PPAR Gamma: From Definition to Molecular Targets and Therapy of Lung Diseases

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate the expression of genes related to lipid and glucose metabolism and inflammation. There are three members: PPARα, PPARβ or PPARγ. PPARγ have several ligands. The natural agonists are omega 9, curcumin, eicosanoids and others. Among the synthetic ligands, we highlight the thiazolidinediones, clinically used as an antidiabetic. Many of these studies involve natural or synthetic products in different pathologies. The mechanisms that regulate PPARγ involve post-translational modifications, such as phosphorylation, sumoylation and ubiquitination, among others. It is known that anti-inflammatory mechanisms involve the inhibition of other transcription factors, such as nuclear factor kB(NFκB), signal transducer and activator of transcription (STAT) or activator protein 1 (AP-1), or intracellular signaling proteins such as mitogen-activated protein (MAP) kinases. PPARγ transrepresses other transcription factors and consequently inhibits gene expression of inflammatory mediators, known as biomarkers for morbidity and mortality, leading to control of the exacerbated inflammation that occurs, for instance, in lung injury/acute respiratory distress. Many studies have shown the therapeutic potentials of PPARγ on pulmonary diseases. Herein, we describe activities of the PPARγ as a modulator of inflammation, focusing on lung injury and including definition and mechanisms of regulation, biological effects and molecular targets, and its role in lung diseases caused by inflammatory stimuli, bacteria and virus, and molecular-based therapy.

Post-treatment with the PPAR-γ agonist pioglitazone inhibits inflammation and bacterial growth during Klebsiella pneumonia

“…Antimicrobial resistance is especially problematic in infections caused by gram-negative bacteria such as Pseudomonas (P.) aeruginosa and microorganisms belonging to the Enterobacteriaceae family, such as Klebsiella (K.) pneumoniae [ 4 , 5 ]. Previous research on the potential of PPAR-γ agonists in gram-negative pneumonia has focused on P. aeruginosa [ 6 ] . PPARγ activation enhanced phagocytosis and killing of Pseudomonas by macrophages, and pretreatment with pioglitazone resulted in lower bacterial counts in lung homogenates of mice infected with this bacterium via the airways [ 7 ].…”

“…The present results of pioglitazone mediated inhibition of inflammatory responses in the lungs during Klebsiella pneumonia is in agreement with the previously described effects of ciglitazone during pneumonia caused by S. pneumoniae -induced pneumonia [ 8 ]. PPAR-γ agonists can exert anti-inflammatory effects on macrophages, including inhibition of proinflammatory cytokine production, via multiple mechanisms, encompassing inhibition of nuclear factor-ĸB and mitogen-activated protein kinases [ 2 , 6 ]. The role of PPAR-γ in the anti-inflammatory potential of macrophages is further supported by the finding that disruption of endogenous PPAR-γ in myeloid cells impairs alternative macrophage activation [ 14 ], and is associated with a spontaneous low-grade inflammatory response in lungs of mice [ 15 ].…”

“…PPAR-γ agonists have been extensively studied in the context of lung inflammation [ 6 , 16 ]. Previous studies have reported on the effects of pre-treatment with a thiazolidinedione in mouse models of Pseudomonas and pneumococcal pneumonia [ 6 – 8 ], and bacterial superinfection following influenza [ 9 ].…”

“…PPAR-γ agonists have been extensively studied in the context of lung inflammation [ 6 , 16 ]. Previous studies have reported on the effects of pre-treatment with a thiazolidinedione in mouse models of Pseudomonas and pneumococcal pneumonia [ 6 – 8 ], and bacterial superinfection following influenza [ 9 ]. The present study is the first to describe the effect of a PPAR-γ agonist during pneumonia caused by K. pneumoniae , a common human respiratory pathogen for which adjunctive therapies are urgently needed [ 5 ].…”

Type 2 Diabetic Sepsis Patients Have a Lower Mortality Rate in Pioglitazone Use: A Nationwide 15-Year Propensity Score Matching Observational Study in Taiwan

“…Currently, pioglitazone is the only TZD available in the market. It is proposed to have a protection effect during the sepsis course by acting as the peroxisome proliferator-activated receptor-gamma (PPARc) agonist [7]. Because of multiple concerns about TZDs' complications, for example, cardiovascular disease and urinary bladder cancer, the prescriptions of TZD decreased significantly, from 9.20% in 2006 to 2.86% in 2012 in Taiwan [8][9][10].…”