Harnessing peroxisome proliferator-activated receptor γ agonists to induce Heme Oxygenase-1: a promising approach for pulmonary inflammatory disorders

Abstract

The activation of peroxisome proliferator-activated receptor (PPAR)-γ has been extensively shown to attenuate inflammatory responses in conditions such as asthma, acute lung injury, and acute respiratory distress syndrome, as demonstrated in animal studies. However, the precise molecular mechanisms underlying these inhibitory effects remain largely unknown. The upregulation of heme oxygenase-1 (HO-1) has been shown to confer protective effects, including antioxidant, antiapoptotic, and immunomodulatory effects in vitro and in vivo. PPARγ is highly expressed not only in adipose tissues but also in various other tissues, including the pulmonary system. Thiazolidinediones (TZDs) are highly selective agonists for PPARγ and are used as antihyperglycemic medications. These observations suggest that PPARγ agonists could modulate metabolism and inflammation. Several studies have indicated that PPARγ agonists may serve as potential therapeutic candidates in inflammation-related diseases by upregulating HO-1, which in turn modulates inflammatory responses. In the respiratory system, exposure to external insults triggers the expression of inflammatory molecules, such as cytokines, chemokines, adhesion molecules, matrix metalloproteinases, and reactive oxygen species, leading to the development of pulmonary inflammatory diseases. Previous studies have demonstrated that the upregulation of HO-1 protects tissues and cells from external insults, indicating that the induction of HO-1 by PPARγ agonists could exert protective effects by inhibiting inflammatory signaling pathways and attenuating the development of pulmonary inflammatory diseases. However, the mechanisms underlying TZD-induced HO-1 expression are not well understood. This review aimed to elucidate the molecular mechanisms through which PPARγ agonists induce the expression of HO-1 and explore how they protect against inflammatory and oxidative responses.

Fig. 1

Pathways in pulmonary inflammation and potential therapeutic interventions. During pulmonary inflammation, proinflammatory factors like CSE, ATP, peptides (e.g., bradykinin, BK and endothelin-1, ET-1), cytokines (TNF-α and IL-1β), and endotoxins (e.g., LTA and LPS) increase. These factors induce inflammatory mediators (e.g., MMPs, adhesion molecules, COX-2, or cPLA₂) through various signaling molecules, including mitochondrial or NOX-derived ROS generation, MAPKs activation, transactivation of growth factor receptors, and transcription factors in pulmonary resident cells (alveolar epithelial cells and tracheal smooth muscle cells). These changes lead to pathological alterations in these cells. Furthermore, potential therapeutic drugs such as PPAR agonists might protect against pulmonary inflammation by inducing antioxidant proteins like HO-1. It is hypothesized that these drugs induce HO-1 expression through ROS-dependent signals, directly preventing lung injury and inflammation

Fig. 2

Schematic pathways for rosiglitazone-induced HO-1 expression in HPAEpiCs. Rosiglitazone triggers HO-1 expression in HPAEpiCs through two distinct pathways: PPARγ-dependent and PPARγ-independent mechanisms. PPARγ-dependent pathway: rosiglitazone enhances HO-1 expression by activating a series of events, including PKCα, AMPKα, p38 MAPKα, SIRT1, Ac-PGC1α deacetylation, NCoR fragmentation, and direct binding of activated PPARγ to the HO-1 promoter’s responsive element. PPARγ-independent pathway: in this pathway, rosiglitazone-induced HO-1 expression occurs via NOX/ROS-dependent phosphorylation of c-Src/Pyk2/Akt, leading to Nrf2 activation. Nrf2 then binds to the ARE region of the HO-1 promoter, stimulating HO-1 expression. Upregulation of HO-1 exerts anti-inflammatory effects, particularly on the expression of adhesion molecules like ICAM-1 and VCAM-1, associated with monocyte/leukocyte accumulation in pulmonary resident cells challenged with LPS. These pathways are adapted from prior studies [62, 70] and represent crucial mechanisms in mitigating inflammation in the lungs