Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors with multiple functions. PPAR-gamma is expressed in the lung epithelium and airway smooth muscle. They function as transcription factors regulating the expression of genes. Expression is upregulated in response to inflammation and is greater in patients with asthma. PPAR-gamma agonists (thiazolidinediones or glitazones) are used for treatment of diabetes type 2.
PPAR-alpha and -gamma pathways. Image source: Wikipedia, GNU Free Documentation License.
Animation of thiazolidinediones mechanism of action and peroxisome proliferator-activated receptors (PPARs).
PPAR-gamma agonists
The medication class of thiazolidinedione (also called glitazones) was introduced in the late 1990s as an adjunctive therapy for diabetes mellitus (type 2). Avandia (rosiglitazone) and Actos (pioglitazone) bind to PPAR-gamma and activate them.
PPAR-gamma agonist as asthma treatment - first human study completed
This study included 32 steroid-naïve adults with persistent asthma who were placed on PPAR-gamma agonist (rosiglitazone) for 3 months. They were evaluated for airway hyperreactivity with serial methacholine challenges. Disclaimer: I was one of the lead investigators and co-wrote the article.
There was an improvement in PC20 which means that the patietns tolerated higher methacholine, typically associated with improved airway hyperreactivity. However, there were no statistically significant improvements in FEV1 or FeNO.
This is the first human study to examine the feasibility of a PPAR-gamma agonist for treatment of asthma. Airway hyperreactivity, assessed by methacholine responsiveness, decreased after 12 weeks of rosiglitazone therapy. However, inhaled steroids have greater and faster effects. A higher frequency of cardiovascular events has bee reported in patients with heart failure treated with thiazolidinediones.
Overall, this proof of concept study hinted at some benefits of PPAR-gamma agonists in asthma. Several larger trials are ongoing.
References:
The use of the peroxisome proliferator-activated receptors γ agonist rosiglitazone to treat airway hyperreactivity. Sandhu MS, Dimov V, Sandhu AK, Walters RW, Wichman T, Casale T. Ann Allergy Asthma Immunol. 2012 Jul;109(1):75-7. Epub 2012 May 24.
The Use of Rosiglitazone to Treat Asthma. ClinicalTrials.gov.
The long Avandia endgame - The Lancet, 2011 http://goo.gl/qcMzN
Peroxisome proliferator-activated receptor γ-mediated suppression of dendritic cell function prevents the onset of atopic dermatitis in mice. JACI. http://goo.gl/Ju6Qz
Peroxisome proliferator-activated receptor, from Wikipedia, the free encyclopedia.
Asthma Treatment can vary from anti-inflammatory and bronchodilator asthma inhalers to oral medications to asthma drugs delivered in an asthma nebulizer or breathing machine.
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