[Frontiers in Bioscience S3, 643-654, January 1, 2011]

Beta-2-receptor regulation of immunomodulatory proteins in airway smooth muscle

Bill T. Ameredes

Department of Internal Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1083

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Beta-2-receptor agonist modulated IMF release by airway smooth muscle
3.1. Human airway smooth muscle as an immunomodulator
3.2. Human airway smooth muscle cytokine and serum stimulatory factors
3.3. GM-CSF release by human airway smooth muscle
3.4. Modulation of human airway smooth muscle GM-CSF release by beta-2-receptor agonists
4. Isomer-based model of beta-2-receptor agonist modulation of IMF release
4.1. The GPCR activation model
4.2. GM-CSF release as an output variable of an agonism/inverse agonism model
4.3. The combined model as a mechanistic postulate
4.4. (S)-albuterol: the sinister half
5. Beta-2-receptor agonist /steroid combinations as IMF co-modulators
5.1. Treatment-based combinatorial rational
5.2. Evidence for associative immunomodulatory mechanisms in human airway smooth muscle
5.3. Isomer enhancement and suppression of steroid effects
6. Summary and perspective: sinister effects on airway function?
7. Acknowledgements
8. References

1. ABSTRACT

Airway smooth muscle (ASM) cells have been shown to secrete significant amounts of immunomodulatory factors (IMFs), many of which are typically ascribed to trafficking leukocytes (e.g., GM-CSF, IL-6, IL-13, and eotaxin), and may be indicative of an immunomodulatory role for ASM in control of airway function, as well as in airway diseases states associated with acute and/or chronic inflammation, such as asthma and COPD. Furthermore, epinephrine analogues such as albuterol, which ligate the G-protein coupled beta-2-receptor and have been clinically applied to promote ASM relaxation and bronchodilation in the treatment of asthma and COPD, also have been reported to downregulate IMF release by ASM, both individually and in additive fashion, in combination with corticosteroids. Based on experimental data, an inverse agonist/agonist model is proposed to explain these behaviors modeled on cell stimulatory states and G-protein coupled receptor activation. The ramifications of the model are considered in light of unexplained paradoxical clinical findings, and may provide a model for the understanding of beta-2-receptor agonist modulation of airway inflammation and function.