scholarly journals Defining Bronchial Asthma with Phosphoinositide 3-Kinase Delta Activation: Towards Endotype-Driven Management

2019 ◽  
Vol 20 (14) ◽  
pp. 3525 ◽  
Author(s):  
Jae Seok Jeong ◽  
Jong Seung Kim ◽  
So Ri Kim ◽  
Yong Chul Lee

Phosphoinositide 3-kinase (PI3K) pathways play a critical role in orchestrating the chronic inflammation and the structural changes of the airways in patients with asthma. Recently, a great deal of progress has been made in developing selective and effective PI3K-targeted therapies on the basis of a vast amount of studies on the roles of specific PI3K isoforms and fine-tuned modulators of PI3Ks in a particular disease context. In particular, the pivotal roles of delta isoform of class I PI3Ks (PI3K-δ) in CD4-positive type 2 helper T cells-dominant disorders such as asthma have been consistently reported since the early investigations. Furthermore, there has been great advancement in our knowledge of the implications of PI3K-δ in various facets of allergic inflammation. This has involved the airway epithelial interface, adaptive T and B cells, potent effector cells (eosinophils and neutrophils), and, more recently, subcellular organelles (endoplasmic reticulum and mitochondria) and cytoplasmic innate immune receptors such as NLRP3 inflammasome, all of which make this PI3K isoform an important druggable target for treating asthma. Defining subpopulations of asthma patients with PI3K-δ activation, namely PI3K-δ-driven asthma endotype, may therefore provide us with a novel framework for the treatment of the disease, particularly for corticosteroid-resistant severe form, an important unresolved aspect of the current asthma management. In this review, we specifically summarize the recent advancement of our knowledge on the critical roles of PI3K-δ in the pathogenesis of bronchial asthma.

2021 ◽  
Vol 22 (9) ◽  
pp. 4356
Author(s):  
Eva Knuplez ◽  
Eva Maria Sturm ◽  
Gunther Marsche

Eosinophils are important effector cells involved in allergic inflammation. When stimulated, eosinophils release a variety of mediators initiating, propagating, and maintaining local inflammation. Both, the activity and concentration of secreted and cytosolic phospholipases (PLAs) are increased in allergic inflammation, promoting the cleavage of phospholipids and thus the production of reactive lipid mediators. Eosinophils express high levels of secreted phospholipase A2 compared to other leukocytes, indicating their direct involvement in the production of lipid mediators during allergic inflammation. On the other side, eosinophils have also been recognized as crucial mediators with regulatory and homeostatic roles in local immunity and repair. Thus, targeting the complex network of lipid mediators offer a unique opportunity to target the over-activation and ‘pro-inflammatory’ phenotype of eosinophils without compromising the survival and functions of tissue-resident and homeostatic eosinophils. Here we provide a comprehensive overview of the critical role of phospholipase-derived lipid mediators in modulating eosinophil activity in health and disease. We focus on lysophospholipids, polyunsaturated fatty acids, and eicosanoids with exciting new perspectives for future drug development.


2017 ◽  
Vol 215 (1) ◽  
pp. 263-281 ◽  
Author(s):  
Matthew T. Stier ◽  
Jian Zhang ◽  
Kasia Goleniewska ◽  
Jacqueline Y. Cephus ◽  
Mark Rusznak ◽  
...  

Group 2 innate lymphoid cells (ILC2s) are effector cells within the mucosa and key participants in type 2 immune responses in the context of allergic inflammation and infection. ILC2s develop in the bone marrow from common lymphoid progenitor cells, but little is known about how ILC2s egress from the bone marrow for hematogenous trafficking. In this study, we identified a critical role for IL-33, a hallmark peripheral ILC2-activating cytokine, in promoting the egress of ILC2 lineage cells from the bone marrow. Mice lacking IL-33 signaling had normal development of ILC2s but retained significantly more ILC2 progenitors in the bone marrow via augmented expression of CXCR4. Intravenous injection of IL-33 or pulmonary fungal allergen challenge mobilized ILC2 progenitors to exit the bone marrow. Finally, IL-33 enhanced ILC2 trafficking to the lungs in a parabiosis mouse model of tissue disruption and repopulation. Collectively, these data demonstrate that IL-33 plays a critical role in promoting ILC2 egress from the bone marrow.


