The role of regulators of G-protein signaling 5 in the pathophysiology of asthma

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NIAID	SIG-7

* FARE Award Winner

Authors

• N Balenga
• Z Yang
• P.R. Cooper
• G Damera
• R Edwards
• C.E. Brightling
• R.A. Panettieri
• K.M. Druey

Abstract

Asthma is a chronic inflammatory disease of the lungs manifested by eosinophilia, smooth muscle hyperplasia and reversible airways obstruction/remodeling. Although the airways of asthmatic patients are hyper-responsive to inflammatory mediators such as histamine, in severe/fatal asthma fixed airway obstruction (i.e. unresponsive to bronchodilators) may occur. Histamine triggers a G protein coupled receptor (GPCR) on the surface of airway smooth muscle cells (ASM) and leads to Galphaq-mediated increases in intracellular Ca2+, resulting in ASM contraction and airway narrowing. Regulators of G-protein Signaling (RGS) proteins switch off GPCR-mediated downstream signaling. We show that the expression of RGS5 is increased in ASM isolated from patients who died of asthma compared to ASM from normal donors. BALB/c mice challenged with allergen (extract of the ubiquitous fungus Aspergillus fumigatus), have increased expression of RGS5 in ASM compared to naïve mice. Human asthmatic ASM cells show lower levels of intracellular Ca2+ release upon stimulation by histamine compared to normal donors. Lentiviral overexpression of RGS5 reduced Ca2+ responses to histamine in control ASM and decreased contraction of small airways in precision cut lung slices (PCLS) of healthy donors. Therefore, increased expression of RGS5 may blunt ASM contraction in severe asthma, resulting in fixed airway obstruction.

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