FBXL19 Targeted STK11 Degradation Enhances Cigarette Smoke-Induced Airway Epithelial Cell Cytotoxicity.

Objective: To investigate the effects of cigarette smoke (CS) on Serine/Threonine Kinase 11 (STK11) and to determine STK11's role in CS-induced airway epithelial cell cytotoxicity.Methods: STK11 expression levels in the lung tissues of smokers with or without COPD and mice exposed to CS or room air (RA) were determined by immunoblotting and RT-PCR. BEAS-2Bs-human bronchial airway epithelial cells were exposed to CS extract (CSE), and the changes in STK11 expression levels were determined by immunoblotting and RT-PCR. BEAS-2B cells were transfected with STK11-specific siRNA or STK11 expression plasmid, and the effects of CSE on airway epithelial cell cytotoxicity were measured. To determine the specific STK11 degradation-proteolytic pathway, BEAS-2Bs were treated with cycloheximide alone or combined with MG132 or leupeptin. Finally, to identify the F-box protein mediating the STK11 degradation, a screening assay was performed using transfection with a panel of FBXL E3 ligase subunits.Results: STK11 protein levels were significantly decreased in the lung tissues of smokers with COPD relative to smokers without COPD. STK11 protein levels were also significantly decreased in mouse lung tissues exposed to CS compared to RA. Exposure to CSE shortened the STK11 mRNA and protein half-life to 4 h in BEAS-2B cells. STK11 protein overexpression attenuated the CSE-induced cytotoxicity; in contrast, its knockdown augmented CSE-induced cytotoxicity. FBXL19 mediates CSE-induced STK11 protein degradation via the ubiquitin-proteasome pathway in cultured BEAS-2B cells. FBXL19 overexpression led to accelerated STK11 ubiquitination and degradation in a dose-dependent manner.Conclusions: Our results suggest that CSE enhances the degradation of STK11 protein in airway epithelial cells via the FBXL19-mediated ubiquitin-proteasomal pathway, leading to augmented cell death.HIGHLIGHTSLung tissues of COPD-smokers exhibited a decreased STK11 RNA and protein expression.STK11 overexpression attenuates CS-induced airway epithelial cell cytotoxicity.STK11 depletion augments CS-induced airway epithelial cell cytotoxicity.CS diminishes STK11 via FBXL19-mediated ubiquitin-proteasome degradation.

The tea catechin epigallocatechin gallate inhibits NF-κB-mediated transcriptional activation by covalent modification.

Potential health benefits of consuming tea are thought to include anti-inflammatory actions of its constituent flavonoids including catechins, which are well-recognized antioxidants. We analyzed and discovered a novel mechanism by which epigallocatechin gallate (EGCG), the most abundant polyphenol in tea and a putative health-promoting constituent, inhibits activation of the nuclear transcription factor NF-κB, which mediates inflammatory responses to cytokines and other agents. We found that EGCG inhibits NF-κB-p65 transcriptional activity, by preventing NF-κB-p65 binding to κBs in normal human bronchial epithelial cells. We also analyzed the chemical mechanism by which EGCG binds directly to NF-κB-p65, and found that it involves covalent reaction via enones within EGCG ring structures, as the oxidizer diamide, which prevents 1, 4-addition reactions, blocked adduct-forming reaction of biotinylated EGCG with NF-κB-p65. Such blockade was inhibited by competing unlabeled EGCG. Furthermore, such covalent binding reflected irreversible reaction of EGCG with sulfhydryls of NF-κB-p65, as it was inhibited by glutathione but not reversible by it. We identified the reactive sulfhydryl moiety as that of cysteine, as S-carboxymethylation to block cysteine sulfhydryls prevented NF-κB-p65-Cys-alkylation reaction with EGCG. We also tested if EGCG can inhibit NF-κB-p65 binding to DNA within the nucleus, after its phosphorylation and translocation (activation). EGCG did not alter intranuclear phosphorylation levels of NF-κB-p65, but strongly repressed DNA-binding ability of activated NF-κB-p65, indicating that EGCG inhibits NF-κB-p65 DNA binding activity even without altering NF-κB-p65 phosphorylation or expression. These findings thus reveal a novel mechanism by which EGCG inhibits transcriptional activity of NF-κB-p65, that may potentially contribute to anti-inflammatory and health-promoting effects of EGCG and consumption of tea.

