Up-regulation of Connective Tissue Growth Factor in Hyperoxia-Induced Lung Fibrosis

Chen, Chung-Ming; Wang, Leng Fang; Chou, Hsiu Chu; Lang, Yaw-Dong; Lai, Yi Ping

doi:10.1203/pdr.0b013e3180987202

Cited by 82 publications

(64 citation statements)

References 31 publications

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“…Prolonged exposure of neonatal rats to hyperoxic conditions has been reported to increase lung fibrosis in a manner similar to that observed for human BPD (3,4). Collagen is the major extracellular matrix component of the lungs and is vital for maintaining the normal lung architecture (28).…”

Section: Discussionmentioning

confidence: 71%

“…Lung injury resolves with fibrosis that is prominent in larger infants who developed bronchopulmonary dysplasia (BPD) after prolonged exposure to oxygen and mechanical ventilation (1,2). Prolonged exposure of neonatal mice to hyperoxic conditions resulted in decreased alveolar septation, increased terminal air space size, and increased lung fibrosis that is similar to human BPD (3,4).…”

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confidence: 99%

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Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

Chou

Huang

et al. 2013

Pediatr Res

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Background: Receptors for advanced glycation end products (RAGE) have been implicated in fibrotic processes. We hypothesized that lung fibrosis induced by maternal lipopolysaccharide (LPS)-mediated inflammation and neonatal hyperoxia involves RAGE in newborn rats. Methods: Pregnant Sprague-Dawley rats received intraperitoneal injections of LPS or normal saline (NS) on 20 and 21 d of gestation. The pups were reared in room air (RA) or an O 2 -enrich atmosphere (O 2 ), creating the four study groups, NS + RA, NS + O 2 , LPS + RA, and LPS + O 2 . The O 2 treatment was >95% O 2 for 7 d, followed by 60% O 2 for 14 d. results: Rat pups born to LPS-injected dams exhibited significantly higher lung interferon-γ and interleukin-1β (IL-1β) on postnatal day 7 than the pups born to NS-injected dams. Rat pups reared in hyperoxia expressed higher lung IL-10 on postnatal day 7, compared with the RA-reared pups. The LPS + O 2 group had significantly higher total collagen and transforming growth factor-β1 on postnatal days 7 and 21 than the NS+RA group. RAGE mRNA and sRAGE protein expression were significantly lower in the LPS + O 2 group on postnatal day 7 than the NS+RA group. conclusion: RAGE may be involved in the pathogenesis of lung fibrosis induced by maternal systemic inflammation and postnatal hyperoxia in rat neonates.

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Section: Discussionmentioning

confidence: 71%

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confidence: 99%

Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

Chou

Huang

et al. 2013

Pediatr Res

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“…Previous studies have shown that hyperoxia induces fibrotic gene expression such as that of CTGF (30). Furthermore, anti-CTGF therapy attenuates hyperoxia-induced alveolar damage and vascular remodeling (31).…”

Section: Discussionmentioning

confidence: 99%

Pentoxifylline and prevention of hyperoxia-induced lung injury in neonatal rats

Almario

Peng

et al. 2012

Pediatr Res

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IntroductIon:Oxygen exposure plays an important role in the pathogenesis of bronchopulmonary dysplasia (BPD). The phosphodiesterase inhibitor pentoxifylline (PTX) has antiinflammatory and antifibrotic effects in multiple organs. It was hypothesized that PTX would have a protective effect on hyperoxia-induced lung injury (hILI). Methods: Newborn sprague-Dawley rats were exposed to >95% oxygen (O 2 ) and injected subcutaneously with normal saline (Ns) or PTX (75 mg/kg) twice a day for 9 d. Ns-injected, room air-exposed pups were controls. at days 4 and 9, lung tissue was collected to assess edema, antioxidant enzyme (aOe) activities, and vascular endothelial growth factor (VeGF) expression. at day 9, pulmonary macrophage infiltration, vascularization, and alveolarization were also examined. results: at day 9, treatment with PTX significantly increased survival from 54% to 88% during hyperoxia. Treatment with PTX significantly decreased lung edema and macrophage infiltration. PTX treatment increased lung aOe activities including those of superoxide dismutase (sOD), catalase (caT), and glutathione peroxidase (GPX). Furthermore, PTX treatment also increased the gene expression of VeGF189 and VeGF165, increased VeGF protein expression, and improved pulmonary vascularization. dIscussIon: These data indicate that the reduced lung edema and inflammation, increased aOe activities, and improved vascularization may be responsible for the improved survival with PTX during hyperoxia. PTX may be a potential therapy in reducing some of the features of BPD in preterm newborns.

