Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Their discovery in the 1990s provided insights into the cellular mechanisms involved in the control of energy homeostasis; the regulation of cell differentiation, proliferation, and apoptosis; and the modulation of important biological and pathological processes related to inflammation, among others. Since then, PPARs have become an exciting therapeutic target for several diseases. PPARs are expressed by many tumors including lung carcinoma cells, and their function has been linked to the process of carcinogenesis in lung. Consequently, intense research is being conducted in this area with the hope of discovering new PPAR-related therapeutic targets for the treatment of lung cancer. This review summarizes the research being conducted in this area and focuses on the mechanisms by which PPARs are believed to affect lung tumor cell biology.

Venkateshwar G. Keshamouni

ShouWei Han

Jesse Roman

Peroxisome Proliferator-Activated Receptors in Lung Cancer

Theodore J. Standiford

PPARs in Lung Biology and Disease

Alveolar macrophages abundantly express PPAR-<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>, with both natural and synthetic agonists maintaining the cell in a quiescent state hyporesponsive to antigen stimulation. Conversely, agonists upregulate expression and function of the cell-surface receptor CD36, which mediates phagocytosis of lipids, apoptotic neutrophils, and other unopsonized materials. These effects led us to investigate the actions of PPAR-<mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> agonists on the Fc<mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> receptor, which mediates phagocytosis of particles opsonized by binding of immunoglobulin G antibodies. We found that troglitazone, rosiglitazone, and 15-deoxy-<mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mi>Δ</mml:mi><mml:mrow><mml:mn>12</mml:mn><mml:mo>,</mml:mo><mml:mn>14</mml:mn></mml:mrow></mml:msup></mml:math>-prostaglandin <mml:math id="E7" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msub><mml:mtext>J</mml:mtext><mml:mn>2</mml:mn></mml:msub></mml:math> increase the ability of alveolar, but not peritoneal, macrophages to carry out phagocytosis mediated by the Fc<mml:math id="E8" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> receptor. Receptor expression was not altered but activation of the downstream signaling proteins Syk, ERK-1, and ERK-2 was observed. Although it was previously known that PPAR-<mml:math id="E9" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> ligands stimulate phagocytosis of unopsonized materials, this is the first demonstration that they stimulate phagocytosis of opsonized materials as well.

David M. Aronoff

Carlos H. Serezani

Jennifer K. Carstens

Teresa Marshall

Srinivasa R. Gangireddy

Marc Peters-Golden

Raju C. Reddy

Stimulatory Effects of Peroxisome Proliferator-Activated Receptor-<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5
t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z"/></g></svg> on Fc <svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g></svg> Receptor-Mediated Phagocytosis by Alveolar Macrophages

PPARs, most notably PPAR-<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>, play a crucial role in regulating the activation of alveolar macrophages, which in turn occupy a pivotal place in the immune response to pathogens and particulates drawn in with inspired air. In this review, we describe the dual role of the alveolar macrophage as both a first-line defender through its phagocytotic activity and a regulator of the immune response. Depending on its state of activation, the alveolar macrophage may either enhance or suppress different aspects of immune function in the lung. We then review the role of PPAR-<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> and its ligands in deactivating alveolar macrophages—thus limiting the inflammatory response that, if unchecked, could threaten the essential respiratory function of the alveolus—while upregulating the cell's phagocytotic activity. Finally, we examine the role that inadequate or inappropriate PPAR-<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> responses play in specific lung diseases.

Monica R. Smith

PPARs in Alveolar Macrophage Biology

Inflammation is a major component in the pathology of chronic lung diseases, including asthma. 
	Anti-inflammatory treatment with corticosteroids is not effective in all patients. Thus, new therapeutic 
	options are required to control diverse cellular functions that are currently not optimally targeted by 
	these drugs in order to inhibit inflammation and its sequelae in lung disease. Peroxisome proliferator 
	activated receptors (PPARs), originally characterised as regulators of lipid and glucose metabolism, 
	offer marked potential in this respect. PPARs are expressed in both lung infiltrating and resident 
	immune and inflammatory cells, as well as in resident and structural cells in the lungs, and play 
	critical roles in the regulation of airway inflammation. In vitro, endogenous and synthetic ligands for 
	PPARs regulate expression and release of proinflammatory cytokines and chemoattractants, 
	and cell proliferation and survival. In murine models of allergen-induced inflammation, PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> and PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B3;</mml:mi></mml:math> ligands reduce the influx of inflammatory cells, cytokine and mucus production, collagen deposition, and airways hyperresponsiveness. The activity profiles of PPAR ligands differ to 
 corticosteroids, supporting the hypothesis that PPARs comprise additional therapeutic targets to 
 mimimise the contribution of inflammation to airway remodelling and dysfunction.

Jane Elizabeth Ward

Xiahui  Tan

Peroxisome Proliferator Activated Receptor Ligands as Regulators of Airway Inflammation and Remodelling in Chronic Lung Disease

Peroxisome proliferator-activated receptors are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARs regulate several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of target genes, including lipid biosynthesis and glucose metabolism. Recently, PPARs and their respective ligands have been implicated as regulators of cellular inflammatory and immune responses. These molecules are thought to exert anti-inflammatory effects by negatively regulating the expression of proinflammatory genes. Several studies have demonstrated that PPAR ligands possess anti-inflammatory properties and that these properties may prove helpful in the treatment of inflammatory diseases of the lung. This review will outline the anti-inflammatory effects of PPARs and PPAR ligands and discuss their potential therapeutic effects in animal models of inflammatory lung disease.

