Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Barnes, Peter J.

doi:10.1124/pr.116.012518

Cited by 98 publications

(82 citation statements)

References 331 publications

(305 reference statements)

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“…The oxidative stress inhibits the protein levels of PTEN in patients with COPD, which results in the persistent activation of the PI3K/Akt pathway and resultant proin-flammatory mediator release. In addition, activation of PI3K signaling, decreased PTEN expression may also be important in corticosteroid resistance and accelerated aging, as well as the increased risk of lung cancer in COPD (Barnes 2016). Crosstalk analysis of significantly enriched pathways obtained two mainly pathway clusters that closely associated with immune and signal transduction respectively, this should be an important clue for studying COPD progression.…”

Section: Discussionmentioning

confidence: 86%

Network and Pathway-Based Prioritization and Analyses of Genes Related to Chronic Obstructive Pulmonary Disease

Sui

et al. 2018

CYTOLOGIA

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Chronic obstructive pulmonary disease (COPD), characterized by long-term breathing problem and poor airflow, is the fourth cause of death in the United States. Although previous studies have provided insights into the effects of genetic factors on COPD, the molecular mechanism is still unknown. Here, we proposed a network and pathway-based method for prioritization and analysis of COPD-related genes. In brief, we firstly obtained COPD-related single nucleotide polymorphisms (SNPs) from dbGaP and COPD as well as normal lung tissues gene expression profiles from Gene Expression Omnibus (GEO). Combined with protein-protein interaction pairs, the SNPs and gene expression profiles were imported into dmGWAS, a R package designed for subnetwork searching, to identify COPD-specific module. What s more, we performed functional analysis for genes in COPD-specific module with the combination of WEB-based GEne SeT AnaLysis Toolkit (WebGestalt) and KEGG Orthology Based Annotation System (KOBAS). A COPD-specific network module containing 812 gene nodes and 2640 interactions was obtained. While, 450 of the 812 genes were annotated by WebGestalt and/or KOBAS, which were considered as reliable COPD-related genes. The annotated genes were found to be significantly associated with immune and signal transduction processes, which is consistent with the development of COPD. Finally, 427 of the 450 annotated genes formed 1389 interaction pairs, which might contribute COPD progression. This study should be helpful for understanding COPD mechanisms and its targeted therapy.

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Section: Discussionmentioning

confidence: 86%

Network and Pathway-Based Prioritization and Analyses of Genes Related to Chronic Obstructive Pulmonary Disease

Sui

et al. 2018

CYTOLOGIA

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“…The JAK / STAT pathway has been suggested as an asthma target through inhibitors of activating cytokines and receptors (Vale, 2016, Weltman and Karim, 1998). JAK pathway inhibitors are in development for a number of inflammatory disorders (O’Shea et al, 2015), and animal models have suggested that targeting this pathway can reduce airway hyperresponsiveness, reflecting the potential for such compounds in both COPD and asthma (Barnes, 2016). The role for JAK / STAT signaling in bronchopulmonary dysplasia is less clear, but it has been suggested that it plays a role in airway smooth muscle mitogenesis, implicated in both asthma and BPD (Simon et al, 2002), and postulated that it may be an alternative mediator of the oxidative stress response in both diseases (Zhou and Hershenson, 2003).…”

Section: Resultsmentioning

confidence: 99%

Pathway centrality in protein interaction networks identifies functional mediators of pulmonary disease

Park

Hescott

Slonim

2017

Preprint

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SummaryIdentification of functional pathways mediating molecular responses may lead to better understanding of disease processes and suggest new therapeutic approaches. We introduce a method to detect such mediating functions using topological properties of protein-protein interaction networks. We introduce the concept of pathway centrality, a measure of communication between disease genes and differentially expressed genes. We find mediating pathways for three pulmonary diseases (asthma; bronchopulmonary dysplasia (BPD); and chronic obstructive pulmonary disease (COPD)) using pathway centrality. Mediating pathways shared by all three pulmonary disorders heavily favor inflammatory or immune responses and include specific pathways such as cytokine production, NF Kappa B, and JAK/STAT signaling. Disease-specific mediators, such as insulin signaling in BPD or homeostasis in COPD, are also highlighted. We support our findings, some of which suggest new treatment approaches, both with anecdotal evidence from the literature and via systematic evaluation using genetic interactions.peer-reviewed)

