Peroxisome Proliferator Activated Receptor Ligands as Regulators of Airway Inflammation and Remodelling in Chronic Lung Disease

Abstract

Inflammation is a major component in the pathology of chronic lung diseases, including asthma. Anti-inflammatory treatment with corticosteroids is not effective in all patients. Thus, new therapeutic options are required to control diverse cellular functions that are currently not optimally targeted by these drugs in order to inhibit inflammation and its sequelae in lung disease. Peroxisome proliferator activated receptors (PPARs), originally characterised as regulators of lipid and glucose metabolism, offer marked potential in this respect. PPARs are expressed in both lung infiltrating and resident immune and inflammatory cells, as well as in resident and structural cells in the lungs, and play critical roles in the regulation of airway inflammation. In vitro, endogenous and synthetic ligands for PPARs regulate expression and release of proinflammatory cytokines and chemoattractants, and cell proliferation and survival. In murine models of allergen-induced inflammation, PPARα and PPARγ ligands reduce the influx of inflammatory cells, cytokine and mucus production, collagen deposition, and airways hyperresponsiveness. The activity profiles of PPAR ligands differ to corticosteroids, supporting the hypothesis that PPARs comprise additional therapeutic targets to mimimise the contribution of inflammation to airway remodelling and dysfunction.

Novel Small Airway Bronchodilator Responses to Rosiglitazone in Mouse Lung Slices

“…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).…”

Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

“…As in the present study, Voelkel and colleagues found little PPARg staining in the medial layer of normal lungs or in the proliferating cells of plexiform lesions, but they did not examine PPARg expression in the pulmonary smooth muscle of patients with IPAH (13). The consequence of elevated PPARg expression within the medial layer and its impact on disease progression warrants further investigation to determine whether increased expression translates into enhanced PPARg activity or responsiveness to endogenous ligand activators, such as the prostaglandin metabolite 5-deoxy-delta-12,14-prostaglandin J 2 (10). The overlapping concentration-response curves to the antiproliferative effects of the PPARg agonist rosiglitazone we observed in PASMCs from normal and IPAH cells suggests not.…”

“…The mechanism of this potentiation is unknown. Treprostinil and rosiglitazone can interact with the ligand-binding domain of PPARg (10,11), so that one agent could enhance the binding of the other ligand activator, thus allowing PPARg to activate at lower agonist concentrations. PPARg also contains many phosphorylation sites (32), so that prostacyclin analogs may modulate PPARg agonist activity in that way.…”

“…However, the extent to which the prostacyclin (IP) receptor mediates the effects of prostacyclin analogs is not clear. Not only can these agents activate other prostanoid receptors (8), but they can also signal through nuclear peroxisome proliferator-activated receptors (PPARs) (9), a family of transcription factors regulating diverse biological processes such as cell growth, apoptosis, inflammation, and insulin sensitivity (10). Activation of PPARs can occur via direct ligand binding or as a consequence of receptor activation (11).…”