Emerging PPAR γ

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 effects. PPARγ 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 PPARγ is pharmaceutically antagonized or genetically PPARγ and are thus independent of classical PPARγ-dependent transcriptional control. Many PPARγ ligands demonstrate direct binding to transcription factors and other proteins, altering their function and contributing to PPARγ-independent inhibition of disease phenotypes. These PPARγ-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

The Effects of Specialized Proresolving Lipid Mediators on B Lymphocyte Function:Implications for B Cell Differentiation and Antibody Production

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology and Immunology, 2013.Inflammation is a natural process classically characterized by heat, redness, swelling and pain. Chronic or uncontrolled inflammation can lead to loss of tissue function and disease. A relatively new concept is that the resolution of inflammation is an active process regulated by anti-inflammatory, as well as proresolution signals. The ligandactivated transcription factor peroxisome proliferator-activated receptor gamma (PPARγ), has important anti-inflammatory functions, such as dampening the production of proinflammatory cytokines. Furthermore, a newly discovered series of lipid mediators called specialized proresolving mediators (SPMs), actively promote the resolution of inflammation. SPMs have multifaceted roles such as reduction of neutrophil infiltration and blunting pro-inflammatory cytokine production. Antibodies can neutralize and help remove inflammatory stimuli such as pathogens, thereby promoting the resolution of inflammation. The effects of PPARγ and SPMs on antibody production remain a major knowledge gap of high interest. Therefore, this thesis examined the link between inflammation resolution and antibody production. To this end, the physiological role of PPARγ on B cell function was first analyzed. Using a B cell-specific PPARγ knockout mouse model, we have shown under physiological conditions that B cell PPARγ expression is required for optimal antibody production. We next addressed a major knowledge gap in inflammation resolution, namely, whether or not SPMs influence B cell antibody production. Interestingly, an ω-3 fatty acid-derived SPM called 17-hydroxydosahexaenoic acid (17-HDHA), enhanced plasma cell differentiation and increased human B cell antibody production in vitro. Furthermore, 17-HDHA increased plasma cell differentiation and antigen-specific antibody production in a pre-clinical influenza immunization mouse model. These new results highlight the effects of SPMs on the adaptive immune system and antibody production. Overall, these results support the concept that anti-inflammatory and proresolving signals are important for enhancing an antibody-mediated immune response. With the B cell-specific PPARγ-deficient mouse model at hand as a powerful tool and the discovery of novel immuno-stimulatory SPMs, there is great potential for developing new therapeutics. These therapeutics could be potentially used to enhance the efficacy of vaccines and could possibly be used in the treatment of inflammatory diseases

Synthesis and Anti-inflammatory and Pro-resolving Activities of 22-OH-PD1, a Monohydroxylated Metabolite of Protectin D1

Protectin D1 (PD1 (<b>3</b>)), a C22-dihydroxylated polyunsaturated fatty acid biosynthesized from all-<i>Z</i>-docosahexaenoic acid, belongs to the new family of endogenous mediators referred to as specialized pro-resolving lipid mediators. PD1 (<b>3</b>) is a natural product that displays potent anti-inflammatory properties together with pro-resolving actions including inhibition of polymorphonuclear leukocyte (PMN) infiltration and promotion of macrophage phagocytosis and efferocytosis. Given its potent endogenous actions, this compound has entered several clinical development programs. Little has been reported on the metabolism of PD1 (<b>3</b>). The synthesis and biological evaluations of the ω-22 monohydroxylated metabolite of PD1 (<b>3</b>), named herein 22-OH-PD1 (<b>6</b>), are presented. LC-MS/MS data of the free acid <b>6</b>, obtained from hydrolysis of the synthetic methyl ester <b>7</b>, matched data for the endogenously produced 22-OH-PD1 (<b>6</b>). Compound <b>6</b> exhibited potent pro-resolving actions by inhibiting PMN chemotaxis in vivo and in vitro comparable to its precursor PD1 (<b>3</b>) and decreased pro-inflammatory mediator levels in inflammatory exudates. The results reported herein provide new knowledge of the metabolism of the protectin class of specialized pro-resolving mediators