Author(s):  
M.J. Witcomb ◽  
M.A. O'Keefe ◽  
CJ. Echer ◽  
C. Nelson ◽  
J.H. Turner ◽  
...  

Under normal circumstances, Pt dissolves only a very small amount of interstitial carbon in solid solution. Even so, an appropriate quench/age treatment leads to the formation of stable Pt2C {100} plate precipitates. Excess (quenched-in) vacancies play a critical role in the process by accommodating the volume and structural changes that accompany the transformation. This alloy system exhibits other interesting properties. Due to a large vacancy/carbon atom binding energy, Pt can absorb excess carbon at high temperatures in a carburizing atmosphere. In regions rich in carbon and vacancies, another carbide phase, Pt7C which undergoes an order-disorder reaction was formed. The present study of Pt carburized at 1160°C and aged at 515°C shows that other carbides in the PtxC series can be produced.


Author(s):  
E.V. Prosekova ◽  
A.I. Turyanskaya ◽  
N.G. Plekhova ◽  
M.S. Dolgopolov ◽  
V.A. Sabynych

Расширение спектра изучаемых клонов Тхелперов определило более сложные иммунные механизмы реализации аллергического воспаления. Цель. Характеристика показателей и взаимосвязей цитокинового профиля сыворотки и субпопуляционного состава Тлимфоцитов периферической крови у детей с бронхиальной астмой и аллергическим ринитом. Материалы и методы. Проведено комплексное обследование 150 детей в возрасте 311 лет с верифицированным диагнозом бронхиальной астмы, аллергического ринита и 30 здоровых сверстников. Иммунологические параметры крови оценивали методом проточной цитометрии, концентрации интерлейкинов и IgE в сыворотке крови определяли методом твердофазного иммуноферментного анализа. При статистической обработке использовали программы Statistica 10 с критическим уровнем значимости р0,05. Результаты. У детей с аллергическими заболеваниями в сыворотке крови определены высокие уровни содержания интерлейкинов4, 8, 13, 17А, сопоставимый с показателями группы контроля уровень IL17F и низкое содержание IFNy. При бронхиальной астме и аллергическом рините у детей выявлено увеличение количества CD3CD8CD45RO, CD3CD8CD45RACD45RO Тлимфоцитов и CD3CD4 Тхелперов и повышение количество Th17 при снижении CD3CD4CD45RO клеток памяти. В группе здоровых детей популяция Th17 составляла 9,491,6, у детей с аллергическими заболеваниями количество данных клеток было значимо выше 14,50,77 (р0,001). Анализ сывороточного содержания цитокинов у детей с изолированным течением БА и в сочетании с аллергическим ринитом выявил разнонаправленные корреляции, отличающиеся по силе и направленности от таковых в группе здоровых детей. Заключение. У детей при изолированном течении бронхиальной астмы и в сочетании с аллергическим ринитом выявлены: сопоставимое с показателями здоровых детей количество CD3CD4 Тклеток, дисбаланс в субпопуляционном составе Тхелперов за счет преобладания Th2 и Th17, активация синтеза IL17A, IL4, IL8, IL13, низкий уровень сывороточного IFNy, изменения силы и направленности взаимосвязей цитокинового профиля и спектра субпопуляций Тлимфоцитов.Expansion of the range of examined Thelper clones has determined more complex immune mechanisms for the implementation of allergic inflammation. Objective. To characterize the parameters and relationships between the serum cytokine profile and Tlymphocyte subpopulation in peripheral blood of children with bronchial asthma and allergic rhinitis. Materials and methods. 150 children aged between 311 years old with bronchial asthma, and allergic rhinitis and 30 healthy volunteers were examined. Immunological parameters were assessed by flow cytometry, the concentration of serum interleukins and IgE were determined by means of enzymelinked immunosorbent assay. Statistical analysis was performed with Statistica 10 program with a critical level of significance p0.05. Results. High levels of interleukins 4, 8, 13, 17A were determined, IL7F level was not significantly different from that in control group and low level of IFNy was found in the serum of children with allergic diseases. The number of CD3CD8CD45RO, CD3CD8CD45RACD45RO Tlymphocytes, CD3CD4 Thelper cells and Th17 were increased and at the same time CD3CD4CD45RO memory cells were decreased In bronchial asthma and allergic rhinitis children. Number of Th17 cells in healthy children was 9.491.6, in allergic children it was significantly higher 14.50.77 (p0.001). Analyses of serum cytokine count in children with isolated BA and in association with allergic rhinitis revealed multidirectional correlations differing in strength and direction from those in the group of healthy children. Conclusion. In children with isolated bronchial asthma and associated with allergic rhinitis the following parameters were found: CD3CD4 Tcells count was comparable to that in healthy children, the imbalance of Thelper subpopulation: prevalence of Th2 and Th17, activation of IL17A, IL4, IL8, IL13 synthesis and low level of serum IFNy.


