This investigation proposes to examine the exaggerated airway narrowing response and impaired beta-adrenoceptor inhibitory response in a model of human asthma. Given the role of the key intracellular second messenger, IP3 in regulating airway smooth muscle (ASM) contractility, as well as the role of certain pro-inflammatory cytokines in mediating the atopic/asthmatic state, two interrelated hypotheses are raised: 1. Changes in constrictor agonists and beta-adrenoceptor mediated responsiveness in atopic/asthmatic ASM are attributed to altered receptor coupled accumulation and/or action of IP3; and 2. The induction of these changes in transmembrane signaling regulation ASM responsiveness is related to Fc receptor-coupled autocrine release and action of specific cytokines in ASM. In addressing these hypotheses, mechanism regulating contractility, receptor and G protein expression, second messenger activation, and cytokine expression and action will be examined in isolated rabbit and human ASM tissue and cultured ASM cells passively sensitized with human atopic/asthmatic serum. To investigate mechanisms underlying altered ASM contractility in the sensitized state, the investigators will examine changes in 1) agonist/receptor-coupled accumulation of IP3; 2) expression and modulatory action of specific G proteins; and 3) the metabolism and binding of IP3 to its Ca2+ mobilizing intracellular receptor. To investigate mechanisms underlying attenuated beta-adrenoceptor-coupled relaxation in sensitized ASM, the investigators propose to examine changes in 1) specific G protein expression and regulation of beta-adrenergic receptor biding and transduction; and 2) beta-adrenoceptor/G protein-coupled modulation of constrictor agonist-induced accumulation on IP3, its metabolism, and its receptor binding. Finally, to address the autorcrine role of cytokines in inducing altered ASM responsiveness in the atopic/asthmatic sensitized state, the investigators will examine whether 1) atopic sensitization of ASM induces the autocrine expression and action of specific cytokines; 2) the latter is attributed to activation of endogenously upregulated Fc receptors on ASM cells; and 3) cytokine-induced changes in ASM responsiveness reflect alterations in the contributions of the separate mechanisms delineated above under objectives cited above. Collectively, these studies should yield important new insights into the potential autocrine role of ASM in the mechanistic interplay between Fc receptor activation, cytokine activation, and altered transmembrane signaling contributing to altered ASM responsiveness in the atopic/asthmatic sensitized state.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058245-03
Application #
6139251
Study Section
Special Emphasis Panel (ZRG2-PHY (01))
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
3
Fiscal Year
2000
Total Cost
$298,513
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hakonarson, Hakon; Grunstein, Michael M (2003) Autocrine regulation of airway smooth muscle responsiveness. Respir Physiol Neurobiol 137:263-76
Grunstein, M M; Hakonarson, H; Leiter, J et al. (2002) IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 282:L520-8
Hakonarson, Hakon; Whelan, Russell; Leiter, Jennifer et al. (2002) T lymphocyte-mediated changes in airway smooth muscle responsiveness are attributed to induced autocrine release and actions of IL-5 and IL-1beta. J Allergy Clin Immunol 110:624-33
Grunstein, M M; Hakonarson, H; Hodinka, R L et al. (2001) Mechanism of cooperative effects of rhinovirus and atopic sensitization on airway responsiveness. Am J Physiol Lung Cell Mol Physiol 280:L229-38
Hakonarson, H; Kim, C; Whelan, R et al. (2001) Bi-directional activation between human airway smooth muscle cells and T lymphocytes: role in induction of altered airway responsiveness. J Immunol 166:293-303
Grunstein, M M; Hakonarson, H; Leiter, J et al. (2001) Autocrine signaling by IL-10 mediates altered responsiveness of atopic sensitized airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 281:L1130-7
Grunstein, M M; Hakonarson, H; Whelan, R et al. (2001) Rhinovirus elicits proasthmatic changes in airway responsiveness independently of viral infection. J Allergy Clin Immunol 108:997-1004
Hakonarson, H; Halapi, E; Whelan, R et al. (2001) Association between IL-1beta/TNF-alpha-induced glucocorticoid-sensitive changes in multiple gene expression and altered responsiveness in airway smooth muscle. Am J Respir Cell Mol Biol 25:761-71
Grunstein, M M; Hakonarson, H; Maskeri, N et al. (2000) Intrinsic ICAM-1/LFA-1 activation mediates altered responsiveness of atopic asthmatic airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 278:L1154-63
Grunstein, M M; Hakonarson, H; Maskeri, N et al. (2000) Autocrine cytokine signaling mediates effects of rhinovirus on airway responsiveness. Am J Physiol Lung Cell Mol Physiol 278:L1146-53

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