Suppression of intestinal ischemia-reperfusion injury by a specific peroxisome proliferator-activated receptor-γ ligand, pioglitazone, in rats

Naito, Yuji; Takagi, Tomohisa; Uchiyama, Kazuhiko; Handa, Osamu; Tomatsuri, Naoya; Imamoto, Eiko; Kokura, Satoshi; Ichikawa, Hiroshi; Yoshida, Norimasa; Yoshikawa, Toshikazu

doi:10.1179/135100002125000983

Cited by 63 publications

(33 citation statements)

References 36 publications

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“…In addition, in vivo animal studies suggest that PMN migration to sites of inflammation is impaired after PPAR-␥ ligand administration. 29,30 Inhibition of PMN chemotaxis in our study was similar irrespective of the specific type of ligand used, either troglitazone or 15d-PGJ 2 , and regardless of whether fMLP or IL-8 was used as the chemoattractant. Furthermore, transfection of a constitutively active PPAR-␥ construct into HL-60 cells induced to differentiate into PMN-like cells inhibited chemotaxis by these cells, thus providing compelling evidence of a PPAR-␥-specific effect.…”

Section: Discussionsupporting

confidence: 54%

Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ

Reddy

Narala

Keshamouni

et al. 2008

Blood

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IntroductionHuman peripheral polymorphonucleocytes (PMNs) represent the predominant cellular component at sites of acute inflammation. These cells serve a critical role in host defense with transendothelial migration of PMNs being a crucial component of the immune/ inflammatory response. 1 In addition to their phagocytic activity, PMNs produce mediators such as reactive oxygen intermediates, cytokines/chemokines, and enzymes. 1,2 The directed migration, or chemotaxis, of PMNs occurs in response to a variety of molecules, including formylmethionyl-leucyl-phenylalanine (fMLP), a bacterial peptide, and chemokines such as IL-8, which are released from sites of inflammation or injury. fMLP and IL-8 bind to receptors on PMNs, resulting in both G-protein-dependent and -independent responses. 3 Emerging evidence indicates that sepsis, most commonly caused by bacteria, results in impaired host defenses, including a reduced ability of PMNs to migrate appropriately. [4][5][6] Moreover, higher mortality rates have been observed in patients with sepsis-induced immune deactivation. 7 Mechanistic pathways resulting in altered leukocyte function during sepsis, however, remain incompletely understood.Peroxisome proliferator-activated receptors (PPARs) are ligandactivated transcription factors belonging to the nuclear hormone receptor family. Three PPAR subtypes (␣, ␤, and ␥), each with a specific pattern of expression, have been identified. PPAR-␥ also exists in 2 isoforms, PPAR-␥1 and PPAR-␥2, with the human PPAR-␥2 protein consisting of 28 additional amino acids compared with PPAR-␥1. Ligands for PPAR-␥ include a variety of compounds, both natural and synthetic. Most of the natural ligands are fatty acids or fatty acid derivatives. Synthetic ligands for PPAR-␥ include the antidiabetic thiazolidinediones such as troglitazone.PPAR-␥ is highly expressed in adipose tissue and plays a crucial role in adipocyte differentiation, 8 but it is also expressed in a variety of tissue and cell types, including a majority of those in the hematopoietic system. In cells of the immune system, treatment with PPAR-␥ ligands typically results in the down-regulation of inflammatory responses. 9 For example, activation of PPAR-␥ in macrophages results in inhibition of cytokine, nitric oxide, and hydrogen peroxide production. 10 Freshly isolated human peripheral PMNs were previously shown to express PPAR-␥ mRNA. 11 Treatment of human PMNs with PPAR-␥ ligands results in decreased adhesion-dependent H 2 O 2 production 12 and blocks up-regulation of the CD11b/CD18 adhesion complex. 13 However, no previous study has examined regulation of PPAR-␥ expression in human PMNs or the specific role this transcription factor may play in the migration of these cells. In this study, we assessed the expression and regulation of PPAR-␥ in PMNs and investigated the effect of PPAR-␥ activation on the ability of PMNs to migrate in response to chemoattractants. Furthermore, we investigated the expression of PPAR-␥ in PMNs during the septic response and the effects on che...

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Section: Discussionsupporting

confidence: 54%

Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ

Reddy

Narala

Keshamouni

et al. 2008

Blood

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“…, and pretreatment with a PPARγ agonist before ischemia significantly reduces neutrophil infiltration (32,33). These protective effects are attenuated by PPARγ antagonists or reduction of PPARγ levels in mutant PPARγ heterozygous animals (32,34).…”

Section: Models Of Intestinal I/r Injury Pparγ Activation Downregulamentioning

confidence: 94%

Involvement of PPAR nuclear receptors in tissue injury and wound repair

Michalik

Wahli²

2006

Journal of Clinical Investigation

198

134

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Tissue damage resulting from chemical, mechanical, and biological injury, or from interrupted blood flow and reperfusion, is often life threatening. The subsequent tissue response involves an intricate series of events including inflammation, oxidative stress, immune cell recruitment, and cell survival, proliferation, migration, and differentiation. In addition, fibrotic repair characterized by myofibroblast transdifferentiation and the deposition of ECM proteins is activated. Failure to initiate, maintain, or stop this repair program has dramatic consequences, such as cell death and associated tissue necrosis or carcinogenesis. In this sense, inflammation and oxidative stress, which are beneficial defense processes, can become harmful if they do not resolve in time. This repair program is largely based on rapid and specific changes in gene expression controlled by transcription factors that sense injury. PPARs are such factors and are activated by lipid mediators produced after wounding. Here we highlight advances in our understanding of PPAR action during tissue repair and discuss the potential for these nuclear receptors as therapeutic targets for tissue injury. An overview of tissue injuryThe clinical significance of tissue injury and the need for therapeutic agents to treat organ damage have called for an improved understanding of the causes of tissue injury and subsequent healing. The complex nature of these processes creates a challenge in identifying the specific cell types and biochemical pathways involved. Moreover, tissue protection and regeneration require tight control of cell survival and death, cell growth and differentiation, and ECM remodeling and breakdown. Chemical, biological, and mechanical stress is deleterious to epithelial tissue, and even whole organs are vulnerable to damage. For example, the liver, which metabolizes nutrients and drugs absorbed from the digestive tract, is particularly susceptible to injury, since all blood leaving the intestines and stomach must pass through it before reaching the rest of the body. Organ damage also occurs in response to an inadequate supply of oxygen (hypoxia), usually caused by blood vessel constriction or obstruction (ischemia). Under normal physiological conditions, oxygenation levels and sensitivity to hypoxia differ among the various organs. Since short periods of ischemia and reperfusion (ischemia/reperfusion, or I/R) cause extensive damage, the goal of the survival response is to maintain tissue viability. As a result, the hypoxia response requires optimal revascularization for efficient recovery.Inflammation is a major component of early healing, and its control is essential for efficient repair. The inflammatory cytokines and eicosanoids produced during the first hours after injury recruit neutrophils and macrophages to the wound. These cells amplify the early response through their production of additional inflammatory mediators. Some of these factors promote cell proliferation and migration and are thus directly involved in wound closure. ...

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“…Rosiglitazone is the most potent and selective PPAR-γ agonist [10]and there is a good correlation between the potency of the TZDs as PPAR-γ agonists in vitro and their efficacy in lowering glucose levels in vivo [11]. PPAR-γ agonists have also been shown to protect the intestine [12, 13, 14], lung [15]and heart [16, 17, 18, 19, 20]against I/R injury. Although there is evidence that rosiglitazone can reduce nephropathy in diabetic Zucker fatty rats [21]and that another PPAR-γ agonist, troglitazone, can protect against non-diabetic glomerulosclerosis in rats [22], there are, to our knowledge, no studies which have investigated the effects of PPAR-γ agonists against I/R injury of the kidney.…”

Section: Introductionmentioning

confidence: 99%

Agonists of Peroxisome-Proliferator Activated Receptor-Gamma Reduce Renal Ischemia/Reperfusion Injury

et al. 2003

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Background/Aims: Recent evidence indicates that peroxisome-proliferator activated receptor (PPAR) agonists protect against ischemia/reperfusion (I/R) injury. Here we investigate the effects of the PPAR-γ agonists, rosiglitazone and ciglitazone, on the renal dysfunction and injury caused by I/R of the rat kidney in vivo. Methods: Rosiglitazone or ciglitazone were administered to male Wistar rats prior to and during reperfusion. Biochemical indicators of renal dysfunction and injury were measured and histological scoring of kidney sections was used to assess renal injury. Expression of PPAR isoforms and intercellular adhesion molecule-1 during renal I/R were assessed using RT-PCR and Northern blot, respectively. Myeloperoxidase activity and activation of poly(ADP-ribose) polymerase (PARP) were used as indicators of polymorphonuclear (PMN) cell infiltration and oxidative stress, respectively. Results: Expression of PPAR-α, PPAR-β and PPAR-γ1 (but not PPAR-γ2) was observed in kidneys with down-regulation of PPAR-α expression during renal I/R. Rosiglitazone and ciglitazone significantly reduced biochemical and histological signs of renal dysfunction and injury. Renal expression of ICAM-1 caused by I/R was reduced by rosiglitazone and ciglitazone which was reflected by decreased PMN infiltration into reperfused renal tissues. Both rosiglitazone and ciglitazone reduced PARP activation indicating a reduction of oxidative stress. Conclusion: These results suggest that the PPAR-γ agonists rosiglitazone and ciglitazone reduce the renal dysfunction and injury associated with I/R of the kidney. We propose that one mechanism underlying the protective effects involves inhibition of the expression of ICAM-1, a reduction of PMN infiltration into renal tissues and subsequent reduction of oxidative stress.

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Suppression of intestinal ischemia-reperfusion injury by a specific peroxisome proliferator-activated receptor-γ ligand, pioglitazone, in rats

Cited by 63 publications

References 36 publications

Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ

Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ

Involvement of PPAR nuclear receptors in tissue injury and wound repair

Agonists of Peroxisome-Proliferator Activated Receptor-Gamma Reduce Renal Ischemia/Reperfusion Injury

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