Studies are proposed to examine the mechanisms by which epithelial cells (EPI), macrophages (MO) and airway smooth muscle cells (ASMC) are activated to communicate signals for granulocyte a) adhesion /migration, b) generation of LTC4, and c) conversion of normally reactive airways into hyperresponsive airways. The central hypothesis is that the endogenous 14 kDa group V PLA2 (gVPLA2) secreted from stimulated EPI, MO or ASMC serves as an intercellular messenger protein that is highly expressed in asthmatic human airways and is inducible during immune sensitization in mouse EPI, MO and ASMC. It is hypothesized that gVPLA2 hydrolyzes the phosphatidylcholine-rich outer plasma membrane of eosinophils to cause subsequent LTC4 secretion by a novel mechanism that is independent of cPLA2 activation.
In Aim 1, studies are proposed to examine the hypothesis that [32-integrin-mediated eosinophil adhesion is regulated by gVPLA2 by a novel mechanism independent of MAPK-mediated cPLA2 phosphorylation. Studies are proposed to demonstrate that gVPLA2 secreted from airway resident cells transmits the signal for induction of (32-integrin adhesion in eosinophils. Further studies are proposed to elucidate the potential pathway by which adhesion is induced under physiological conditions by gVPLA2.
In Aim 2, studies are proposed to examine the cellular entry and intracellular action of endogenous gVPLA2 in mediating augmented secretion of LTC4 during transcellular communication. Further studies are proposed to test the specificity of gVPLA2 by using a neutralizing mAb against gVPLA2 or TAT-dn-cPLA2.
In Aim 3, studies are proposed to examine the mechanisms of gVPLA2 and cPLA2 in the mediation of airway inflammation and airway hyperresponsiveness (AHR) in acute and chronic murine models of asthma. Based upon preliminary data, studies are proposed to test the hypothesis that endogenous secretion of gVPLA2 mediates AHR in immune sensitized mice. The effect of MCL-3G1, a mAb against gVPLA2, in blocking AHR to methacholine or gVPLA2 challenge in pre/post OA-challenge mice will be assessed. Further studies using immune-sensitized gVPLA2-knockout and cPLA2-knockout mice will be generated to establish the specific role of these enzymes in AHR and inflammatory cell migration in vivo. Data derived from these studies should elucidate a new endogenous mechanism of transcellular communication that initiates airway inflammation and AHR.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Noel, Patricia
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Duan, Yingli; Learoyd, Jonathan; Meliton, Angelo Y et al. (2012) Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury. Respir Res 13:4
Dudek, Steven M; Muñoz, Nilda M; Desai, Anjali et al. (2011) Group V phospholipase A2 mediates barrier disruption of human pulmonary endothelial cells caused by LPS in vitro. Am J Respir Cell Mol Biol 44:361-8
Meliton, A Y; Muñoz, N M; Osan, C M et al. (2010) Leukotriene D4 activates {beta}2-integrin adhesion in human polymorphonuclear leukocytes. Eur Respir J 35:402-9
Duan, Yingli; Learoyd, Jonathan; Meliton, Angelo Y et al. (2010) Inhibition of Pyk2 blocks airway inflammation and hyperresponsiveness in a mouse model of asthma. Am J Respir Cell Mol Biol 42:491-7
Zhu, Xiangdong; Boetticher, Evan; Wang, Lin et al. (2008) Proline-rich tyrosine kinase 2 regulates spreading and migration of eosinophils after beta2-integrin adhesion. Am J Respir Cell Mol Biol 39:263-9
Meliton, Angelo Y; Munoz, Nilda M; Zhu, Xiangdong et al. (2008) Attenuated translocation of group IVa phospholipase A2 and up-regulated annexin-1 synthesis by glucocorticoid blocks beta 2-integrin adhesion in neutrophils. J Leukoc Biol 83:344-51
Munoz, Nilda M; Meliton, Angelo Y; Arm, Jonathan P et al. (2007) Deletion of secretory group V phospholipase A2 attenuates cell migration and airway hyperresponsiveness in immunosensitized mice. J Immunol 179:4800-7
Meliton, Angelo Y; Munoz, Nilda M; Leff, Alan R (2007) Blockade of avidity and focal clustering of beta 2-integrin by cysteinyl leukotriene antagonism attenuates eosinophil adhesion. J Allergy Clin Immunol 120:1316-23