Murine models of asthma

Kips, Johan; Anderson, Gary P.; Fredberg, Jeffrey J.; Herz, Udo; Inman, Mark D.; Jordana, Manel; Kemeny, David M.; Lötvall, Jan; Pauwels, Romain; Plopper, Charles G.; Schmidt, D.; Sterk, Peter J.; Oosterhout, Antoon J. M. van; Vargaftig, B.B.; Chung, Kian Fan

doi:10.1183/09031936.03.00026403

Cited by 182 publications

(129 citation statements)

References 53 publications

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“…The recruitment and accumulation of eosinophils in the airway lumen and lung tissue after allergen provocation is a defining feature found in both asthma patients (10) and animal models of allergic respiratory inflammation (11). G␣ i -coupled CCR3 receptor-ligand interactions promoting chemotaxis are primarily responsible for the allergen-induced accumulation of pulmonary eosinophils (12).…”

Section: Resultsmentioning

confidence: 99%

Gα_i2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation

Pero¹,

Borchers

Spicher

et al. 2007

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

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The trafficking of leukocytes from the blood to sites of inflammation is the cumulative result of receptor-ligand-mediated signaling events associated with the leukocytes themselves as well as with the underlying vascular endothelium. Our data show that G␣i signaling pathways in the vascular endothelium regulate a critical step required for leukocyte diapedesis. In vivo studies using knockout mice demonstrated that a signaling event in a non-lymphohematopoietic compartment of the lung prevented the recruitment of proinflammatory leukocytes. Intravital microscopy showed that blockade was at the capillary endothelial surface and ex vivo studies of leukocyte trafficking demonstrated that a G␣i-signaling event in endothelial cells was required for transmigration. Collectively, these data suggest that specific G␣i2-mediated signaling between endothelial cells and leukocytes is required for the extravasation of leukocytes and for tissue-specific accumulation.G proteins ͉ inflammation ͉ knockout mice ͉ leukocyte trafficking ͉ pulmonary models

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Section: Resultsmentioning

confidence: 99%

Gα_i2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation

Pero¹,

Borchers

Spicher

et al. 2007

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

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“…A sthma is a Th2 lymphocyte-associated inflammatory airway disease characterized by airway eosinophilia, airway obstruction, and bronchial hyperresponsiveness (1). ATP is now considered an important mediator in this disease (2).…”

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confidence: 99%

P2Y2 Receptor Regulates VCAM-1 Membrane and Soluble Forms and Eosinophil Accumulation during Lung Inflammation

Vanderstocken

Bondue

Horckmans

et al. 2010

The Journal of Immunology

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ATP has been defined as a key mediator of asthma. In this study, we evaluated lung inflammation in mice deficient for the P2Y2 purinergic receptor. We observed that eosinophil accumulation, a distinctive feature of lung allergic inflammation, was defective in OVA-treated P2Y2-deficient mice compared with OVA-treated wild type animals. Interestingly, the upregulation of VCAM-1 was lower on lung endothelial cells of OVA-treated P2Y2−/− mice compared with OVA-treated wild type animals. Adhesion assays demonstrated that the action of UTP on leukocyte adhesion through the regulation of endothelial VCAM-1 was abolished in P2Y2-deficient lung endothelial cells. Additionally, the level of soluble VCAM-1, reported as an inducer of eosinophil chemotaxis, was strongly reduced in the bronchoalveolar lavage fluid (BALF) of P2Y2-deficient mice. In contrast, we observed comparable infiltration of macrophages and neutrophils in the BALF of LPS-aerosolized P2Y2+/+ and P2Y2−/− mice. This difference could be related to the much lower level of ATP in the BALF of LPS-treated mice compared with OVA-treated mice. Our data define P2Y2 as a regulator of membrane and soluble forms of VCAM-1 and eosinophil accumulation during lung inflammation.

