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Emerging PPAR?-Independent Role of PPAR? Ligands in Lung Diseases.

ABSTRACT: Peroxisome proliferator activated receptor (PPAR)-? is a nuclear hormone receptor that is activated by multiple agonists including thiazolidinediones, prostaglandins, and synthetic oleanolic acids. Many PPAR? ligands are under investigation as potential therapies for human diseases. These ligands modulate multiple cellular pathways via both PPAR?-dependent and PPAR?-independent mechanisms. Here, we review the role of PPAR? and PPAR? ligands in lung disease, with emphasis on PPAR?-independent effects. PPAR? ligands show great promise in moderating lung inflammation, as antiproliferative agents in combination to enhance standard chemotherapy in lung cancer and as treatments for pulmonary fibrosis, a progressive fatal disease with no effective therapy. Some of these effects occur when PPAR? is pharmaceutically antagonized or genetically PPAR? and are thus independent of classical PPAR?-dependent transcriptional control. Many PPAR? ligands demonstrate direct binding to transcription factors and other proteins, altering their function and contributing to PPAR?-independent inhibition of disease phenotypes. These PPAR?-independent mechanisms are of significant interest because they suggest new therapeutic uses for currently approved drugs and because they can be used as probes to identify novel proteins and pathways involved in the pathogenesis or treatment of disease, which can then be targeted for further investigation and drug development.

SUBMITTER: Kulkarni AA

PROVIDER: S-EPMC3385049 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Emerging PPARγ-Independent Role of PPARγ Ligands in Lung Diseases.

Kulkarni Ajit A AA Woeller Collynn F CF Thatcher Thomas H TH Ramon Sesquile S Phipps Richard P RP Sime Patricia J PJ

PPAR research 20120618

Peroxisome proliferator activated receptor (PPAR)-γ is a nuclear hormone receptor that is activated by multiple agonists including thiazolidinediones, prostaglandins, and synthetic oleanolic acids. Many PPARγ ligands are under investigation as potential therapies for human diseases. These ligands modulate multiple cellular pathways via both PPARγ-dependent and PPARγ-independent mechanisms. Here, we review the role of PPARγ and PPARγ ligands in lung disease, with emphasis on PPARγ-independent eff ...[more]

PMID: 22778711

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Project description:Mast cells (MCs) are granular cells of the innate immune system which develop from CD34+/CD117+ progenitors and play a role in orchestrating adaptive immune responses. They have a well-known role in allergic reactions following immunoglobulin (Ig)E-mediated activation of the cell-surface expressed IgE high-affinity receptor (Fc?RI). MCs can also respond to various other stimuli due to the expression of a variety of receptors including toll-like receptors (TLRs), immunoglobulin (IgG) receptors (Fc?R), complement receptors such as C5a (CD88) expressed by skin MCs, neuropeptides receptors including nerve growth factor receptor, (NGFR), cytokines receptors such as (IL)-1R and IL-3R, and chemokines receptors including CCR-1 and CCR-3. MCs release three groups of mediators upon degranulation differentiated according to their chemical composition, storage, and time to release. These include preformed mediators (mainly histamine, tryptase, and chymase), de novo synthesized mediators such as prostaglandin (PG)D2, leukotriene (LT)B4 and LTD4, and cytokines including IL-1?, IL-3, tumor necrosis factor (TNF)?, and transforming growth factor(TGF)-?. Emerging evidence indicates a role for IgE-independent MC activation in the late-stage asthmatic response as well as in non-allergic airway diseases including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. MC infiltration/activation has been reported in some, but not all, studies of lung cancer. MC-derived TNF-? possesses tumor-suppressive activity while IL-1? supports tumor progression and metastasis. In IPF lungs, an increase in density of tryptase- and chymase-positive MCs (MCTC) and overexpression of TGF-? support the fibrosis progression. MC-derived chymase activates latent TGF-? that induces the differentiation of fibroblasts to matrix-producing myofibroblasts. In summary, increasing evidence highlights a critical role of MCs in non-allergic diseases that may indicate new approaches for therapy.

Dataset Information

Emerging PPAR?-Independent Role of PPAR? Ligands in Lung Diseases.

Publications

Emerging PPARγ-Independent Role of PPARγ Ligands in Lung Diseases.

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