Pathobiology of Severe Asthma

Bittar, Humberto E. Trejo; Yousem, Samuel A.; Wenzel, Sally E.

doi:10.1146/annurev-pathol-012414-040343

Cited by 106 publications

(81 citation statements)

References 209 publications

(225 reference statements)

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“…[32][33][34][35] If these immune responses persist in the airway wall, structural changes, such as goblet cell metaplasia, basement membrane thickening, hypertrophy of ASM, and subepithelial fibrosis, can occur and these structural changes are summarized under the term airway remodeling. 2 …”

Section: Cell Populations Involved In Airway Inflammationmentioning

confidence: 99%

“…Moreover, induction of different subsets of T cells expressing specific cytokine profiles is discussed as the main reason for the development of heterogeneous asthma phenotypes. 2 Induced by DCs, effector T-cell responses are mainly controlled by regulatory T cells (Tregs). These cells are important for suppression of adaptive immune responses and thus for the clearance of immune responses by acting via direct cell contact-dependent or indirect cytokine-dependent mechanisms.…”

Section: Dendritic Cellsmentioning

confidence: 99%

“…It has been speculated that these asthma phenotypes also differ in their pathobiology. 2 By far the best understood immunological pathways are in allergic asthma. Indeed, in allergeninduced airway inflammation, T-helper type 2 (Th2) cells have a pivotal role.…”

mentioning

confidence: 99%

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Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

Reuter

Beckert

Taube

2016

Laboratory Investigation

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Bronchial asthma and chronic obstructive pulmonary disease (COPD) are chronic diseases that are associated with inflammation and structural changes in the airways and lungs. Recent findings have implicated Wnt pathways in critically regulating inflammatory responses, especially in asthma. Furthermore, canonical and noncanonical Wnt pathways are involved in structural changes such as airway remodeling, goblet cell metaplasia, and airway smooth muscle (ASM) proliferation. In COPD, Wnt pathways are not only associated with structural changes in the airways but also involved in the development of emphysema. The present review summarizes the role and function of the canonical and noncanonical Wnt pathway with regard to airway inflammation and structural changes in asthma and COPD. Further identification of the role and function of different Wnt molecules and pathways could help to develop novel therapeutic options for these diseases.

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Section: Cell Populations Involved In Airway Inflammationmentioning

confidence: 99%

Section: Dendritic Cellsmentioning

confidence: 99%

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Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

Reuter

Beckert

Taube

2016

Laboratory Investigation

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“…In order to analyze the autophagic flux, Beas-2B cells were transfected with mCherry-eGFP-LC3-expressing plasmids. The cells were pooled and seeded in chamber slides at a density of 2x10 4 . The level of autophagic flux was determined via examination of the punctate pattern of eGFP and mCherry expression by counting the puncta per cell.…”

Section: Immunofluorescent Microscopy Of Cells Exhibiting Lc3-positivementioning

confidence: 99%

“…Evidence obtained from environmental and epidemiological studies has revealed a marked association between fine particulate air pollution and multiple health issues, including respiratory illnesses (for example, respiratory track inflammation, asthma, acute bronchitis and lung cancer) as well as cardiovascular disease mortality (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

Wang

et al. 2015

Molecular Medicine Reports

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Abstract. Particulate matter 2.5 (PM 2.5 ) is a significant risk factor for asthma. A recent study revealed that autophagy was associated with asthma pathogenesis. However, the specific mechanisms underlying PM 2.5 -induced autophagy in asthma have remained elusive. In the present study, PM 2.5 -induced autophagy was evaluated in Beas-2B human bronchial epithelial cells and the potential molecular mechanisms were investigated. Using electron microscopy, immunofluorescence staining and immunoblot studies, it was confirmed that PM 2.5 induced autophagy in Beas-2B cells as a result of PM 2.5 -mediated inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in Beas-2B cells. LY294002, a PI3K inhibitor, reduced the accumulation of microtubule-associated protein 1 light chain 3 II and attenuated the effect of PM 2.5 . Phosphorylated (p-)p38, p-extracellular signal-regulated kinase and p-c-Jun N-terminal kinase were dephosphorylated following exposure to PM 2.5 . The roles of p53, reactive oxygen species scavenger tetramethylthiourea and autophagy inhibitor 3-methyladenine in PM 2.5 -induced autophagy in Beas-2B cells were also investigated. The results suggested that the PI3K/Akt/mTOR signaling pathway may be a key contributor to PM 2.5 -induced autophagy in Beas-2B cells. The results of the present study therefore provided an a insight into potential future clinical applications targeting these signaling pathways, for the prevention and/or treatment of PM 2.5 -induced lung diseases. IntroductionAcute and chronic exposure to particulate matter (PM), particularly fine particles with aerodynamic diameters of ≤2.5 µm PM 2.5 , has been shown to increase the number of hospital admissions for respiratory causes amongst the general population (1). Evidence obtained from environmental and epidemiological studies has revealed a marked association between fine particulate air pollution and multiple health issues, including respiratory illnesses (for example, respiratory track inflammation, asthma, acute bronchitis and lung cancer) as well as cardiovascular disease mortality (2-4).Increasing evidence supporting a link between traffic-associated air pollution and the incidence of childhood asthma has emerged; however, published estimates highlight the variability observed between populations (5,6). Asthma is a common worldwide respiratory symptom complex, frequently involving airway inflammation, which results in clinically significant physiological airway dysfunction. Asthma pathogenesis is complex, and multiple factors have roles in the development of the disease (7).Autophagy describes an evolutionarily conserved and tightly regulated lysosomal pathway, responsible for the degradation of macromolecules, including proteins, glycogen, lipids, nucleotides and organelles, via several complex pathways (8).Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial ...

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microRNA‐23a contributes to asthma by targeting BCL2 in airway epithelial cells and CXCL12 in fibroblasts

Jin

Bao

Roth

et al. 2019

Journal Cellular Physiology

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The deregulated cross-talk between airway epithelial cells with subepithelial fibroblasts during inflammation drives the pathogenesis of asthma. Bioinformatics analysis and luciferase activity assay suggested that B cell lymphoma-2 (BCL2) and CXC ligand 12 (CXCL12) are potential targets of miR-23a. The aim of this study was to elucidate the effect of microRNA-23a (miR-23a) on BCL2, and CXCL12 in asthma. In E3 rats, miR-23a was upregulated in lung tissues after antigen-induced pulmonary inflammation during acute and chronic inflammation. Immunohistochemistry showed downregulation of BCL2 in the epithelium and of CXCL12 in subepithelial fibroblasts and smooth muscle cells.Treatment of isolated cells with miR-23a mimic or inhibitor modified the expression of BCL2 and of CXCL12 in the expected cell type-specific manner. Moreover, in epithelial cells, interleukin-4 upregulated miR-23a expression and thereby decreased the expression of BCL2, while increasing the caspase-3 expression, which was followed by apoptosis. In fibroblasts, the expression of miR-23a was increased by thymic stromal lymphopoietin (TSLP). Consequently, the CXCL12 expression was abrogated. The phosphorylation of CREB was also downregulated by TSLP through the action of miR-23a. This study describes a novel mechanism, where miR-23a is an important cell type-specific regulator for asthma-associated airway wall remodeling parameter. Thus, miR-23a may present a potential new target for the therapy of asthma. K E Y W O R D Sasthma, BCL2, cell-type specificity, CXCL12, miR-23a

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Pathobiology of Severe Asthma

Cited by 106 publications

References 209 publications

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

microRNA‐23a contributes to asthma by targeting BCL2 in airway epithelial cells and CXCL12 in fibroblasts

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