Regulation of inflammation by PPARs: a future approach to treat lung inflammatory diseases?

Abstract

Lung inflammatory diseases, such as acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis, represent a major health problem worldwide. Although glucocorticoids are the most potent anti-inflammatory drug in asthma, they exhibit major side effects and have poor activity in lung inflammatory disorders such as ALI or COPD. Therefore, there is growing need for the development of alternative or new therapies to treat inflammation in the lung. Peroxisome proliferator-activated receptors (PPARs), including the three isotypes PPARalpha, PPARbeta (or PPARdelta) and PPARgamma, are transcription factors belonging to the nuclear hormone receptor superfamily. PPARs, and in particular PPARalpha and PPARgamma, are well known for their critical role in the regulation of energy homeostasis by controlling expression of a variety of genes involved in lipid and carbohydrate metabolism. Synthetic ligands of the two receptor isotypes, the fibrates and the thiazolidinediones, are clinically used to treat dyslipidaemia and type 2 diabetes, respectively. Recently however, PPARalpha and PPARgamma have been shown to exert a potent anti-inflammatory activity, mainly through their ability to downregulate pro-inflammatory gene expression and inflammatory cell functions. The present article reviews the current knowledge of the role of PPARalpha and PPARgamma in controlling inflammation, and presents different findings suggesting that PPARalpha and PPARgamma activators may be helpful in the treatment of lung inflammatory diseases.

Pioglitazone attenuates endotoxin-induced acute lung injury by reducing neutrophil recruitment

“…Previous studies have suggested that PPAR-c ligands reduce the expression of inflammatory cytokine genes and the production of inflammatory cytokines [11,12]. Consequently, PPAR-a and PPAR-c agonists may be helpful in the treatment of acute inflammatory diseases, such as ALI [13]. In this context, several studies have proven a beneficial role for PPAR-c agonists in models of allergic airway inflammation and bleomycin-induced ALI [14,15].…”

Dynamics of lung macrophage activation in response to helminth infection

“…Furthermore, it has been demonstrated that activating PPAR␥ in the absence of IL-4 and IL-13 is sufficient to drive M2 qualities in macrophages [58], suggesting it may play an independent role in alternative activation. In particular, the activation of these factors appears to be essential for the regulation of pulmonary inflammation by lung macrophages and may represent a crucial regulatory component capable of shifting lung macrophages to a protective phenotype [59,60].…”

Combinations of oseltamivir and fibrates prolong the mean survival time of mice infected with the lethal H7N9 influenza virus

“…In this study, we found that fibrates affected the virus titres. It is known that both PPAR-a and PPAR-c agonists have anti-inflammatory and immunomodulatory activities, and several investigators have suggested that they might be used to treat acute lung injury (Becker et al, 2006;Cuzzocrea, 2006;Paola & Cuzzocrea, 2007). One study showed that glitazones (PPAR-c agonists) inhibit respiratory syncytial virus infection in human lung epithelial cells, probably by inhibiting viral gene expression and not earlier adhesion or fusion processes (Arnold & König, 2006).…”