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IRAK-1 & active TGF-beta: Counter-regulators in emphysema?

Institution: University of California, San Francisco
Investigator(s): George Su, M.D.
Award Cycle: 2003 (Cycle 12) Grant #: 12FT-0123 Award: $69,000
Subject Area: Pulmonary Disease
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Pulmonary emphysema is a debilitating lung disease and worldwide health problem attributed to tobacco smoking. For years, significant scientific effort has been placed into elucidating mechanisms for the development and maintenance of this disease.

Our laboratory has recently reported that a cell surface protein (integrin v6) residing on lung alveolar cells may be critical in the development of pulmonary emphysema. A unique and specific function of the integrin v6, namely activation of an inflammatory effector termed transforming growth factor-beta (TGF-), is responsible for this effect. Clarification of the molecular steps participating in integrin v6-mediated TGF- activation could therefore provide important insights into the molecular pathogenesis of pulmonary emphysema.

We have also reported that integrin v6-mediated TGF- activation decreases the expression of an enzyme termed macrophage metalloelastase (Mmp-12). Therefore, it appears that integrin v6-mediated TGF- activation acts as a modulator by inhibiting Mmp-12. Mmp-12 has been strongly implicated in the development of pulmonary emphysema. Mmp-12 is able to digest specific targets in lung tissue which leads to the characteristic destruction of alveolar walls seen in pulmonary emphysema.

The important inflammatory effector interleukin-1  (IL-1) has been shown to be increased in smokers and is known to induce Mmp-12. We have recently shown that IL-1 also induces integrin v6-mediated TGF- activation.

Therefore, we hypothesize that IL-1 can simultaneously induce counterregulatory pathways responsible for the development of pulmonary emphysema: direct induction of Mmp-12 and indirect inhibition of Mmp-12 through integrin v6-mediated TGF- activation. The dynamic equilibrium regulated by this novel pathway may prove critical to the development and maintenance of pulmonary emphysema in tobacco smokers.

Our proposed studies will further characterize the signaling pathway between IL-1 and integrin v6-mediated TGF- activation. We strongly suspect that a known IL-1 signaling intermediate, interleukin-1 associated kinase-1 (IRAK-1), is a critical component of this pathway. We plan to demonstrate that manipulating IRAK-1 activity will alter the balance of the IL-1-induced counterregulatory pathways described above and result in changes in expression and activity of Mmp-12.

It is our hope that characterization of this novel pathway will provide important clues to how tobacco smoking leads to the development, maintenance, and progression of pulmonary emphysema. Furthermore, identifying relevant signaling mechanisms will provide new targets for the design of new and powerful treatment strategies for this devastating and largely untreatable disease.
Publications

Integrin beta5 subunit-null mice are protected from ventilator-induced lung injury.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Su G, Frank J, Matthay MA, Pittet JF, Sheppard D ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Integrin avbeta5 is a crucial regulator of pulmonary endothelial vacular permeability and VE-cadherin phosphorylation
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Su G, Frank J, Matthay Ma, Pittet JF, Sheppard D ABS
Yr: 0 Vol: Nbr: Abs: Pg: