PPARs: Key Regulators of Airway Inflammation and Potential Therapeutic Targets in Asthma

Abstract

Asthma affects approximately 300 million people worldwide, significantly impacting quality of life and healthcare costs. While current therapies are effective in controlling many patients’ symptoms, a large number continue to experience exacerbations or treatment-related adverse effects. Alternative therapies are thus urgently needed. Accumulating evidence has shown that the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors, comprising PPARα, PPARβ/δ, and PPARγ, is involved in asthma pathogenesis and that ligand-induced activation of these receptors suppresses asthma pathology. PPAR agonists exert their anti-inflammatory effects primarily by suppressing pro-inflammatory mediators and antagonizing the pro-inflammatory functions of various cell types relevant to asthma pathophysiology. Experimental findings strongly support the potential clinical benefits of PPAR agonists in the treatment of asthma. We review current literature, highlighting PPARs’ key role in asthma pathogenesis and their agonists’ therapeutic potential. With additional research and rigorous clinical studies, PPARs may become attractive therapeutic targets in this disease.

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

“…PPARγ promotes lipogenesis during anabolism by acting on the adipose tissue. Besides, this receptor is a participant in inflammatory reactions [4] and a regulator of the immune system in the lungs [10,40]. The binding of specific ligands to PPARγ regulates the transcription of target genes and inhibits the activation of immune cells and the expression of inflammatory factors [8].…”

“…All isoforms of PPARs are involved in the regulation of lipid metabolism, with its violation being one of the most important mechanisms in the asthma pathogenesis. Such wide expression of PPARs in the bronchopulmonary system, their anti-inflammatory properties, and their ability to regulate lipid metabolism are of particular interest, because the receptors may be a prospective therapeutic target for asthma treatment [4,10].…”

“…Lakshmi et al have shown that the PPARγ deficiency contributes to the development of airway hyperresponsiveness, bronchial remodeling, and the inhibition of MUC5AC activity [70]. However, inter-pretation of PPARγ level in asthma requires particulars, because this parameter can change depending on the stage of inflammation (initiation or resolution) [4]. In response to the action of the allergen, Th2 cells express PPARγ, which promotes the synthesis of the IL-33 receptor on the surface of Th2 cells.…”

“…It indicates that there are subendotypes that include disturbances at different structural levels. For example, chronic inflammation in asthma can be inhibited both by the intracellular signaling pathways and by the activity of inflammatory genes [4]. The change in the activity of some receptors affects the functioning of others and contributes to the development of chronic inflammation.…”

The future of bronchodilation: looking for new classes of bronchodilators

“…In particular, increased expression levels of PPAR-γ in ASM, epithelium and mucosal eosinophils and macrophages have been found in human airway biopsies from patients with asthma [78]. When activated, PPAR-γ exhibits several biological functions that are performed via regulation of transcription factors, notably stimulating the nuclear factor-κB-negative regulator IkBα [79].…”