Epigallocatechin gallate diminishes cigarette smoke-induced oxidative stress, lipid peroxidation, and inflammation in human bronchial epithelial cells.

Cigarette smoke (CS), the major risk factor of chronic obstructive pulmonary disease (COPD), contains numerous free radicals that can cause oxidative stress and exaggerated inflammatory responses in the respiratory system. Lipid peroxidation which is oxidative degradation of polyunsaturated fatty acids and results in cell damage has also been associated with COPD pathogenesis. Increased levels of lipid peroxidation as well as its end product 4-hydroxynonenal have indeed been detected in COPD patients. Additionally, reactive oxygen species such as those contained in CS can activate nuclear factor-κB signaling pathway, initiating cascades of proinflammatory mediator expression. As emerging evidence attests to the antioxidative and anti-inflammatory properties of tea catechins, we sought to determine whether epigallocatechin gallate, the most abundant tea catechin, can provide protection against oxidative stress, lipid peroxidation, and inflammatory responses caused by CS. We found that EGCG treatment blocked cigarette smoke extract (CSE)-induced oxidative stress as indicated by decreased production and accumulation of reactive oxygen species in airway epithelial cells (AECs). Likewise, lipid peroxidation in CSE-stimulated AECs was suppressed by EGCG. Our findings further suggest that EGCG sequestered 4-hydroxynonenal and interfered with its protein adduct formation. Lastly, we show that EGCG inhibited nuclear factor-κB activation and the downstream expression of proinflammatory mediators. In summary, our study describing the antioxidative and anti-inflammatory effects of EGCG in CSE-exposed AECs provide valuable information about the therapeutic potential of this tea catechin for COPD.

Epigallocatechin gallate suppresses inflammation in human coronary artery endothelial cells by inhibiting NF-κB.

The endothelium is a critical regulator of vascular homeostasis, controlling vascular tone and permeability as well as interactions of leukocytes and platelets with blood vessel walls. Consequently, endothelial dysfunction featuring inflammation and reduced vasodilation are considered central to cardiovascular disease (CVD) pathogenesis and have become a therapeutic area of focus. Type II endothelial cell (EC) activation by stress-related stimuli such as tumor necrosis factor-α (TNF-α) initiates the nuclear factor-κB (NF-κB) signaling pathway, a master regulator of inflammatory responses. Because dysregulated NF-κB signaling has been tightly linked to several CVDs, EC-specific inhibition of NF-κB represents an attractive pharmacological strategy. As accumulating evidence highlights the clinical benefits of tea catechin for multiple diseases including CVDs, we sought to determine whether the tea catechin epigallocatechin gallate (EGCG) that displays antioxidative, anti-inflammatory, hypolipidemic, anti-thrombogenic, and anti-hypertensive properties offers protection against CVDs by suppressing the canonical NF-κB pathway. Our findings indicate that EGCG downregulates multiple components of the TNF-α-induced NF-κB signaling pathway and thereby reduces the consequent increase in inflammatory gene transcription and protein expression. Furthermore, EGCG blocked type II EC activation, evidenced by diminished EC leakage and monocyte adhesion in EGCG-treated cells. In summary, our study advances knowledge of EGCG's anti-inflammatory effects on the NF-κB pathway and hence its benefits on endothelial health, supporting its therapeutic potential for CVDs.

Bidirectional interaction of airway epithelial remodeling and inflammation in asthma.

Asthma is a chronic disease of the airways that has long been viewed predominately as an inflammatory condition. Accordingly, current therapeutic interventions focus primarily on resolving inflammation. However, the mainstay of asthma therapy neither fully improves lung function nor prevents disease exacerbations, suggesting involvement of other factors. An emerging concept now holds that airway remodeling, another major pathological feature of asthma, is as important as inflammation in asthma pathogenesis. Structural changes associated with asthma include disrupted epithelial integrity, subepithelial fibrosis, goblet cell hyperplasia/metaplasia, smooth muscle hypertrophy/hyperplasia, and enhanced vascularity. These alterations are hypothesized to contribute to airway hyperresponsiveness, airway obstruction, airflow limitation, and progressive decline of lung function in asthmatic individuals. Consequently, targeting inflammation alone does not suffice to provide optimal clinical benefits. Here we review asthmatic airway remodeling, focusing on airway epithelium, which is critical to maintaining a healthy respiratory system, and is the primary defense against inhaled irritants. In asthma, airway epithelium is both a mediator and target of inflammation, manifesting remodeling and resulting obstruction among its downstream effects. We also highlight the potential benefits of therapeutically targeting airway structural alterations. Since pathological tissue remodeling is likewise observed in other injury- and inflammation-prone tissues and organs, our discussion may have implications beyond asthma and lung disease.

