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Current Drug Discovery Technologies


ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Mechanistic Systems Biology of Inflammatory Gene Expression in Airway Smooth Muscle as Tool for Asthma Drug Development

Author(s): Chi-Ming Hai

Volume 5, Issue 4, 2008

Page: [279 - 288] Pages: 10

DOI: 10.2174/157016308786733582

Price: $65


There is compelling evidence that airway smooth muscle cells may function as inflammatory cells in the airway system by producing multiple inflammatory cytokines in response to a large array of external stimuli such as acetylcholine, bradykinin, inflammatory cytokines, and toll-like receptor activators. However, how multiple extracellular stimuli interact in the regulation of inflammatory gene expression in an airway smooth muscle cell remains poorly understood. This review addresses the mechanistic systems biology of inflammatory gene expression in airway smooth muscle by discussing: a) redundancy underlying multiple stimulus-product relations in receptor-mediated inflammatory gene expression, and their regulation by convergent activation of Erk1/2 mitogen-activated protein kinase (MAPK), b) Erk1/2 MAPK-dependent induction of phosphatase expression as a negative feedback mechanism in the robust maintenance of inflammatory gene expression, and c) cyclooxygenase 2-dependent regulation of the differential temporal dynamics of early and late inflammatory gene expression. It is becoming recognized that a single-target approach is unlikely to be effective for the treatment of inflammatory airway diseases because airway inflammation is a result of complex interactions among multiple inflammatory mediators and cells types in the airway system. Understanding the mechanistic systems biology of inflammatory gene expression in airway smooth muscle and other cell types in the airway system may lead to the development of multi-target drug regimens for the treatment of inflammatory airway diseases such as asthma.

Keywords: ASM, asthma, cyclooxygenase, cytokine, inflammation, MAPK, mathematical, model

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