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“…Our study shows that NE increases integrin-mediated adhesion of M□ and modulate cytokine release from M□ through Src activation since Src kinase inhibitor PP2 inhibited the increase in cytokine expression. Recently, activated Hck (hematopoietic cell kinase), a myeloid-specific Src family kinase, was implied in lung –associated diseases (56,57). It has been shown that mice with a constitutively active Hck mutant develop in the lungs areas of mild emphysema and fibrosis (58).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Elastase Activates Macrophage MMPs, Promotes Cell Adhesion and Cytokine Production Via Integrin-Src Kinases Pathway

Krotova

Khodayari

Oshins

et al. 2018

Preprint

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There are a number of diseases characterized by the presence of neutrophil elastase (NE) activity in tissues including cystic fibrosis and alpha-1-antitrypsin deficiency induced lung destruction. It is generally accepted that NE actively contributes to this pathological process, but the precise mechanisms has yet to be determined. We hypothesized that NE activates the macrophages (M ) pro-inflammatory program. We demonstrate that following NE exposure, monocytederived M release proteolytic activity composed of several matrix metalloproteinases (MMPs) which could contribute to extracellular matrix (ECM) degradation. NE upregulates expression of M derived pro-inflammatory cytokines including TNFα, IL-1β, and IL-8. Thus, NE-activated M can contribute to tissue destruction through the proteolytic activity of metalloproteinases and by supporting chronic inflammation through expression of pro-inflammatory cytokines. We also demonstrate that NE increases M adhesion that is attenuated by antibodies specific to integrin subunits. We show that the effects of NE on M can be mediated through an activation of integrin pathways. In support of integrin involvement, we demonstrate that NE activates the Src kinase family, a hallmark of integrin signaling activation. Moreover, pretreatment of macrophages with a specific Src kinase inhibitor, PP2, completely prevents NE-induced inflammatory cytokine production. Taken together these findings indicate that NE has effect on lung destruction that extends beyond direct proteolytic degradation of matrix proteins. MATERIALS AND METHODSReagents: All cell culture reagents unless specified elsewhere, were purchased from Life Technologies, (Carlsbad, CA, USA). All chemicals not specified are from Sigma-Aldrich (St.Louis, MO, USA). Fluorogenic peptide was purchased from R&D Systems (Minneapolis, MN, USA). Collagen Type I from rat tail (Corning), PP2 Src inhibitor -2µM (Calbiochem). Cell culture: Primary peripheral blood mononuclear cells (PBMCs) were obtained from outpatient healthy volunteers (UF IRB protocol 08-2007). Monocyte-derived M were obtained from PBMCs plated in serum-free RPMI. Unattached lymphocytes were washed out after 1 h, and adherent monocytes were differentiated in M by culturing for 10 days in RPMI with 10% FBS with both GM-CSF (1 ng/ml) and M-CSF (10 ng/ml). MMP activity: MMP activity was assessed by a fluorogenic assay measuring 7methoxycoumarin group (Mca) release from synthetic peptide Mca-PLGL-Dpa-AR-NH2 (RnD Systems, Minneapolis, MN, USA). After treatment with NE, media from M were collected, and aliquots of conditioned media were mixed with MMP assay buffer containing 10 µM fluorogenic peptide. Changes in fluorescence was monitored hourly at 320/405 nm. Zymography: Media collected from unstimulated or NE-stimulated M were analyzed by gelatin zymography. Samples were mixed with 2x Laemmli loading buffer without heating, and subjected to electrophoresis on 8% polyacrylamide gel containing 1 mg/ml gelatin. After gel electrophoresis was performed at 4°C, gels were incuba...

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Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Cited by 98 publications

References 331 publications

Network and Pathway-Based Prioritization and Analyses of Genes Related to Chronic Obstructive Pulmonary Disease

Network and Pathway-Based Prioritization and Analyses of Genes Related to Chronic Obstructive Pulmonary Disease

Pathway centrality in protein interaction networks identifies functional mediators of pulmonary disease

Neutrophil Elastase Activates Macrophage MMPs, Promotes Cell Adhesion and Cytokine Production Via Integrin-Src Kinases Pathway

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