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“…These species were initially selected because both have been used extensively as animal models (14,20) with which to explore airway reactivity. In view of the strainrelated differences in airway responses to agonists (19), we selected a mouse (BALB/c) and rat (Sprague-Dawley) strain with average airway responsiveness for the present study.…”

mentioning

confidence: 99%

The contribution of Ca²⁺ signaling and Ca²⁺ sensitivity to the regulation of airway smooth muscle contraction is different in rats and mice

Bai

Sanderson²

2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Bai Y, Sanderson MJ. The contribution of Ca 2ϩ signaling and Ca 2ϩ sensitivity to the regulation of airway smooth muscle contraction is different in rats and mice. Am J Physiol Lung Cell Mol Physiol 296: L947-L958, 2009. First published April 3, 2009 doi:10.1152/ajplung.90288.2008.-To determine the relative contributions of Ca 2ϩ signaling and Ca 2ϩ sensitivity to the contractility of airway smooth muscle cells (SMCs), we compared the contractile responses of mouse and rat airways with the lung slice technique. Airway contraction was measured by monitoring changes in airway lumen area with phase-contrast microscopy, whereas changes in intracellular calcium concentration ([Ca 2ϩ ]i) of the SMCs were recorded with laser scanning microscopy. In mice and rats, methacholine (MCh) or serotonin induced concentration-dependent airway contraction and Ca 2ϩ oscillations in the SMCs. However, rat airways demonstrated greater contraction compared with mice, in response to agonist-induced Ca 2ϩ oscillations of a similar frequency. Because this indicates that rat airway SMCs have a higher Ca 2ϩ sensitivity compared with mice, we examined Ca 2ϩ sensitivity with Ca 2ϩ -permeabilized airway SMCs in which the [Ca 2ϩ ]i was experimentally controlled. In the absence of agonists, high [Ca 2ϩ ]i induced a sustained contraction in rat airways but only a transient contraction in mouse airways. This sustained contraction of rat airways was relaxed by Y-23672, a Rho kinase inhibitor, but not affected by GF-109203X, a PKC inhibitor. The subsequent exposure of Ca 2ϩ -permeabilized airway SMCs, with high [Ca 2ϩ ]i, to MCh elicited a further contraction of rat airways and initiated a sustained contraction of mouse airways, without changing the [Ca 2ϩ ]i of the SMCs. Collectively, these results indicate that airway SMCs of rats have a substantially higher innate Ca 2ϩ sensitivity than mice and that this strongly influences the transduction of the frequency of Ca 2ϩ oscillations into the contractility of airway SMCs. lung slices; Ca 2ϩ oscillations; confocal microscopy; asthma; hyperresponsiveness ASTHMA IS CHARACTERIZED BY airway inflammation and airway hyperresponsiveness to nonspecific stimulation. Although airway inflammation is known to result in airway remodeling, airway hyperresponsiveness occurs in the early stages of asthma when no obvious airway remodeling is discernable. Consequently, the fundamental mechanism leading to the excessive contraction of airway smooth muscle cells (SMCs) remains unknown. A straightforward hypothesis is that the innate contractility of the SMCs has been enhanced in asthmatic airways. However, the experimental evidence addressing the contractile responses of asthmatic SMCs in vitro is inconsistent. Increased (4, 6, 18, 21), normal (4, 5, 10, 34), and even reduced (12, 33, 37) airway constriction has been reported in human asthmatic or animal airways. These discrepancies may also result from the different protocols, methods, and parameters used to evaluate SMCs contraction.To determine whether the cont...

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Murine models of asthma

Cited by 182 publications

References 53 publications

Gα_i2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation

Gα_i2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation

P2Y2 Receptor Regulates VCAM-1 Membrane and Soluble Forms and Eosinophil Accumulation during Lung Inflammation

The contribution of Ca²⁺ signaling and Ca²⁺ sensitivity to the regulation of airway smooth muscle contraction is different in rats and mice

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Murine models of asthma

Cited by 182 publications

References 53 publications

Gαi2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation

Gαi2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation

P2Y2 Receptor Regulates VCAM-1 Membrane and Soluble Forms and Eosinophil Accumulation during Lung Inflammation

The contribution of Ca2+ signaling and Ca2+ sensitivity to the regulation of airway smooth muscle contraction is different in rats and mice

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Gα_i2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation

Gα_i2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation

The contribution of Ca²⁺ signaling and Ca²⁺ sensitivity to the regulation of airway smooth muscle contraction is different in rats and mice