Phosphoinositide 3-kinase-δ inhibitor reduces vascular permeability in a murine model of asthma

Lee, Kyung Sun; Park, Seoung Ju; Kim, So Ri; Min, Kyung Hoon; Jin, Sun; Puri, Kamal D.; Lee, Yong Chul

doi:10.1016/j.jaci.2006.04.041

Cited by 67 publications

(80 citation statements)

References 60 publications

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“…Recent studies further supported this finding describing a contribution to 24 allergen-IgE-induced mast cell activation and vascular permeability which is a common characteristics of chronic inflammations such as asthma (Lee et al, 2006a). Pharmalogical inhibition of p110δ resulted in a significant reduction of serum levels of IgE, attenuation of airway inflammation and hyperresponsiveness, by preventing vascular leakage in murine asthma models (Lee et al, 2006a;Lee et al, 2006b). …”

Section: Pi3k and Diseasesmentioning

confidence: 75%

Targeting receptor tyrosine kinase signaling in acute myeloid leukemia

Doepfner¹,

Boller²,

Arcaro³

2007

Critical Reviews in Oncology/Hematology

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Targeting receptor tyrosine kinase signaling in acute myeloid leukemia The main goal of this work was therefore aimed at gaining deeper insight into RTK signaling in a panel of AML cell lines and patient blast cells. A broad potein expression analysis was set up in order to identify cancer-specific expression patterns of signaling molecules and to uncover potential molecular targets. Using different approaches the molecular function and the feasibility of targeting the candidate proteins was investigated. Novel specific inhibitors were tested and neutralizing antibodies and RNA interference (RNAi) were used to block or down-regulate the individual proteins. Our study of the IGF-IR/PI3K signaling system in AML cells uncovered a novel role for autocrine IGF-I signaling in the growth and survival of these cancer cells. Besides, we could show that targeting this signaling branch in combination with commonly used chemotherapeutical agents represents an interesting novel approach for AML therapy.As protein expression analysis revealed highly variable expression levels of the mammalian target of rapamycin (mTOR) in the panel of cells analyzed, further interest was laid on the role of mTOR in AML. Cells expressing low levels of mTOR were compared to cells expressing high levels of this protein and a siRNA screen was aimed at uncovering human kinases that modulate the sensitivity to the mTOR inhibitor rapamycin. Preliminary results suggest that mTOR plays a crucial role in cell growth and survival in a subset of AML cells and that rapamycin in combination with certain RTK or Syk/ZAP70 inhibitors has potential for AML therapy. In summary, our study of the RTK/PI3K signaling system in distinct human cancers has provided novel insights into the importance and the complexity of this network for tumor growth and survival. Moreover, the analysis of specific components of this crucial signaling network has uncovered potential molecular targets for future cancer therapy.

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Section: Pi3k and Diseasesmentioning

confidence: 75%

Targeting receptor tyrosine kinase signaling in acute myeloid leukemia

Doepfner¹,

Boller²,

Arcaro³

2007

Critical Reviews in Oncology/Hematology

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“…Measurement of PI3K enzyme activity in lung tissues PI3K enzyme activity in lung tissues was measured as described previously [16]. The amount of PIP3 produced was quantified by PIP3 competition enzyme immunoassays (Echelon Inc., Salt Lake City, UT, USA).…”

Section: Measurement Of Tgf-bmentioning

confidence: 99%

“…Some studies have reported that PI3K inhibition reduces Th2 cytokine production, pulmonary eosinophilia, and airway inflammation and hyperresponsiveness in a mouse model of asthma [13,14]. Additionally, PI3K signalling, including p110d isoform, is associated with the regulation of VEGF expression and activation [15,16]. Along the same lines, PI3K has also been shown to play an important role in VEGFmediated signalling, and VEGF-induced PI3K activation has been linked to biologically diverse roles of VEGF, such as cell migration, vascular permeability, cell survival and cell proliferation [17].…”

mentioning

confidence: 99%

Inhibition of VEGF blocks TGF-β₁production through a PI3K/Akt signalling pathway

et al. 2007

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Vascular endothelial growth factor (VEGF) is a mediator of airway inflammation and remodelling in asthma. Transforming growth factor (TGF)-β1plays pivotal roles in diverse biological processes, including tissue remodelling and repair in a number of chronic lung diseases. However, there are few studies elucidating the interactions between VEGF and TGF-β1in allergic airway disease.A murine model of allergic airway disease was used to define the mechanism by which VEGF induces subepithelial fibrosis and to investigate a potential relationship between VEGF and TGF-β1and the mechanisms by which VEGF signalling regulates TGF-β1expression in allergic airway disease.The ovalbumin (OVA)-inhaled murine model revealed the following typical pathophysiological features of allergic airway disease in the lungs: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased peribronchial fibrosis, and increased levels of VEGF and TGF-β1. Administration of VEGF inhibitors reduced the pathophysiological signs of allergic airway disease and decreased the increased TGF-β1levels and peribronchial fibrosis, including phosphoinositide 3-kinase (PI3K) activity after OVA inhalation. In addition, the increased TGF-β1levels and collagen deposition after OVA inhalation were decreased by administration of PI3K inhibitors.These results suggest that inhibition of vascular endothelial growth factor attenuates peribronchial fibrosis, at least when mediated by regulation of transforming growth factor-β1expression through phosphoinositide 3-kinase/Akt pathway in a murine model of allergic airway disease.

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“…Phosphorylation of myosin light chain by MLCK leads to actin-mediated endothelial cell contraction and increases permeability of endothelial junctional barrier. Activation of phosphatidylinositol 3-kinase (PI3K), whose expression was induced on both day 3 and day 5, has also been shown to increase vascular permeability (Abid et al, 2004;Lee et al, 2006;Serban et al, 2008). In addition, induction of MMP14 was observed on day 5.…”

Section: Mapk-mediated Modulation Of Intercellular Junctions In Respomentioning

confidence: 99%

Retinal Vein Occlusion Induced by a MEK Inhibitor - Impact of Oxidative Stress on the Blood-Retinal Barrier

Yang¹,

Huang²

2012

Oxidative Stress and Diseases

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Phosphoinositide 3-kinase-δ inhibitor reduces vascular permeability in a murine model of asthma

Cited by 67 publications

References 60 publications

Targeting receptor tyrosine kinase signaling in acute myeloid leukemia

Targeting receptor tyrosine kinase signaling in acute myeloid leukemia

Inhibition of VEGF blocks TGF-β₁production through a PI3K/Akt signalling pathway

Retinal Vein Occlusion Induced by a MEK Inhibitor - Impact of Oxidative Stress on the Blood-Retinal Barrier

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Phosphoinositide 3-kinase-δ inhibitor reduces vascular permeability in a murine model of asthma

Cited by 67 publications

References 60 publications

Targeting receptor tyrosine kinase signaling in acute myeloid leukemia

Targeting receptor tyrosine kinase signaling in acute myeloid leukemia

Inhibition of VEGF blocks TGF-β1production through a PI3K/Akt signalling pathway

Retinal Vein Occlusion Induced by a MEK Inhibitor - Impact of Oxidative Stress on the Blood-Retinal Barrier

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Inhibition of VEGF blocks TGF-β₁production through a PI3K/Akt signalling pathway