Involvement of PPAR nuclear receptors in tissue injury and wound repair

Abstract

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. ...

The Synthetic Peroxisome Proliferator-Activated Receptor-γ Agonist Ciglitazone Attenuates Neuroinflammation and Accelerates Encapsulation in Bacterial Brain Abscesses

“…In addition, in terms of disease chronicity, brain abscesses typically last for weeks before treatment and resolution, which is quite distinct from the chronic disorders that PPAR-␥ agonists have been reported to inhibit fibrosis (i.e., scleroderma, idiopathic pulmonary fibrosis, hepatic cirrhosis, and others) (55), which present themselves over months or years. Finally, another important concept to consider is that fibrotic responses typically ensue when inflammation is reduced (55). This relationship is in agreement with our findings, in that through its ability to attenuate proinflammatory mediator expression and bacterial burdens, ciglitazone enhances brain abscess encapsulation and fibrosis.…”

“…This finding was revealed by enhanced fibronectin deposition and the earlier appearance of myofibroblasts expressing ␣-smooth muscle actin. This finding is at direct odds with other literature demonstrating that PPAR-␥ agonists attenuate myofibroblast differentiation or fibrosis in models of pathological fibrosis such as scleroderma or pulmonary/hepatic fibrosis (52)(53)(54)(55)(56). However, it is important to acknowledge a fundamental difference between these models of excessive fibrosis vs brain abscess in which a highly regulated fibrotic wall forms in a region-specific manner.…”

Pioglitazone promotes survival and prevents hepatic regeneration failure after partial hepatectomy in obese and diabetic KK-Ay mice

“…33 Because TZDs, synthetic PPAR-␥ ligands, not only improve insulin resistance but also inhibit activation of Kupffer cells 21,22 and transactivation of hepatic stellate cells, [34][35][36] these chemicals are believed to be suitable for prevention/treatment of hepatic inflammation and fibrogenesis in NASH. Indeed, a placebo-controlled randomized study has demonstrated the therapeutic efficacy of pioglitazone on NASH in terms of both metabolic and histological improvement.…”

From the metabolic syndrome to NAFLD or vice versa?

“…A second mechanism, transrepression, may explain the antiinflammatory actions of PPARs. It involves interfering with other transcription-factor pathways in a DNA-independent way [112]. Various fatty acids serve as endogenous ligands for PPARs, and three PPARs, designated PPARα, PPARγ, and PPARδ have been identified to date with different effects in terms of gene expression, as summarized in Fig.…”