Glucocorticoid Receptor α Mediates Roflumilast's Ability to Restore Dexamethasone Sensitivity in COPD.

Background: Glucocorticoids are commonly prescribed to treat inflammation of the respiratory system; however, they are mostly ineffective for controlling chronic obstructive pulmonary disease (COPD)-associated inflammation. This study aimed to elucidate the molecular mechanisms responsible for such glucocorticoid inefficacy in COPD, which may be instrumental to providing better patient outcomes. Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor with anti-inflammatory properties in severe COPD patients who have a history of exacerbations. Roflumilast has a suggested ability to mitigate glucocorticoid resistance, but the mechanism is unknown. Methods: To understand the mechanism that mediates roflumilast-induced restoration of glucocorticoid sensitivity in COPD, we tested the role of glucocorticoid receptor α (GRα). Roflumilast's effects on GRα expression and transcriptional activity were assessed in bronchial epithelial cells from COPD patients. Results: We found that both GRα expression and activity are downregulated in bronchial epithelial cells from COPD patients and that roflumilast stimulates both GRα mRNA synthesis and GRα's transcriptional activity in COPD bronchial epithelial cells. We also demonstrate that roflumilast enhances dexamethasone's ability to suppress pro-inflammatory mediator production, in a GRα-dependent manner. Discussion: Our findings highlight the significance of roflumilast-induced GRα upregulation for COPD therapeutic strategies by revealing that roflumilast restores glucocorticoid sensitivity by sustaining GRα expression.

Cigarette smoke downregulates Nur77 to exacerbate inflammation in chronic obstructive pulmonary disease (COPD).

Cigarette smoke (CS) contains multiple gaseous and particulate materials that can cause lung inflammation, and smoking is the major cause of chronic obstructive pulmonary disease (COPD). We sought to determine the mechanisms of how CS triggers lung inflammation. Nur77, a nuclear hormone receptor belonging to the immediate-early response gene family, controls inflammatory responses, mainly by suppressing the NF-κB signaling pathway. Because it is unknown if Nur77's anti-inflammatory role modulates COPD, we assessed if and how Nur77 expression and activity are altered in CS-induced airway inflammation. In lung tissues and bronchial epithelial cells from COPD patients, we found Nur77 was downregulated. In a murine model of CS-induced airway inflammation, CS promoted lung inflammation and also reduced Nur77 activity in wild type (WT) mice, whereas lungs of Nur77-deficient mice showed exaggerated CS-induced inflammatory responses. Our findings in in vitro studies of human airway epithelial cells complemented those in vivo data in mice, together showing that CS induced threonine-phosphorylation of Nur77, which is known to interfere with its anti-inflammatory functions. In summary, our findings point to Nur77 as an important regulator of CS-induced inflammatory responses and support the potential benefits of Nur77 activation for COPD treatment.

Molecular, chemical, and structural characterization of prostaglandin A2 as a novel agonist for Nur77.

Nur77 is a transcription factor belonging to the NR4A subfamily of nuclear hormone receptors. Upon induction, Nur77 modulates the expression of its target genes and controls a variety of biological and pathophysiological processes. Prior research that revealed a structurally atypical ligand-binding domain (LBD) and failed to locate an endogenous ligand had led to a classification of Nur77 as an orphan receptor. However, several more recent studies indicate that small synthetic molecules and unsaturated fatty acids can bind to Nur77. Discovery of additional endogenous ligands will facilitate our understanding of the receptor's functions and regulatory mechanisms. Our data have identified prostaglandin A2 (PGA2), a cyclopentenone prostaglandin (PG), as such a ligand. Cyclopentenone PGs exert their biological effects primarily by forming protein adducts via the characteristic electrophilic ß-carbon(s) located in their cyclopentenone rings. Our data show that PGA2 induces Nur77 transcriptional activity by forming a covalent adduct between its endocyclic ß-carbon, C9, and Cys566 in the receptor's LBD. The importance of this endocyclic ß-carbon was substantiated by the failure of PGs without such electrophilic properties to react with Nur77. Calculated chemical properties and data from reactive molecular dynamic simulations, intrinsic reaction co-ordinate modeling, and covalent molecular docking also corroborate the selectivity of PGA2's C9 ß-carbon towards Nur77's Cys. In summary, our molecular, chemical, and structural characterization of the PGA2-Nur77 interaction provides the first evidence that PGA2 is an endogenous Nur77 agonist.

