title: 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 PPAR alpha and -gamma subtypes. Activation of PPAR gamma by natural and synthetic ligands inhibits serum-induced cell growth more effectively than does the steroid dexamethasone, and induces apoptosis. Moreover, PPAR gamma activation, like dexamethasone, inhibits the release of GM-CSF. However, PPAR gamma ligands, but not dexamethasone, similarly inhibits G-CSF release. These results reveal a novel anti-inflammatory pathway in human airway smooth muscle, where PPAR gamma activation has additional anti-inflammatory effects to those of steroids. Hence, PPAR ligands might act as potential treatments in human respiratory diseases.
authors.affiliation: Respiratory Pharmacology Group, Department of Cardiothoracic Surgery, Faculty of Medicine, The National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom. h.j.patel@ic.ac.uk
authors.forename: Hema J
authors.initials: HJ
authors.lastname: Patel
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000628:therapy*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology; D045162:Thiazolidinediones; D014132:Trachea / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000893:Anti-Inflammatory Agents; D006131:Growth Inhibitors; D007375:Interleukin-1; D008024:Ligands; D020033:Protein Isoforms; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D016179:Granulocyte Colony-Stimulating Factor; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C006253:pirinixic acid; D015230:Prostaglandin D2; C039671:ciglitazone