PPARγLigands Regulate Noncontractile and Contractile Functions of Airway Smooth Muscle: Implications for Asthma Therapy

Abstract

In asthma, the increase in airway smooth muscle (ASM) can contribute to inflammation, airway wall remodeling and airway hyperresponsiveness (AHR). Targetting peroxisome proliferator-activated receptor γ (PPARγ), a receptor upregulated in ASM in asthmatic airways, may provide a novel approach to regulate these contributions. This review summarises experimental evidence that PPARγ ligands, such as rosiglitazone (RGZ) and pioglitazone (PGZ), inhibit proliferation and inflammatory cytokine production from ASM in vitro. In addition, inhaled administration of these ligands reduces inflammatory cell infiltration and airway remodelling in mouse models of allergen-induced airways disease. PPARγ ligands can also regulate ASM contractility, with acute treatment eliciting relaxation of mouse trachea in vitro through a PPARγ-independent mechanism. Chronic treatment can protect against the loss of bronchodilator sensitivity to β 2-adrenoceptor agonists and inhibit the development of AHR associated with exposure to nicotine in utero or 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 PPARγ agonists to target the noncontractile and contractile functions of ASM to improve outcomes for patients with poorly controlled asthma.

Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease

“…These actions are in addition to its previously reported inhibitory effects on chronic allergen-induced inflammation, airway wall remodeling, and AHR (reviewed by Ref. 8).…”

“…Numerous studies suggest that PPAR␥ ligands can inhibit allergen-induced inflammation and the development of airway remodeling and airway hyperresponsiveness (AHR) in vivo (reviewed in Ref. 8), as well as exert direct dilator effects on airway smooth muscle (ASM) in vitro (3,12).…”

Novel Small Airway Bronchodilator Responses to Rosiglitazone in Mouse Lung Slices

“…PPARg is the target for the thiazolidinedione class of synthetic antidiabetic agents, including RGZ (39), PGZ, and CGZ as well as the proposed endogenous agonist 15 d-PGJ 2 . Activation of PPARg results in suppression of cytokine production from activated macrophages and monocytes, T cells, airway epithelial cells, and ASMCs (10). In human ASMC cultures, we and others have shown that PPARg ligands also decrease proliferation (14,27,40), with inhibition prevented by the PPARg antagonist GW9662 (27).…”

“…PPARg is a widely expressed ligandactivated transcription factor implicated in human lung diseases associated with inflammation and remodeling (10,14). PPARg is the target for the thiazolidinedione class of synthetic antidiabetic agents, including RGZ (39), PGZ, and CGZ as well as the proposed endogenous agonist 15 d-PGJ 2 .…”

“…RGZ and ciglitazone (CGZ) regulate ASMC proliferation and the production of inflammatory mediators such as GM-CSF in vitro (10). Consistent with these actions, chronic treatment with PPARg agonists inhibits inflammatory cell influx, airway wall remodeling, and the development of airways hyperresponsiveness to the bronchoconstrictor methacholine (MCh) in mice with ovalbumin-induced airway disease (11)(12)(13)(14)(15) (reviewed in Reference 10).…”