Key Functions and Therapeutic Prospects of Nur77 in Inflammation Related Lung Diseases

The transcription factor Nur77 belongs to the NR4A subfamily of nuclear hormone receptors. It features an atypical ligand-binding site that precludes canonical ligand binding, leading to the designation orphan nuclear receptor. However, recent studies show that small molecules can interact with the receptor and modulate its activity by inducing a conformational change in the Nur77 ligand-binding site. Nur77 expression and activation are rapidly induced by various physiological and pathologic stimuli. Once expressed, Nur77 initiates transcriptional activity and modulates expression of its target genes. Both in vitro and in vivo evidence shows that Nur77 dampens the immune response to proinflammatory stimuli, such as tumor necrosis factor-α, Toll-like receptor ligands, and oxidized lipids, primarily by suppressing NF-κB signaling. Although studies focusing on Nur77's role in lung pathophysiology are currently incomplete, available data support its involvement in the pathogenesis of lung diseases, including asthma, acute lung injury, and pulmonary fibrosis, and thus suggest a therapeutic potential for Nur77 activation in these diseases. This review addresses the mechanisms that control Nur77 as well as its known roles in inflammation-related lung diseases. Evidence regarding the therapeutic potential of Nur77-targeting molecules will also be presented. Although current knowledge is limited, additional research followed by clinical studies may firmly identify Nur77 as a pharmacologic target for inflammation-related lung diseases.

Identification and Molecular Characterization of Peroxisome Proliferator-Activated Receptor δ as a Novel Target for Covalent Modification by 15-Deoxy-Δ12,14-prostaglandin J2.

PPARδ belongs to the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors. Upon activation by an agonist, PPARδ controls a variety of physiological processes via regulation of its target genes. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a cyclopentenone prostaglandin that features an electrophilic, α,ß-unsaturated ketone (an enone) in the cyclopentenone ring. Many of 15d-PGJ2's biological effects result from covalent interaction between C9 and the thiol group of a catalytic cysteine (Cys) in target proteins. In this study, we investigated whether 15d-PGJ2 activates PPARδ by forming a covalent adduct. Our data show that 15d-PGJ2 activates PPARδ's transcriptional activity through formation of a covalent adduct between its endocyclic enone at C9 and Cys249 in the receptor's ligand-binding domain. As expected, no adduct formation was seen following a Cys-to-Ser mutation at residue 249 (C249S) of PPARδ or with a PGD2/PGJ2 analogue that lacks the electrophilic C9. Furthermore, the PPARδ C249S mutation weakened induction of the receptor's DNA binding activity by 15d-PGJ2, which highlights the biological significance of our findings. Calculated chemical properties as well as data from molecular orbital calculations, reactive molecular dynamics simulations, and intrinsic reaction coordinate modeling also supported the selectivity of 15d-PGJ2's C9 toward PPARδ's Cys thiol. In summary, our results provide the molecular, chemical, and structural basis of 15d-PGJ2-mediated PPARδ activation, designating 15d-PGJ2 as the first covalent PPARδ ligand to be identified.

Airway Epithelial Cell Peroxisome Proliferator-Activated Receptor γ Regulates Inflammation and Mucin Expression in Allergic Airway Disease.

