Airway Smooth Muscle Cell as Therapeutic Target of Inflammation
Abstract:Airway inflammation is an outcome of complex interactions of multiple cell types in an inflammatory network. In recent years, it has become clear that a single target approach is unlikely to be effective for the treatment of inflammatory airway diseases such as asthma. This recognition suggests an alternative approach of targeting multiple cell types and/or mediators. Airway smooth muscle (ASM) cells are unique in serving the dual function of bronchoconstriction and inflammation in the airway system. ASM cells respond to a large array of external stimuli such as acetylcholine, bradykinin, inflammatory cytokines, and cyclic stretch with the expression of inflammatory mediators such as cytokines and cyclooxygenase products. Ca2+ influx through voltage-gated and transient receptor potential channels are important mechanisms of Ca2+-dependent transcription in ASM cells. Calcineurin and Ca2+, calmodulin-dependent kinase (CaMK) are Ca2+-sensitive enzymes that regulate the activation of the two transcription factors, nuclear factor of activated T-cells (NFAT) and cyclic AMP response element binding protein (CREB). Erk1/2 and p38 mitogen-activated protein kinases are signaling enzymes that couple receptor activation to gene transcription by phosphorylating CREB and stabilizing mRNA against de-adenylation. CREB is a unique transcription factor that is phosphorylated by both CaMK II and Erk1/2 MAPK. Nuclear factor κB (NFκB) appears to be a universal transcription factor that regulates the transcription of almost all inflammatory genes. Detailed understanding of the cellular components and interactions in the inflammatory network of the airway system may lead to rational targeting of multiple cells and mediators in the treatment of airway inflammation.
Document Type: Research Article
Affiliations: Department of Molecular Pharmacology, Physiology & Biotechnology, Brown University, Box G-B3,171 Meeting Street, Providence, Rhode Island 02912, USA.
Publication date: 2007-01-01
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