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“…The clinical association of CTGF with BPD is best established by studies demonstrating increased CTGF concentrations in bronchoalveolar lavage fluid from preterm infants developing BPD (5) and increased CTGF expression in lung tissues of infants who died of BPD (6). Multiple studies have examined the potential role of CTGF in experimental BPD and demonstrated that increased CTGF expression is associated with chronic hyperoxia as well as mechanical ventilationinduced lung injury in neonatal rodents (6)(7)(8)(9)(10). Recent studies from our laboratory utilizing genetic gain-of-function and biological loss-of-function approaches have provided compelling evidence that a novel signaling network orchestrated by CTGF plays an important role in BPD pathogenesis (6,11,12).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

et al. 2016

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Background: Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants. Connective tissue growth factor (CTGF) plays an important role in tissue development and remodeling. We have previously shown that targeted overexpression of CTGF in alveolar type II epithelial cells results in BPD-like pathology and activates β-catenin in neonatal mice. Methods: Utilizing this transgenic mouse model and ICG001, a specific pharmacological inhibitor of β-catenin, we tested the hypothesis that β-catenin signaling mediates the effects of CTGF in the neonatal lung. Newborn CTGF mice and control littermates received ICG001 (10 mg/kg/dose) or placebo (dimethyl sulfoxide, equal volume) by daily i.p. injection from postnatal day 5 to 15. Alveolarization, vascular development, and pulmonary hypertension (PH) were analyzed. results: Administration of ICG001 significantly downregulated expression of cyclin D1, collagen 1a1, and fibronectin, which are the known target genes of β-catenin signaling in CTGF lungs. Inhibition of β-catenin signaling improved alveolar and vascular development and decreased pulmonary vascular remodeling. More importantly, the improved vascular development and vascular remodeling led to a decrease in PH. conclusion: β-Catenin signaling mediates the autocrine and paracrine effects of CTGF in the neonatal lung. Inhibition of CTGF-β-catenin signaling may provide a novel therapy for BPD. INTRODUCTIONBronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants (1). Over the past four decades, the incidence of this disease has significantly increased as a result of improved survival of extremely-low-birthweight infants (2). The pathology of BPD is increasingly being recognized as a developmental arrest of the immature lung caused by injurious stimuli such as mechanical ventilation, oxygen exposure, and intrauterine or postnatal infections. Larger and simplified alveoli, decreased vascular growth, and variable interstitial fibrosis are the key pathological features observed in lungs of infants who died of BPD (1). The combination of decreased vascular growth and excessive pulmonary vascular remodeling leads to pulmonary hypertension (PH) which significantly contributes to the morbidity and mortality of these infants (3). Yet, the underlying cellular and molecular mechanisms are poorly defined, and there is no effective therapy.Connective tissue growth factor (CTGF) is a matricellular protein that plays an important role in tissue development and remodeling (4). Recent studies have highlighted the potential role of CTGF in BPD development and progression. The clinical association of CTGF with BPD is best established by studies demonstrating increased CTGF concentrations in bronchoalveolar lavage fluid from preterm infants developing BPD (5) and increased CTGF expression in lung tissues of infants who died of BPD (6). Multiple studies have examined the potential role of CTGF in experimental BPD and demonstrated that increased CTG...

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Up-regulation of Connective Tissue Growth Factor in Hyperoxia-Induced Lung Fibrosis

Cited by 82 publications

References 31 publications

Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

Pentoxifylline and prevention of hyperoxia-induced lung injury in neonatal rats

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

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Up-regulation of Connective Tissue Growth Factor in Hyperoxia-Induced Lung Fibrosis

Cited by 82 publications

References 31 publications

Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

Pentoxifylline and prevention of hyperoxia-induced lung ­injury in neonatal rats

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

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Pentoxifylline and prevention of hyperoxia-induced lung injury in neonatal rats