scholarly journals Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma

2016 ◽  
Vol 113 (17) ◽  
pp. E2355-E2362 ◽  
Author(s):  
Arnab Ghosh ◽  
Cynthia J. Koziol-White ◽  
Kewal Asosingh ◽  
Georgina Cheng ◽  
Lisa Ruple ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Guanylate Cyclase ◽  
Human Lung ◽  
Soluble Guanylate Cyclase ◽  
Alternative Pathway ◽  
Allergic Inflammation ◽  
Normal Lung ◽  
Airway Smooth Muscle Cells ◽  
Muscle Enzyme

Asthma is defined by airway inflammation and hyperresponsiveness, and contributes to morbidity and mortality worldwide. Although bronchodilation is a cornerstone of treatment, current bronchodilators become ineffective with worsening asthma severity. We investigated an alternative pathway that involves activating the airway smooth muscle enzyme, soluble guanylate cyclase (sGC). Activating sGC by its natural stimulant nitric oxide (NO), or by pharmacologic sGC agonists BAY 41–2272 and BAY 60–2770, triggered bronchodilation in normal human lung slices and in mouse airways. Both BAY 41–2272 and BAY 60–2770 reversed airway hyperresponsiveness in mice with allergic asthma and restored normal lung function. The sGC from mouse asthmatic lungs displayed three hallmarks of oxidative damage that render it NO-insensitive, and identical changes to sGC occurred in human lung slices or in human airway smooth muscle cells when given chronic NO exposure to mimic the high NO in asthmatic lung. Our findings show how allergic inflammation in asthma may impede NO-based bronchodilation, and reveal that pharmacologic sGC agonists can achieve bronchodilation despite this loss.

scholarly journals Soluble guanylate cyclase modulators blunt hyperoxia effects on calcium responses of developing human airway smooth muscle

2015 ◽  
Vol 309 (6) ◽  
pp. L537-L542 ◽  
Author(s):  
Rodney D. Britt ◽  
Michael A. Thompson ◽  
Ine Kuipers ◽  
Alecia Stewart ◽  
Elizabeth R. Vogel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Guanylate Cyclase ◽  
Therapeutic Strategy ◽  
Soluble Guanylate Cyclase ◽  
Novel Drugs ◽  
Intracellular Ca ◽  
Recurrent Wheeze ◽  
Airway Tone ◽  
Sgc Stimulators

Exposure to moderate hyperoxia in prematurity contributes to subsequent airway dysfunction and increases the risk of developing recurrent wheeze and asthma. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) axis modulates airway tone by regulating airway smooth muscle (ASM) intracellular Ca2+ ([Ca2+]i) and contractility. However, the effects of hyperoxia on this axis in the context of Ca2+/contractility are not known. In developing human ASM, we explored the effects of novel drugs that activate sGC independent of NO on alleviating hyperoxia (50% oxygen)-induced enhancement of Ca2+ responses to bronchoconstrictor agonists. Treatment with BAY 41–2272 (sGC stimulator) and BAY 60-2770 (sGC activator) increased cGMP levels during exposure to 50% O2. Although 50% O2 did not alter sGCα1 or sGCβ1 expression, BAY 60-2770 did increase sGCβ1 expression. BAY 41-2272 and BAY 60-2770 blunted Ca2+ responses to histamine in cells exposed to 50% O2. The effects of BAY 41-2272 and BAY 60-2770 were reversed by protein kinase G inhibition. These novel data demonstrate that BAY 41-2272 and BAY 60-2770 stimulate production of cGMP and blunt hyperoxia-induced increases in Ca2+ responses in developing ASM. Accordingly, sGC stimulators/activators may be a useful therapeutic strategy in improving bronchodilation in preterm infants.

