CELLULAR MECHANISMS REGULATING AIRWAY MUSCLE GROWTH

  • PANETTIERI, REYNOLD ALEXANDER (PI)

Project Details

Description

Asthma, a chronic disease characterized by airway hyperreactivity, is an extraordinarily common pulmonary impairment. Although the primary defects that underlie airway hyperreactivity are unknown, Increased smooth muscle mass In airways of patients with chronic severe asthma has been a well documented pathologic finding. This Increase In airway smooth muscle mass (ASM) is due, In large part, to Increases In the number of airway myocytes. Little Information Is available however, with respect to factors that Induce ASM cell proliferation. Such alterations may have Important consequences In determining airway caliber and force generation by the muscle. We postulate that chronic stimulation of ASM by contractile agonists may Induce ASM cell proliferation. Preliminary data has shown that histamine, which plays a crucial role In causing acute bronchoconstriction In asthmatic patients, Induces ASM cell proliferation. Other potent contractile agonists did not Induce cell growth. This evidence suggests that substantial differences exist with respect to the mechanisms that couple agonist-receptor activation and cell proliferation. This proposal seeks to define the cellular and nuclear signalling processes that regulate contractile agonist-induced proliferation of human ASM cells. A key hypothesis of the proposal Is that agonist?.Induced cell proliferation Is, activated by protein kinase C and mediated by expression of early response genes. To determine the role of protein kinase C In mediating this cell growth, enzyme Inhibitors and Isoenzyme-specific neutralizing antibodies will be microinjected and attendant alterations In DNA synthesis determined In cells stimulated with agonists. To Identify important signalling events upstream from protein kinase C activation, the magnitude and time course of agonist activation of PI- and PC-PLC generated diacylglycerol (DAG) will be investigated and compared to those levels that stimulate cell proliferation. In order to further dissect critical regulatory pathways, we will determine the sites at which protein kinase A (A-kinase) modulates cell proliferation. Preliminary data has demonstrated that A-kinase completely abolishes protein kinase C-dependent ASM cell proliferation. This observation may have Important therapeutic Implications for Inhibiting ASM cell proliferation. Finally, the role of early response gene activation In mediating agonist-induced cell growth will be characterized. Experiments designed to Inhibit specific oncoproteins will determine whether these genes are necessary In the signal transduction of agonist-induced ASM cell proliferation. These results should clarify the critical cellular and nuclear mechanisms by which agonists induce airway smooth muscle cell growth. These studies will be necessary before the role of ASM cell proliferation In the pathogenesis asthma can be addressed, and therapeutic measures to prevent these alterations developed.
StatusFinished
Effective start/end date7/1/917/31/96

Funding

  • National Heart, Lung, and Blood Institute

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