance is induced early in life and is an important mechanism of protection from diseases, such as asthma. Respiratory syncytial virus (RSV) is a main cause of bronchiolitis and pneumonia in infants. Clinical studies have found that there is a strong association between RSV infection in infancy and later development of asthma, but the underlying mechanisms are unclear. A mouse model of immune tolerance induced by oral feeding of ovalbumin(OVA) was successfully established in our previous studies. We found that RSV infection could break the oral immune tolerance state.RSV infection increased the mRNA expression of IL-17A and IL-17A/Foxp3(the transcription factor forkhead box P3) in OT mice, but the mRNA expression of IL-4 and other T helper(Th)2 cytokines did not change significantly. As detected by flow cytometry analysis, RSV infection elevated Th17 cell levels and correspondingly decreased Regulatory T(Treg) cell levels in the hilar lymph nodes (HLNs) and mesenteric lymph nodes (MLNs), but there were no significant differences in the spleen or peripheral blood.We hypothesized that an imbalance in Th cells played an important role in RSV infection compromising asthma tolerance.RSV infection disrupted asthma tolerance by increasing the Th17/Treg ratio rather than the Th1/Th2 ratio'.Therefore, altering the Th17/Treg ratio has been identified as a potential therapeutic target in asthma caused by RSV or another virus.

Serum sphingolipid profile in asthma.

Sphingolipids metabolism is an important cell process and plays critical roles in asthma. However, the involvement of sphingolipids in the pathogenesis of asthma and its subtypes is unknown. The present study aimed to determine the role of sphingolipids in asthma and its subtypes. Clinical data from 51 asthma patients and 9 healthy individuals were collected and serum samples were performed to analyze the levels of serum sphingolipids by liquid chromatography-mass spectrometry-based targeted metabolomics. Results showed that the levels of sphingomyelin (SM) including SM34:2, SM38:1, and SM40:1 were significantly decreased in asthmatic patients compared to healthy controls. Moreover, serum SM levels were obviously decreased in the blood noneosinophilic asthma (bNEA) group compared with blood eosinophilic asthma group. Similar tendencies of serum SM level changes were observed in the early-onset group compared with late-onset group. Correlation analysis revealed that SM 40:1 was negatively related to sputum IL-17A (r=-0.621, P=0.042). The present study presented that the SM may be a protective factor of asthma and contributes to the mechanism of asthma, especially bNEA. SM may be a potential biomarker and therapeutic target in asthma.

Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma.

Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5–10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes.

Ku70 modulation alleviates murine allergic asthma features and restores mitochondrial function in lungs

The airway epithelium is continuously exposed to a variety of pollutants and allergens, thanks to both natural and manmade environmental pollution. With numerous protective mechanisms, the airway epithelium protects the lungs. DNA repair mechanism is one such protective response and its failure could lead to the accumulation of DNA mutations. Our lab had earlier demonstrated the dysfunctional mitochondria in airway epithelium of the asthmatic mice lungs. Here, we show that Ku70 modulation by the administration of Ku70 plasmid attenuates asthma features and reduces mitochondrial dysfunction in the lungs of allergen exposed mice. Ku70 is a key DNA repair protein with diverse roles including VDJ recombination, telomere maintenance, and maintenance of cell homeostasis. Recently, we found a reduction in Ku70 expression in asthmatic airway epithelium, and this was associated with mitochondrial dysfunction in asthmatic condition. In this study, we have shown that Ku70 over-expression in asthmatic mice attenuated airway hyperresponsiveness, airway inflammation, sub-epithelial fibrosis along with reduction in TGF-β with no effect in IL-13 levels and goblet cell metaplasia. Ku70 over-expression in asthmatic mice reduced 8-isoprostane, a marker of oxidative stress, and restored the mitochondrial function in asthmatic mice. We further found these roles of Ku70 to be independent of DNA damage as Ku70 overexpressed mice did not show any reduction in DNA tail, an index of DNA damage. Thus, our findings indicate that Ku70 can attenuate crucial features of asthma along with the restoration of mitochondrial function. This implies that Ku70 could be a therapeutic target for asthma without affecting DNA repair function.

Взаимоотношения толл-подобных рецепторов и ядерных транскрипционных факторов при бронхиальной астме