Regulation of IL-1β-induced GM-CSF production in human airway smooth muscle cells by carbon monoxide

2003 ◽  
Vol 284 (1) ◽  
pp. L50-L56 ◽  
Author(s):  
Ruiping Song ◽  
Wen Ning ◽  
Fang Liu ◽  
Bill T. Ameredes ◽  
William J. Calhoun ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
P38 Mapk ◽  
Airway Smooth Muscle ◽  
Guanylate Cyclase ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Gm Csf

Asthma, a chronic inflammatory disease of the airways, involves the increased expression of inflammatory mediators, including granulocyte-monocyte colony-stimulating factor (GM-CSF). Heme oxygenase-1 (HO-1), a stress-response protein, confers protection against oxidative stress. We hypothesized that carbon monoxide (CO), a byproduct of HO-1-dependent heme catabolism, regulates GM-CSF synthesis in human airway smooth muscle cells (HASMC). IL-1β treatment induced a time-dependent induction of GM-CSF in HASMC. Furthermore, IL-1β stimulated the major MAPK pathways, including ERK1/ERK2, JNK, and p38 MAPK. Exposure of HASMC to CO at low concentration (250 ppm) markedly inhibited IL-1β-induced GM-CSF synthesis (>90%) compared with air-treated controls. CO treatment inhibited IL-1β-induced ERK1/2 activation but did not inhibit JNK and p38 MAPK. Furthermore, CO increased cGMP levels in HASMC. Inhibition of guanylate cyclase by IH-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1–1 (ODQ) abolished the inhibitory effects of CO on GM-CSF synthesis and ERK1/2 activation. Collectively, these data demonstrate that the inhibitory effect of CO on GM-CSF synthesis depends on ERK1/2 MAPK and guanylate cyclase/cGMP-dependent pathways.

Human lung mast cells modulate the functions of airway smooth muscle cells in asthma

Allergy ◽  
2011 ◽  
Vol 66 (9) ◽  
pp. 1231-1241 ◽  
Author(s):  
H. Alkhouri ◽  
F. Hollins ◽  
L. M. Moir ◽  
C. E. Brightling ◽  
C. L. Armour ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Mast Cells ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Human Lung ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells

scholarly journals Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy

2012 ◽  
Vol 302 (1) ◽  
pp. L120-L132 ◽  
Author(s):  
Lioubov I. Brueggemann ◽  
Priyanka P. Kakad ◽  
Robert B. Love ◽  
Julian Solway ◽  
Maria L. Dowell ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Potassium Channels ◽  
Guinea Pig ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Channel Blocker ◽  
Human Lung ◽  
Airway Smooth Muscle Cells ◽  
Qrt Pcr ◽  
Channel Activator

Expression and function of Kv7 (KCNQ) voltage-activated potassium channels in guinea pig and human airway smooth muscle cells (ASMCs) were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), patch-clamp electrophysiology, and precision-cut lung slices. qRT-PCR revealed expression of multiple KCNQ genes in both guinea pig and human ASMCs. Currents with electrophysiological and pharmacological characteristics of Kv7 currents were measured in freshly isolated guinea pig and human ASMCs. In guinea pig ASMCs, Kv7 currents were significantly suppressed by application of the bronchoconstrictor agonists methacholine (100 nM) or histamine (30 μM), but current amplitudes were restored by addition of a Kv7 channel activator, flupirtine (10 μM). Kv7 currents in guinea pig ASMCs were also significantly enhanced by another Kv7.2–7.5 channel activator, retigabine, and by celecoxib and 2,5-dimethyl celecoxib. In precision-cut human lung slices, constriction of airways by histamine was significantly reduced in the presence of flupirtine. Kv7 currents in both guinea pig and human ASMCs were inhibited by the Kv7 channel blocker XE991. In human lung slices, XE991 induced robust airway constriction, which was completely reversed by addition of the calcium channel blocker verapamil. These findings suggest that Kv7 channels in ASMCs play an essential role in the regulation of airway diameter and may be targeted pharmacologically to relieve airway hyperconstriction induced by elevated concentrations of bronchoconstrictor agonists.

Sign in / Sign up

Export Citation Format

Share Document