Glucocorticosteroids And ²2-adrenoceptor Agonists Synergistically Prevent The Induction Of A Hypocontractile, Proliferative Airway Smooth Muscle Phenotype

In asthma, the increase in airway smooth muscle (ASM) can contribute to inflammation, airway wall remodeling and airway hyperresponsiveness (AHR). Targetting peroxisome proliferator-activated receptorγ(PPARγ), a receptor upregulated in ASM in asthmatic airways, may provide a novel approach to regulate these contributions. This review summarises experimental evidence that PPARγligands, such as rosiglitazone (RGZ) and pioglitazone (PGZ), inhibit proliferation and inflammatory cytokine production from ASMin vitro. In addition, inhaled administration of these ligands reduces inflammatory cell infiltration and airway remodelling in mouse models of allergen-induced airways disease. PPARγligands can also regulate ASM contractility, with acute treatment eliciting relaxation of mouse tracheain vitrothrough a PPARγ-independent mechanism. Chronic treatment can protect against the loss of bronchodilator sensitivity toβ2-adrenoceptor agonists and inhibit the development of AHR associated with exposure to nicotinein uteroor following allergen challenge. Of particular interest, a small clinical trial has shown that oral RGZ treatment improves lung function in smokers with asthma, a group that is generally unresponsive to conventional steroid treatment. These combined findings support further investigation of the potential for PPARγagonists to target the noncontractile and contractile functions of ASM to improve outcomes for patients with poorly controlled asthma.

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Guanylyl cyclases, nitric oxide, natriuretic peptides, and airway smooth muscle function

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00033.2003 ◽

2003 ◽

Vol 285 (5) ◽

pp. L973-L983 ◽

Cited By ~ 57

Author(s):

Ahmed M. Hamad ◽

Andrew Clayton ◽

Baharul Islam ◽

Alan J. Knox

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Airway Smooth Muscle ◽

Natriuretic Peptides ◽

Large Body ◽

Second Messenger ◽

Antiproliferative Effects ◽

Cyclic Monophosphate ◽

Guanylyl Cyclases ◽

Adrenoceptor Agonists

Airway smooth muscle (ASM) plays an important role in asthma pathophysiology through its contractile and proliferative functions. The cyclic nucleotides adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP) are second messengers capable of mediating the effects of a variety of drugs and hormones. There is a large body of evidence to support the hypothesis that cAMP is a mediator of the ASM's relaxant effects of drugs, such as β2-adrenoceptor agonists, in human airways. Although most attention has been paid to this second messenger and the signal transduction pathways it activates, recent evidence suggests that cGMP is also an important second messenger in ASM with important relaxant and antiproliferative effects. Here, we review the regulation and function of cGMP in ASM and discuss the implications for asthma pathophysiology and therapeutics. Recent studies suggest that activators of soluble and particulate guanylyl cyclases, such as nitric oxide donors and natriuretic peptides, have both relaxant and antiproliferative effects that are mediated through cGMP-dependent and cGMP-independent pathways. Abnormalities in these pathways may contribute to asthma pathophysiology, and therapeutic manipulation may complement the effects of β2-adrenoceptor agonists.

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