Curcumin augments lung maturation, preventing neonatal lung injury by inhibiting TGF-β signaling

Abstract

Curcumin has potent antioxidant and anti-inflammatory properties, and it modulates signaling of peroxisome proliferator-activated receptor-␥ (PPAR␥), an important molecule in the pathobiology of BPD. However, its role in the prevention of BPD is not known. We determined 1) if curcumin enhances neonatal lung maturation, 2) if curcumin protects against hyperoxia-induced neonatal lung injury, and 3) if this protection is mediated by blocking TGF-␤. Embryonic day 19 fetal rat lung fibroblasts were exposed to 21% or 95% O 2 for 24 h following 1 h of treatment with curcumin. Curcumin dose dependently accelerated e19 fibroblast differentiation [increased parathyroid hormone-related protein (PTHrP) receptor, PPAR␥, and adipocyte differentiation-related protein (ADRP) levels and triolein uptake] and proliferation (increased thymidine incorporation). Pretreatment with curcumin blocked the hyperoxia-induced decrease (PPAR␥ and ADRP) and increase (␣-smooth muscle actin and fibronectin) in markers of lung injury/repair, as well as the activation of TGF-␤ signaling. In a separate set of experiments, neonatal Sprague-Dawley rat pups were exposed to 21% or 95% O 2 for 7 days with or without intraperitoneal administration of curcumin. Analysis for markers of lung injury/repair [PTHrP receptor, PPAR␥, ADRP, fibronectin, TGF-␤ receptor (activin receptor-like kinase 5), and Smad3] and lung morphology (radial alveolar count) demonstrated that curcumin effectively blocks TGF-␤ activation and hyperoxia-induced lung injury. Therefore, curcumin accelerates lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and prevents hyperoxiainduced neonatal lung injury, possibly by blocking TGF-␤ activation, suggesting that it is a potential intervention against BPD. bronchopulmonary dysplasia; hyperoxia; transforming growth factor-␤ APPROXIMATELY 30% of premature infants with birth weights Ͻ1,000 g develop bronchopulmonary dysplasia (BPD) (15). The "new" BPD is characterized by abnormal lung cytoarchitecture, characterized by deranged alveolarization, with minimal large and small airway changes, and relatively mild inflammation and fibrosis (9). Infants with BPD are at significant risk of increased morbidity and mortality. They are unable to oxygenate efficiently and often require O 2 supplementation well into childhood. Although the pathogenesis of BPD is not completely understood, hyperoxia, inflammation, and/or ventilator exposure of the premature lung are the principal causative factors (33). More importantly, there is no effective intervention to prevent or treat BPD (3).Mesenchymal interstitial fibroblasts play an important role in lung development and injury/repair (16,34,36,38). During lung development and injury/repair, alveolar interstitial fibroblasts (AIFs) differentiate into lipid-laden AIFs (lipofibroblasts), which promote alveolar epithelial cell proliferation and differentiation (36). However, if AIFs lose their lipogenic phenotype and transdifferentiate to a myogenic phenotype, i.e., myofibroblasts, the...

Activin A contributes to the development of hyperoxia-induced lung injury in neonatal mice

“…These findings correlated strongly to the reduction of Smad 3 phosphorylation in a manner similar to that reported in curcumin inhibition of TGFβ activity (5). The common signaling intermediates used by TGFβ and activin during hyperoxic lung injury suggest that activin may contribute to lung development and BPD-related pathology.…”

“…Specifically, TGFβ1 treatment of hyperoxia damaged AEC2 improved cell survival, migration, and secretion of proangiogenic ligands such as vascular endothelial growth factor (VEGF) and matrix proteins such as fibronectin. However, inhibition of TGFβ signaling by curcumin and PPARγ agonist, rosiglitazone, were protective against hyperoxia-induced lung injury in neonatal rat models of BPD (5,6). These reports point to the need for better understanding of TGFβ signaling within the context of BPD.…”

Animal models of bronchopulmonary dysplasia. The term rat models

“…Also, PTX treatment increased both gene and protein expression of VEGF and improved pulmonary vascularization, but it did not show beneficial effects in terms of improving alveolarization or attenuating pulmonary fibrosis (3). Administration of curcumin, a potent anti-inflammatory and antioxidant agent, in the rat model of BPD has been shown to inhibit oxidative stress and also effectively blocked activation of TGF-␤ and subsequent hyperoxia-induced lung injury (47,48). More recently the effects of resveratrol, which exhibit anti-inflammatory and antioxidant activities, has been assessed in the rat BPD model (43).…”

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…Certainly, therapeutic agents such as corticosteroids and even ␤ 2 -agonists can reduce proliferation (19,86). Furthermore, peroxisome proliferatoractivated receptor (PPAR)-␥ ligands can blunt ASM proliferation, migration, and ECM formation (63,72,73,250,293), and this mechanism may be of interest, given its emerging role in lung development and injury (180,220,247,260). Finally, there is increasing interest in atypical anti-inflammatory stimuli such as vitamin D (44,50).…”