The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma

Abstract

Aim: Rosiglitazone is one of the specific PPARγ agonists showing potential therapeutic effects in asthma. Though PPARγ activation was considered protective in inhibiting airway inflammation and remodeling in asthma, the specific mechanisms are still unclear. This study was aimed to investigate whether heme oxygenase-1 (HO-1) related pathways were involved in rosiglitazone-activated PPARγ signaling in asthma treatment. Methods: Asthma was induced in mice by multiple exposures to ovalbumin (OVA) in 8 weeks. Prior to every OVA challenge, the mice received rosiglitazone (5 mg/kg, po). After the mice were sacrificed, the bronchoalveolar lavage fluid (BALF), blood samples and lungs were collected for analyses. The activities of HO-1, MMP-2 and MMP-9 in airway tissue were assessed, and the expression of PPARγ, HO-1 and p21 proteins was also examined. Results: Rosiglitazone administration significantly attenuated airway inflammation and remodeling in mice with OVA-induced asthma, which were evidenced by decreased counts of total cells, eosinophils and neutrophils, and decreased levels of IL-5 and IL-13 in BALF, and by decreased airway smooth muscle layer thickness and reduced airway collagen deposition. Furthermore, rosiglitazone administration significantly increased PPARγ, HO-1 and p21 expression and HO-1 activity, decreased MMP-2 and MMP-9 activities in airway tissue. All the therapeutic effects of rosiglitazone were significantly impaired by co-administration of the HO-1 inhibitor ZnPP. Conclusion: Rosiglitazone effectively attenuates airway inflammation and remodeling in OVA-induced asthma of mice by activating PPARγ/HO-1 signaling pathway.

Haem oxygenase‐1 up‐regulation by rosiglitazone via ROS‐dependent Nrf2‐antioxidant response elements axis or PPARγ attenuates LPS‐mediated lung inflammation

“…HO‐1 has been shown to protect against the inflammatory responses induced by various insults including LPS (Liu et al ., ; Xu et al ., ). Therefore, we confirmed these results in an in vivo study.…”

“…On the other hand, PPARγ activation by rosiglitazone significantly increases HO‐1 expression and attenuates airway inflammation and remodelling (Xu et al ., ). In this study, blockade of PPARγ by its antagonist (GW9662) or siRNA, diminished rosiglitazone‐mediated PPARγ phosphorylation and promoter activity in HPAEpiCs, suggesting the dependence of PPARγ on HO‐1 expression.…”

Diabetes and Lung Disease: An Underestimated Relationship

“…Reduced airway inflammation and mucus production [123,124]. Beneficial effect on lung fibrosis in IPF and in bleomycin-induced lung injury [127,128].…”

Activation of peroxisome proliferation–activated receptor‐γ inhibits transforming growth factor‐β1‐induced airway smooth muscle cell proliferation by suppressing Smad–miR‐21 signaling

“…It has been confirmed to play important roles in regulating substrate metabolism, inflammatory responses, cell proliferation, and apoptosis (Balupillai et al, ; Han et al, ; Ivanova, Myasoedova, Melnichenko, & Orekhov, ). Furthermore, activation of PPAR‐γ has been shown to attenuate airway remodeling in a murine model of asthma (J. Xu et al, ) and inhibit the proliferation of human ASMCs in vitro (Ward, Gould, Harris, Bonacci, & Stewart, ), suggesting that PPAR‐γ might be a potential target for the treatment of airway remodeling in asthma. A study by Green, Murphy, Kang, Searles, and Hart () has also demonstrated that activation of PPAR‐γ attenuates hypoxia‐induced proliferation of human pulmonary artery smooth muscle cells (PASMCs) through the downregulation of miR‐21.…”