Airway epithelial cells (AECs) orchestrate inflammatory responses to airborne irritants that enter the respiratory system. A viscous mucus layer produced by goblet cells in the airway epithelium also contributes to a physiological defense mechanism through the physical and chemical barriers it provides. Dysregulation or impairment in these functions has been implicated as a cause of the chronic inflammation and tissue remodeling that constitute major pathological features of asthma. In particular, mucus hypersecretion leading to airway obstruction and impaired pulmonary function is associated with morbidity and mortality in asthma patients. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor involved in a variety of cellular processes. Accumulating evidence indicates that PPARγ agonists antagonize exaggerated inflammatory responses, yet PPARγ's precise role in airway remodeling/mucus hypersecretion has yet to be defined. In this study, we created an AEC-specific PPARγ (AEC-PPARγ) deletion to investigate PPARγ's functions in a murine model of allergic airway disease. AEC-PPARγ deficiency exaggerated airway hyperresponsiveness, inflammation, cytokine expression, and tissue remodeling. We also found that PPARγ directly bound to a PPAR response element found in MUC5AC and repressed gene expression. Likewise, PPARγ regulated mucin and inflammatory factors in primary human bronchial epithelial cells. In light of the current standard therapies' limited and inadequate direct effect on airway mucus hypersecretion, our study showing AEC-PPARγ's role as a transcriptional repressor of MUC5AC highlights this receptor's potential as a pharmacological target for asthma.

Role of GPx3 in PPARγ-induced protection against COPD-associated oxidative stress.

Cigarette smoke, a source of numerous oxidants, produces oxidative stress and exaggerated inflammatory responses that lead to irreversible lung tissue damage. It is the single, most significant risk factor for chronic obstructive pulmonary disease (COPD). Although an intrinsic defense system that includes both enzymatic and non-enzymatic modulators exists to protect lung tissues against oxidative stress, impairment of these protective mechanisms has been demonstrated in smokers and COPD patients. The antioxidant enzyme GSH peroxidase (GPx) is an important part of this intrinsic defense system. Although cigarette smoke has been shown to downregulate its expression and activity, the underlying mechanism is not known. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear hormone receptor with antioxidant effects. PPARγ activation has demonstrated protective effects against cigarette smoke-induced oxidative stress and inflammation. Molecular mechanisms for PPARγ's antioxidant function likewise remain to be elucidated. This study explored the link between PPARγ and GPx3 and found a positive association in cigarette smoke extract (CSE)-exposed human bronchial epithelial cells. Moreover, we provide evidence that identifies GPx3 as a PPARγ transcriptional target. Attenuation of antioxidant effects in the absence of GPx3 highlights the antioxidant's prominent role in mediating PPARγ's function. We also demonstrate that ligand-mediated PPARγ activation blocks CSE-induced reactive oxygen species and hydrogen peroxide production via upregulation of GPx3. In summary, our findings describing the molecular mechanisms involving GPx3 and PPARγ in CSE-induced oxidative stress and inflammation may provide valuable information for the development of more effective therapeutics for COPD.

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

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, PPARß/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.

Emerging pharmaceutical therapies for COPD.

COPD, for which cigarette smoking is the major risk factor, remains a worldwide burden. Current therapies provide only limited short-term benefit and fail to halt progression. A variety of potential therapeutic targets are currently being investigated, including COPD-related proinflammatory mediators and signaling pathways. Other investigational compounds target specific aspects or complications of COPD such as mucus hypersecretion and pulmonary hypertension. Although many candidate therapies have shown no significant effects, other emerging therapies have improved lung function, pulmonary hypertension, glucocorticoid sensitivity, and/or the frequency of exacerbations. Among these are compounds that inhibit the CXCR2 receptor, mitogen-activated protein kinase/Src kinase, myristoylated alanine-rich C kinase substrate, selectins, and the endothelin receptor. Activation of certain transcription factors may also be relevant, as a large retrospective cohort study of COPD patients with diabetes found that the peroxisome proliferator-activated receptor γ (PPARγ) agonists rosiglitazone and pioglitazone were associated with reduced COPD exacerbation rate. Notably, several therapies have shown efficacy only in identifiable subgroups of COPD patients, suggesting that subgroup identification may become more important in future treatment strategies. This review summarizes the status of emerging therapeutic pharmaceuticals for COPD and highlights those that appear most promising.

PPAR Agonists for the Prevention and Treatment of Lung Cancer.

Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies. Recently, a family of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs), has attracted significant attention for its role in various malignancies including lung cancer. Three PPARs, PPARα, PPARß/δ, and PPARγ, display distinct biological activities and varied influences on lung cancer biology. PPARα activation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPARγ is also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPARα and PPARγ, whether PPARß/δ activation is anti- or protumorigenic or even inconsequential currently remains an open question that requires additional investigation. This review of current literature emphasizes the multifaceted effects of PPAR agonists in lung cancer and discusses how they may be applied as novel therapeutic strategies for the disease.