2021 ◽  
Vol 22 (15) ◽  
pp. 8298
Author(s):  
Hugo Christian Monroy-Ramirez ◽  
Marina Galicia-Moreno ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Arturo Santos ◽  
...  

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.


2015 ◽  
Vol 94 (1) ◽  
pp. 51-59 ◽  
Author(s):  
Yen-Lin Lin ◽  
Shun-Hua Chen ◽  
Jiu-Yao Wang

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 5041-5052 ◽  
Author(s):  
Sophea Heng ◽  
Ana Cervero ◽  
Carlos Simon ◽  
Andrew N. Stephens ◽  
Ying Li ◽  
...  

Establishment of endometrial receptivity is vital for successful embryo implantation; its failure causes infertility. Epithelial receptivity acquisition involves dramatic structural changes in the plasma membrane and cytoskeleton. Proprotein convertase 5/6 (PC6), a serine protease of the proprotein convertase (PC) family, is up-regulated in the human endometrium specifically at the time of epithelial receptivity and stromal cell decidualization. PC6 is the only PC member tightly regulated in this manner. The current study addressed the importance and mechanisms of PC6 action in regulating receptivity in women. PC6 was dysregulated in the endometrial epithelium during the window of implantation in infertile women of three demographically different cohorts. Its critical role in receptivity was evidenced by a significant reduction in mouse blastocyst attachment of endometrial epithelial cells after PC6 knockdown by small interfering RNA. Using a proteomic approach, we discovered that PC6 cleaved the key scaffolding protein, ezrin-radixin-moesin binding phosphoprotein 50 (EBP50), thereby profoundly affecting its interaction with binding protein ezrin (a key protein bridging actin filaments and plasma membrane), EBP50/ezrin cellular localization, and cytoskeleton-membrane connections. We further validated this novel PC6 regulation of receptivity in human endometrium in vivo in fertile vs. infertile patients. These results strongly indicate that PC6 plays a key role in regulating fundamental cellular remodeling processes, such as plasma membrane transformation and membrane-cytoskeletal interface reorganization. PC6 cleavage of a crucial scaffolding protein EBP50, thereby profoundly regulating membrane-cytoskeletal reorganization, greatly extends the current knowledge of PC biology and provides substantial new mechanistic insight into the fields of reproduction, basic cellular biology, and PC biochemistry.


Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2828 ◽  
Author(s):  
Linna Wang ◽  
Xiaoli Wang ◽  
Tingting Li ◽  
Yihua Zhang ◽  
Hui Ji

The inflammatory response mediated by microglia plays a critical role in the progression of ischemic stroke. Phosphoinositide 3-kinase gamma (PI3Kγ) has been implicated in multiple inflammatory and autoimmune diseases, making it a promising target for therapeutic intervention. The aim of this study was to evaluate the efficacy of 8e, a hydrogen sulfide (H2S) releasing derivative of 3-n-butylphthalide (NBP), on brain damage and PI3Kγ signaling following cerebral ischemia injury. 8e significantly reduced sensorimotor deficits, focal infarction, brain edema and neural apoptosis at 72 h after transient middle cerebral artery occlusion (tMCAO). The NOX2 isoform of the NADPH oxidase family is considered a major enzymatic source of superoxide. We found that the release of superoxide, together with the expression of NOX2 subunits p47phox, p-p47phox, and the upstream PI3Kγ/AKT signaling were all down-regulated by 8e, both in the penumbral region of the rat brain and in the primary cultured microglia subjected to oxygen-glucose deprivation (OGD). With the use of siRNA and pharmacological inhibitors, we further demonstrated that 8e regulates the formation of superoxide in activated microglia through the PI3Kγ/AKT/NOX2 signaling pathway and subsequently prevents neuronal death in neighboring neurons. Our experimental data indicate that 8e is a potential candidate for the treatment of ischemic stroke and PI3Kγ-mediated neuroinflammation.


2003 ◽  
Vol 285 (3) ◽  
pp. H946-H954 ◽  
Author(s):  
Junjie Chen ◽  
Sheng-Kwei Song ◽  
Wei Liu ◽  
Mark McLean ◽  
J. Stacy Allen ◽  
...  

Structural remodeling of myocardium after infarction plays a critical role in functional adaptation. Diffusion tensor magnetic resonance imaging (DTMRI) provides a means for rapid and nondestructive characterization of the three-dimensional fiber architecture of cardiac tissues. In this study, microscopic structural changes caused by MI were evaluated in Fischer 344 rats 4 wk after infarct surgery. DTMRI studies were performed on 15 excised, formalin-fixed rat hearts of both infarct (left anterior descending coronary artery occlusion, n = 8) and control (sham, n = 7) rats. Infarct myocardium exhibited increased water diffusivity (41% increase in trace values) and decreased diffusion anisotropy (37% decrease in relative anisotropy index). The reduced diffusion anisotropy correlated negatively with microscopic fiber disarray determined by histological analysis ( R = 0.81). Transmural courses of fiber orientation angles in infarct zones were similar to those of normal myocardium. However, regional angular deviation of the diffusion tensor increased significantly in the infarct myocardium and correlated strongly with microscopic fiber disarray ( R = 0.86). These results suggest that DTMRI may provide a valuable tool for defining structural remodeling in diseased myocardium at the cellular and tissue level.


1995 ◽  
Vol 10 (6) ◽  
pp. 270-282
Author(s):  
Stella Kourembanas

Persistent pulmonary hypertension of the newborn (PPHN) is a common cause of respiratory failure in the full-term neonate. Molecular and cellular studies in vascular biology have revealed that endothelial-derived mediators play a critical role in the pathogenesis and treatment of PPHN. Endothelial-derived vasoconstrictors, like endothelin, may increase smooth muscle cell contractility and growth, leading to the physiologic and structural changes observed in the pulmonary arterioles of infants with this disease. On the other hand, decreased production of the endothelial-derived relaxing factor, nitric oxide, may exacerbate pulmonary vasoreactivity and lead to more severe pulmonary hypertension. Exogenous (inhaled) nitric oxide therapy reduces pulmonary vascular resistance and improves oxygenation. The safety and efficacy of this therapy in reducing the need for extracorporeal membrane oxygenation and decreasing long-term morbidity is being tested in several trials nationally and abroad. Understanding the basic mechanisms that regulate the gene expression and production of these vasoactive mediators will lead to improved preventive and therapeutic strategies for PPHN.


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