Rosanna  Di Paola

Salvatore  Cuzzocrea

Peroxisome Proliferator-Activated Receptors and Acute Lung Injury

Pulmonary fibrosis is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis (IPF) have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors (PPARs) play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPAR<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPAR<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> agonist significantly inhibited the fibrotic response, while PPAR<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> knockout mice developed more serious fibrosis. PPAR<mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>/<mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>δ</mml:mi></mml:math> appears to play a critical role in regulating the transition from inflammation to
wound healing. PPAR<mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>/<mml:math id="E7" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>δ</mml:mi></mml:math> agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPAR<mml:math id="E8" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> agonists. PPAR<mml:math id="E9" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> ligands oppose the profibrotic effect of TGF-<mml:math id="E10" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. 
PPAR<mml:math id="E11" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPAR<mml:math id="E12" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> and PPAR<mml:math id="E13" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.

Heather F. Lakatos

Thomas H. Thatcher

R. Matthew Kottmann

Tatiana M. Garcia

Richard P. Phipps

Patricia J. Sime

The Role of PPARs in Lung Fibrosis

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily that regulate diverse physiological processes ranging from lipogenesis to inflammation. Recent evidence has established potential roles of PPARs in both systemic and pulmonary vascular disease and function. Existing treatment strategies for pulmonary hypertension, the most common manifestation of pulmonary vascular disease, are limited by an incomplete understanding of the underlying disease pathogenesis and lack of efficacy indicating an urgent need for new approaches to treat this disorder. Derangements in pulmonary endothelial-derived mediators and endothelial dysfunction have been shown to play a pivotal role in pulmonary hypertension pathogenesis. Therefore, the following review will focus on selected mediators implicated in pulmonary vascular dysfunction and evidence that PPARs, in particular PPAR<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>, participate in their regulation and may provide a potential novel therapeutic target for the treatment of pulmonary hypertension.

Rachel E. Nisbet

Roy L. Sutliff

C. Michael Hart

The Role of Peroxisome Proliferator-Activated Receptors in Pulmonary Vascular Disease

Understanding lung development has significant importance to public health because of the fact that interruptions in the normal developmental processes can have prominent effects on childhood and adult lung health. It is widely appreciated that the retinoic acid (RA) pathway plays an important role in lung development. Additionally, PPARs are believed to partner with receptors of this pathway and therefore could be considered extensions of retinoic acid function, including during lung development. This review will begin by introducing the relationship between the retinoic acid pathway and PPARs followed by an overview of lung development stages and regulation to conclude with details on PPARs and the retinoic acid pathway as they may relate to lung development.

Dawn M. Simon

Thomas J. Mariani

Role of PPARs and Retinoid X Receptors in the Regulation of Lung Maturation and Development

PPAR<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> ligands inhibit the proliferation of non-small cell lung carcinoma (NSCLC) cells in vitro. The mechanisms responsible for this effect remain incompletely elucidated, but PPAR<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> ligands appear to inhibit the mammalian target of rapamycin (mTOR) pathway. We set out to test the hypothesis that PPAR<mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> ligands activate tuberous sclerosis complex-2 (TSC2), a tumor suppressor gene that inhibits mTOR signaling. We found that the PPAR<mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> ligand rosiglitazone stimulated the phosphorylation of TSC2 at serine-1254, but not threonine-1462. However, an antagonist of PPAR<mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> and PPAR<mml:math id="E7" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> siRNA did not inhibit these effects. Rosiglitazone also increased the phosphorylation of p38 MAPK, but inhibitors of p38 MAPK and its downstream signal MK2 had no effect on rosiglitazone-induced activation of TSC2. Activation of TSC2 resulted in downregulation of phosphorylated p70S6K, a downstream target of mTOR. A TSC2 siRNA induced p70S6K phosphorylation at baseline and inhibited p70S6K downregulation by rosiglitazone. When compared to a control siRNA in a thymidine incorporation assay, the TSC2 siRNA reduced the growth inhibitory effect of rosiglitazone by fifty percent. These observations suggest that rosiglitazone inhibits NSCLC growth partially through phosphorylation of TSC2 via PPAR<mml:math id="E8" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>-independent pathways.

Ying Zheng

Rosiglitazone, an Agonist of  PPAR<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5
t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z"/></g></svg>, Inhibits Non-Small Cell Carcinoma Cell Proliferation In Part through Activation of Tumor Sclerosis Complex-2

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<p><em>PPAR Research</em> publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.</p>


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<p>Chief Editor, Dr Xiao-Jie Lu, is dedicated to basic and translational research on liver diseases. His research at Nanjing Medical University, China, focuses&nbsp;on exploring these diseases' underlying mechanisms that may be translatable to novel diagnostic biomarkers or therapeutic targets.</p>


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PPAR Research publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.

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PPAR Research | Hindawi

PPAR Research

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<p>Papers are published upon acceptance, regardless of the Special Issue publication date.</p>


PPAR Research

PPARs in Lung Biology and Disease

PPARs in Lung Biology and Disease

Articles

Peroxisome Proliferator-Activated Receptors in Lung Cancer

PPARs in Lung Biology and Disease

Stimulatory Effects of Peroxisome Proliferator-Activated Receptor- on Fc Receptor-Mediated Phagocytosis by Alveolar Macrophages

PPARs in Alveolar Macrophage Biology

Peroxisome Proliferator Activated Receptor Ligands as Regulators of Airway Inflammation and Remodelling in Chronic Lung Disease

Peroxisome Proliferator-Activated Receptors and Acute Lung Injury

The Role of PPARs in Lung Fibrosis

The Role of Peroxisome Proliferator-Activated Receptors in Pulmonary Vascular Disease

Role of PPARs and Retinoid X Receptors in the Regulation of Lung Maturation and Development

Rosiglitazone, an Agonist of PPAR, Inhibits Non-Small Cell Carcinoma Cell Proliferation In Part through Activation of Tumor Sclerosis Complex-2