Transforming growth factor ß suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-ß inhibitory elements.

Transforming growth factor ß (TGF-ß) contributes to wound healing and, when dysregulated, to pathological fibrosis. TGF-ß and the anti-fibrotic nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) repress each other's expression, and such PPARγ down-regulation is prominent in fibrosis and mediated, via previously unknown SMAD-signaling mechanisms. Here, we show that TGF-ß induces the association of SMAD3 with both SMAD4, needed for translocation of the complex into the nucleus, and the essential context-sensitive co-repressors E2F4 and p107. The complex mediates TGF-ß-induced repression by binding to regulatory elements in the target promoter. In the PPARG promoter, we found that the SMAD3-SMAD4 complex binds both to a previously unknown consensus TGF-ß inhibitory element (TIE) and also to canonical SMAD-binding elements (SBEs). Furthermore, the TIE and SBEs independently mediated the partial repression of PPARG transcription, the first demonstration of a TIE and SBEs functioning within the same promoter. Also, TGF-ß-treated fibroblasts contained SMAD complexes that activated a SMAD target gene in addition to those repressing PPARG transcription, the first finding of such dual activity within the same cell. These findings describe in detail novel mechanisms by which TGF-ß represses PPARG transcription, thereby facilitating its own pro-fibrotic activity.

PPARγ as a Novel Therapeutic Target in Lung Cancer.

Lung cancer is the leading cause of cancer-related death, with more than half the patients having advanced-stage disease at the time of initial diagnosis and thus facing a poor prognosis. This dire situation poses a need for new approaches in prevention and treatment. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. Its involvement in adipocyte differentiation and glucose and lipid homeostasis is well-recognized, but accumulating evidence now suggests that PPARγ may also function as a tumor suppressor, inhibiting development of primary tumors and metastases in lung cancer and other malignancies. Besides having prodifferentiation, antiproliferative, and proapoptotic effects, PPARγ agonists have been shown to prevent cancer cells from acquiring the migratory and invasive capabilities essential for successful metastasis. Angiogenesis and secretion of certain matrix metalloproteinases and extracellular matrix proteins within the tumor microenvironment are also regulated by PPARγ. This review of the current literature highlights the potential of PPARγ agonists as novel therapeutic modalities in lung cancer, either as monotherapy or in combination with standard cytotoxic chemotherapy.

PPARγ in Bacterial Infections: A Friend or Foe?

Peroxisome proliferator-activated receptor γ (PPARγ) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPARγ activation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPARγ agonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPARγ and its activation during bacterial infections, with focus on the potential of PPARγ agonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPARγ agonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system.

Nitrated Fatty Acids Reverse Cigarette Smoke-Induced Alveolar Macrophage Activation and Inhibit Protease Activity via Electrophilic S-Alkylation.

Nitrated fatty acids (NFAs), endogenous products of nonenzymatic reactions of NO-derived reactive nitrogen species with unsaturated fatty acids, exhibit substantial anti-inflammatory activities. They are both reversible electrophiles and peroxisome proliferator-activated receptor γ (PPARγ) agonists, but the physiological implications of their electrophilic activity are poorly understood. We tested their effects on inflammatory and emphysema-related biomarkers in alveolar macrophages (AMs) of smoke-exposed mice. NFA (10-nitro-oleic acid or 12-nitrolinoleic acid) treatment downregulated expression and activity of the inflammatory transcription factor NF-κB while upregulating those of PPARγ. It also downregulated production of inflammatory cytokines and chemokines and of the protease cathepsin S (Cat S), a key mediator of emphysematous septal destruction. Cat S downregulation was accompanied by decreased AM elastolytic activity, a major mechanism of septal destruction. NFAs downregulated both Cat S expression and activity in AMs of wild-type mice, but only inhibited its activity in AMs of PPARγ knockout mice, pointing to a PPARγ-independent mechanism of enzyme inhibition. We hypothesized that this mechanism was electrophilic S-alkylation of target Cat S cysteines, and found that NFAs bind directly to Cat S following treatment of intact AMs and, as suggested by in silico modeling and calculation of relevant parameters, elicit S-alkylation of Cys25 when incubated with purified Cat S. These results demonstrate that NFAs' electrophilic activity, in addition to their role as PPARγ agonists, underlies their protective effects in chronic obstructive pulmonary disease (COPD) and support their therapeutic potential in this disease.