Phosphoinositide 3-kinase γ required for lipopolysaccharide-induced transepithelial neutrophil trafficking in the lung

Reutershan, Jörg; Saprito, Mary S.; Wu, Dan; Rückle, Thomas; Ley, Klaus

doi:10.1183/09031936.00085509

Cited by 21 publications

(17 citation statements)

References 57 publications

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“…Aerolised TG100-115, a double-selective compound blocking both PI3Kc and PI3Kd, inhibited pulmonary neutrophilia induced by both intranasal LPS and smoke exposure in a murine COPD model [90]. AS605240, a PI3Kc-selective inhibitor, reduced polymorphonuclear leukocyte migration in vitro and polymorphonuclear leukocyte infiltration into the lung in vivo in a murine model of LPS-induced lung injury [91]. Interestingly, interventional treatment with TG100-115 was successful even in a steroid-resistant form of COPD, induced in mice by cigarette smoke exposure [90].…”

Section: Review: Anti-inflammatory Strategies For Copdmentioning

confidence: 99%

Emerging anti-inflammatory strategies for COPD

et al. 2012

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The hallmark of chronic obstructive pulmonary disease (COPD) is an enhanced or abnormal inflammatory immune response of the lungs to inhaled particles and gases, usually from cigarette smoke, characterised by increased numbers of neutrophils, activated macrophages and activated T-lymphocytes (Tc1 and Th1 cells). Therefore, suppression of the inflammatory response is a logical approach to the treatment of COPD. Despite the inflammatory nature of COPD, currently available anti-inflammatory therapies provide little or no benefit in COPD patients and may have detrimental effects. For this reason, there is an urgent need to discover effective and safe anti-inflammatory treatments that might prevent the relentless progression of the disease. In recent years, attention has largely been focused on inhibition of recruitment and activation of inflammatory cells, and on antagonism of their products. In this review, we put together a summary of the state-of-the-art development of clearly and/or potentially useful anti-inflammatory strategies in COPD.

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Section: Review: Anti-inflammatory Strategies For Copdmentioning

confidence: 99%

Emerging anti-inflammatory strategies for COPD

et al. 2012

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“…While p110α and p110β isoforms are widely expressed, and genetic knock-out mice of these isoforms lead to a lethality at an early embryonic stage, p110δ and p110γ isoforms are predominantly expressed in leukocytes; thus, mice deprived of p110δ or p110γ isoforms are viable and display reduced inflammatory responses. Therefore, PI3K-δ and PI3K-γ isoforms have been considered to be suitable targets for inflammatory diseases [12][13][14][15]. However, data on the roles of these isoforms in airway/lung inflammation are limited.…”

Section: Introductionmentioning

confidence: 97%

PI3K-γ Inhibition Ameliorates Acute Lung Injury Through Regulation of IκBα/NF-κB Pathway and Innate Immune Responses

Kim

et al. 2011

J Clin Immunol

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“…Lung endothelial cells express both CXCR2 and the ligand for ␣4 integrins, VCAM-1 (12)(13)(14). Blocking of either ␣4 integrins or VCAM-1 with monoclonal antibody suppresses antigen-induced MCp recruitment to lung (6).…”

Section: Reduced Vcam-1 Transcription and Expression On Endothelium Imentioning

confidence: 99%

Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors

Hallgren

Jones

Abonia

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

101

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chemokine receptors ͉ endothelium ͉ lung inflammation T he bronchial inflammation in atopic asthma and in allergeninduced mouse models of pulmonary inflammation is characterized by the influx of various effector cell populations including Th2 cells, eosinophils, basophils, and mast cells (MC). The MC numbers increase both in the smooth muscle and in the epithelium of the airways of humans with atopic asthma (1, 2). Moreover, there is marked hyperplasia of intraepithelial (IE) MC in mice with antigen-induced Th2-mediated inflammation of the airways, although normal mouse lung lacks appreciable numbers of MC (3, 4). That antigen-induced airways hyperreactivity is diminished in MC-deficient strains indicates the importance of the MC to the biology of the host response (3, 5).Recruitment of MC progenitors (MCp) to the lung of sensitized, aerosolized antigen-challenged BALB/c mice is rapid and depends on expression of ␣4␤1 or ␣4␤7 integrins because this response was blocked by mAb to these integrins, with the counterligand being vascular cell adhesion molecule 1 (VCAM-1) (6). Because transendothelial migration of cells into tissues characteristically involves not only adhesion but also directed migration, we turned our attention to possible chemokine receptors on the MCp. Using null mouse strains lacking CCR3, CCR5, or CXCR2, which are known to be expressed by cultured mouse bone marrow-derived MC (mBMMC) and/or by human cord blood-derived MC (7-9), we investigated the requirement for these receptors on MCp recruitment to antigensensitized and challenged mice. We find that MCp recruitment to the lung of sensitized, BALB/c mice after three daily aerosolized antigen challenges depends on CXCR2 function in the lung parenchyma/microvasculature rather than on the MCp with selectivity for the MCp relative to other mononuclear cells. The deficiency in CXCR2 is associated with a reduction in VCAM-1 expression in the lung and with a reduction in the subsequent appearance of mature mucosal MC in the trachea, suggesting that the recruitment is a prerequisite for the IE MC hyperplasia. Results Reduced MCp Recruitment to Lung of Sensitized and Antigen-Challenged CXCR2 ؊/؊ Mice. We demonstrated that MCp recruitment to the lung of ovalbumin (OVA)-sensitized and aerosolized OVA-challenged BALB/c mice approaches a plateau after only three daily challenges (6). To evaluate any effect resulting from the loss of expression of a chemokine receptor, the numbers of mononuclear cells (MNC) and MCp in the lung of sensitized, antigen-challenged wild-type (WT) (BALB/c) and CXCR2-null mice were compared. Sensitized WT and CXCR2 Ϫ/Ϫ mice that were not challenged with aerosolized antigen show similar low levels of MNC and MCp in the lung as noted previously (Fig.

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Phosphoinositide 3-kinase γ required for lipopolysaccharide-induced transepithelial neutrophil trafficking in the lung

Cited by 21 publications

References 57 publications

Emerging anti-inflammatory strategies for COPD

Emerging anti-inflammatory strategies for COPD

PI3K-γ Inhibition Ameliorates Acute Lung Injury Through Regulation of IκBα/NF-κB Pathway and Innate Immune Responses

Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors

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