title: Electrophilic PPARγ Ligands Attenuate IL-1β and Silica-Induced Inflammatory Mediator Production in Human Lung Fibroblasts via a PPARγ-Independent Mechanism.
abstract: Acute and chronic lung inflammation is associated with numerous important disease pathologies including asthma, chronic obstructive pulmonary disease and silicosis. Lung fibroblasts are a novel and important target of anti-inflammatory therapy, as they orchestrate, respond to, and amplify inflammatory cascades and are the key cell in the pathogenesis of lung fibrosis. Peroxisome proliferator-activated receptor gamma (PPARγ) ligands are small molecules that induce anti-inflammatory responses in a variety of tissues. Here, we report for the first time that PPARγ ligands have potent anti-inflammatory effects on human lung fibroblasts. 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO) and 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) inhibit production of the inflammatory mediators interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), COX-2, and prostaglandin (PG)E(2) in primary human lung fibroblasts stimulated with either IL-1β or silica. The anti-inflammatory properties of these molecules are not blocked by the PPARγ antagonist GW9662 and thus are largely PPARγ independent. However, they are dependent on the presence of an electrophilic carbon. CDDO and 15d-PGJ(2), but not rosiglitazone, inhibited NF-κB activity. These results demonstrate that CDDO and 15d-PGJ(2) are potent attenuators of proinflammatory responses in lung fibroblasts and suggest that these molecules should be explored as the basis for novel, targeted anti-inflammatory therapies in the lung and other organs.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Rochester, 601 Elmwood Avenue, P.O. Box 692, Rochester, NY 14642, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hogan
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.forename: Ramil E
authors.initials: RE
authors.lastname: Sapinoro
authors.forename: Michael N
authors.initials: MN
authors.lastname: Gurell
authors.forename: Heather E
authors.initials: HE
authors.lastname: Ferguson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pollock
authors.forename: Carolyn
authors.initials: C
authors.lastname: Jones
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime