Activation of Peroxisome Proliferator-Activated Receptors in Human Airway Smooth Muscle Cells Has a Superior Anti-inflammatory Profile to Corticosteroids: Relevance for Chronic Obstructive Pulmonary Disease Therapy

Abstract

Airway smooth muscle is actively involved in the inflammatory process in diseases such as chronic obstructive pulmonary disease and asthma by 1) contributing to airway narrowing through hyperplasia and hypertrophy and 2) the release of GM-CSF and G-CSF, which promotes the survival and activation of infiltrating leukocytes. Thus, the identification of novel anti-inflammatory pathways in airway smooth muscle will have important implications for the treatment of inflammatory airway disease. This study identifies such a pathway in the activation of peroxisome proliferator-activated receptors (PPARs). PPAR ligands are known therapeutic agents in the treatment of diabetes; however, their role in human airway disease is unknown. We demonstrate, for the first time, that human airway smooth muscle cells express PPARα and -γ subtypes. Activation of PPARγ by natural and synthetic ligands inhibits serum-induced cell growth more effectively than does the steroid dexamethasone, and induces apoptosis. Moreover, PPARγ activation, like dexamethasone, inhibits the release of GM-CSF. However, PPARγ ligands, but not dexamethasone, similarly inhibits G-CSF release. These results reveal a novel anti-inflammatory pathway in human airway smooth muscle, where PPARγ activation has additional anti-inflammatory effects to those of steroids. Hence, PPAR ligands might act as potential treatments in human respiratory diseases.

Peroxisome proliferator–activated receptor γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model☆

“…26,27 In smooth muscle cells PPAR-c activation has additional anti-inflammatory effects compared with the effects of corticosteroids. 28 We demonstrated that PPARc was expressed by eosinophils and that PPAR-c agonists were able to inhibit eosinophil chemotaxis and antibodydependent cellular cytotoxicity reactions in vitro. 29 Furthermore, in a murine model of asthma, treatment with a PPAR-c agonist also inhibited the development of allergic inflammation, including pulmonary eosinophilia and airway AHR.…”

Peroxisome Proliferator‐Activated Receptors: Potential Therapeutic Targets in Lung Disease?

“…13,36,37 Long-term effects include subepithelial fibrosis and epithelial metaplasia. 89 Both the type 2 T helper cell Fig.…”

“…Following their identification, a rapidly increasing number of articles and reviews have been written, including those that focus on PPAR expression, function, and regulation, 2,3 as well as their role in lipid and glucose metabolism, [4][5][6][7] diabetes and obesity, [8][9][10] atherosclerosis, 4,8,11 cellular proliferation/differentiation, [12][13][14][15] neurological diseases, [16][17][18] and inflammation/immunity. 7,[19][20][21] These publications are recommended to readers who want additional information on these topics.…”

“…7,[19][20][21]25,26 In lung tissue, both PPARa and PPARg are expressed in alveolar macrophages and airway epithelial cells. 6,13 PPARb/d is also expressed in primary airway epithelial cells, and to a lesser extent in epithelial cell lines. 27 PPARg2 is the predominant form in epithelial cell lines (A549, BEAS-2B, and NCI-H292), whereas PPARg1 is the major variant in primary type II cells.…”

“…27 PPARg2 is the predominant form in epithelial cell lines (A549, BEAS-2B, and NCI-H292), whereas PPARg1 is the major variant in primary type II cells. 27 Of relevance to the pulmonary immune/inflammatory response, PPARg is also expressed in endothelial 25,[28][29][30][31][32][33] and smooth muscle cells 13,26,34,35 of the pulmonary vasculature, and in leukocytes (neutrophils, eosinophils, and mast cells). 25,36,37 The widespread distribution of PPARs in the airway, along with their many physiological roles, suggests that they may play important roles in both lung health and disease.…”