Бронхиальная астма (БА) является широко распространенным, хроническим, гетерогенным заболеванием. В течение последних нескольких лет клинические исследования предоставили новую информацию о фенотипировании, эндотипировании и вариантах лечения астмы. При всей эффективности традиционных методов лечения БА у ряда пациентов заболевание либо частично контролируется, либо не контролируется, несмотря на интенсивное, основанное на рекомендациях лечение. Данное состояние вопроса делает крайне актуальным дальнейшее изучение патогенеза хронического воспаления при БА для поиска и разработки новых терапевтических стратегий. Развитие и прогрессирование БА обусловлены активацией внутриклеточных сигнальных путей и генов воспаления в ответ на действие триггерных факторов. Внутриклеточными модуляторами воспалительной реакции на генном уровне являются ядерные транскрипционные факторы, к которым относят активирующий протеин-1 (activator protein-1, AP-1) и ядерный фактор каппа B (nuclear factor-kappa B, NF-kB), обладающие провоспалительной активностью. К внутриклеточным модуляторам относят также рецептор глюкокортикоидов (glucocorticoid receptor, GR) и рецепторы, активирующие пролиферацию пероксисом (peroxisome proliferator-activated receptors, PPARs) с противоспалительной активностью. Взаимоотношения между провоспалительными и противовоспалительными ядерными транскрипционными факторами являются предметом пристального изучения в настоящее время, так как последние могут служить мишенью для разработки стратегий управления активностью воспалительного процесса, в том числе при БА. Важную роль в сигнальных механизмах воспалительной реакции играют толл-подобные рецепторы (TLRs), инициирующие воспаление через активацию NF-kB и AP-1. В то же время, TLRs обладают способностью модулировать экспрессию PPARs и GR, противовоспалительный механизм действия которых осуществляется за счет подавления активности NF-kB и АР-1. В данном обзоре суммированы современные взгляды на структуру, функцию ядерных транскрипционных факторов и TLRs, а также их участие в патогенезе хронического воспаления при БА. Регуляция взаимоотношений между TLRs и ядерными транскрипционными факторами может быть важной терапевтической мишенью при БА. Bronchial asthma is a common, chronic and heterogeneous disease. During the last few years, clinical studies have provided new information about asthma phenotyping, endotyping, and therapeutic options. With all effectiveness of traditional asthma treatments, in a number of patients the disease is either controlled partially or not controlled, despite intensive, recommendation-based treatment. This makes further study of the pathogenesis of asthma-related chronic inflammation essential for developing new therapeutic strategies. The development and progression of asthma are caused by activation of intracellular signaling pathways and inflammation genes in response to action of trigger factors. Intracellular modulators of the inflammatory response at the gene level are nuclear transcription factors, which include proinflammatory activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kB). Intracellular modulators also include the glucocorticoid receptor (GR)) and peroxisome proliferator-activated receptors (PPARs), which have an anti-inflammatory activity. The relationship between pro- and anti-inflammatory nuclear transcription factors is presently under close investigation since it may represent a target for strategies of managing the inflammatory process, including in asthma. Toll-like receptors (TLRs) play an important role in the signaling mechanisms that initiate inflammation through activation of NF-kB and AP-1. At the same time, TLRs can modulate the expression of PPARs and GR, which have an anti-inflammatory action due to suppressing the activity of NF-kB and AP-1. This review summarizes current views on the structure and function of nuclear transcription factors and TLRs, as well as their participation in the pathogenesis of chronic inflammation in asthma. Regulation of the relationship between TLRs and nuclear transcription factors may be an important therapeutic target in asthma.

Pulmonary Surfactants: a New Therapeutic Target in Asthma.

Purpose of ReviewLung tissues are highly susceptible to airway inflammation as they are inevitably exposed to inhaled pathogens and allergens. In the lungs, clearance of infectious agents and regulation of inflammatory responses are important for the first-line defense, where surfactants play a role in host defense mechanisms. In this review, clinical significance of pulmonary surfactants in asthma has been highlighted.Recent FindingsSurfactants, such as surfactant protein A (SP-A) and SP-D released from alveolar epithelium, reduce pathogen infection and control immune-cell activation. Especially, SP-D directly binds to eosinophil surface, leading to inhibition of extracellular trap formation and reduction in airway inflammation. Production of surfactants is commonly determined by both genetic (single nucleotide polymorphisms) and environmental factors influencing processes involved in the development of asthma. In addition, nintedanib (an intracellular inhibitor of tyrosine kinases) could increase SP-D levels and is used in patients with idiopathic pulmonary fibrosis. These findings may provide a possible application of SP-D in asthma.SummarySurfactants are key players contributing to host defense through maintaining the immune system. As clinical implications of surfactants involved in asthma have been suggested, further translational studies are needed to apply surfactants as an effective therapeutic target in patients with asthma.

Transcriptomic analysis delineates potential signature genes and miRNAs associated with the pathogenesis of asthma

Asthma is a multifarious disease affecting several million people around the world. It has a heterogeneous risk architecture inclusive of both genetic and environmental factors. This heterogeneity can be utilised to identify differentially expressed biomarkers of the disease, which may ultimately aid in the development of more localized and molecularly targeted therapies. In this respect, our study complies with meta-analysis of microarray datasets containing mRNA expression profiles of both asthmatic and control patients, to identify the critical Differentially Expressed Genes (DEGs) involved in the pathogenesis of asthma. We found a total of 30 DEGs out of which 13 were involved in the pathway and functional enrichment analysis. Moreover, 5 DEGs were identified as the hub genes by network centrality-based analysis. Most hub genes were involved in protease/antiprotease pathways. Also, 26 miRNAs and 20 TFs having an association with these hub genes were found to be intricated in a 3-node miRNA Feed-Forward Loop. Out of these, miR-34b and miR-449c were identified as the key miRNAs regulating the expression of SERPINB2 gene and SMAD4 transcription factor. Thus, our study is suggestive of certain miRNAs and unexplored pathways which may pave a way to unravel critical therapeutic targets in asthma.