Activation of the Renin-Angiotensin System in Hyperoxia-Induced Lung Fibrosis in Neonatal Rats

Jiang, Jiunn Song; Lang, Yaw-Dong; Chou, Hsin Hua; Shih, Chwen‐Ming; Wu, Meng Ying; Chen, Chung-Ming; Wang, Leng-Fang

doi:10.1159/000329451

Cited by 23 publications

(17 citation statements)

References 37 publications

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“…Because the activation of RAS has been reported to induce lung fibrosis both in transgenic animals and in disease models 14, 25, 26 , it was reasonable to hypothesize that the lung fibrosis observed in vitamin D deficient mice is associated with the increased expression of RAS components. To clarify this, we administered RAS antagonists to the vitamin D deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system

Shi

Liu

Yao

et al. 2017

Sci Rep

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Pulmonary fibrosis, which influences lung function and exacerbates a patient’s condition, is the ultimate stage of many lung diseases. Vitamin D deficiency is associated with pulmonary fibrosis and impaired lung function, but the underlying mechanism has not yet been fully elucidated. Moreover, vitamin D deficiency may cause over-activation of the renin-angiotensin system (RAS), which aggravates extracellular matrix (ECM) deposition and lung fibrosis. This study aims to investigate the effect of chronic vitamin D deficiency on lung fibrosis in otherwise healthy mice and to explore the role of RAS in this process. Mice were depleted of vitamin D through diet control and were compared with healthy subjects. Chronic vitamin D deficiency destructs lung structures, impairs lung development and stimulates ECM deposition. RAS components are also found to increase. These effects seem to worsen with prolonged vitamin D deficiency. By giving RAS blockers, these changes can be largely rescued. However, a smooth muscle relaxant whose regulatory effect on blood pressure is independent of RAS does not show similar effects. This study demonstrated that chronic vitamin D deficiency may induce RAS activation, which subsequently stimulates the expression of profibrotic factors and activates the fibrotic cascade. This profibrotic effect of RAS is independent of elevated blood pressure.

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Section: Discussionmentioning

confidence: 99%

Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system

Shi

Liu

Yao

et al. 2017

Sci Rep

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“…The nursing mothers were rotated between the O 2 treatment and the RA control litters every 24 h to avoid oxygen toxicity in the mothers. In our previous study, neonatal rats exposed to >95% O 2 for 1 week and followed by 2 weeks in 60% O 2 exhibited lung fibrosis [12]. Immediately after death, the right lung was ligated and the left lung was fixed by tracheal instillation of 10% buffered formalin at a pressure of 25 cm H 2 O.…”

Section: Methodsmentioning

confidence: 99%

Maternal Nicotine Exposure Exacerbates Neonatal Hyperoxia-Induced Lung Fibrosis in Rats

Huang

Chou²,

Lin³

et al. 2014

Neonatology

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Background: Maternal nicotine exposure increases lung collagen in fetal and newborn animals. Connective tissue growth factor (CTGF) plays a role in hyperoxia-induced pulmonary fibrosis. Objective: To determine whether pre- and postnatal nicotine exposure can augment CTGF expression and postnatal hyperoxia-induced lung fibrosis. Methods: Nicotine was administered to pregnant Sprague-Dawley rats at a dose of 6 mg/kg/day from gestational days 7-21 (prenatal nicotine-treated group) and gestational day 7 to postnatal day 14 (pre- and postnatal nicotine-treated group). A control group of pregnant dams was injected with an equal volume of saline. Within 12 h of birth, rats were exposed to room air or 1 week of >95% O₂ and an additional 2 weeks of 60% O₂ (3 weeks of hyperoxia). Lungs were taken for total collagen, CTGF expression and histological analyses. Results: In each maternal treatment group, the rats reared in hyperoxia had a higher total collagen compared with rats reared in room air on postnatal days 7 and 21. Collagen content was significantly higher in rats born to pre- and postnatal nicotine-treated dams than rats born to saline-treated and prenatal nicotine-treated dams on postnatal days 7 and 21. Pre- and postnatal nicotine exposure and neonatal hyperoxia exposure increased CTGF expression on postnatal days 7 and 21. Conclusions: CTGF may be involved in the pathogenesis of lung fibrosis induced by maternal nicotine and neonatal hyperoxia, and maternal nicotine exposure exacerbates neonatal hyperoxia-induced lung fibrosis. These results are relevant to neonates who require supplemental oxygen and are exposed to the breast milk of smoking mothers during infancy.

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“…demonstrated the existence of an angiotensin/ TGF-β1 "autocrine loop" in human lung myofibroblasts. More important in the context of the neonatal lung, Jiang et al (12). showed the activation of the angiotensin system in hyperoxiainduced lung fibrosis in neonatal rats.…”

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confidence: 99%

Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts

Oarhe

Dang

et al. 2015

Pediatr Res

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BACKGROUND Angiotensin (ANG) II is involved in experimental hyperoxia-induced lung fibrosis. Angiotensin-converting enzyme-2 (ACE-2) degrades ANG II and is thus protective, but is downregulated in adult human and experimental lung fibrosis. Hyperoxia is a known cause of chronic fibrotic lung disease in neonates, but the role of ACE-2 in neonatal lung fibrosis is unknown. We hypothesized that ACE-2 in human fetal lung cells might be downregulated by hyperoxic gas. METHODS Fetal human lung fibroblast IMR90 cells were exposed to hyperoxic (95% O2/5% CO2) or normoxic (21% O2/5% CO2) gas in vitro. Cells and culture media were recovered separately for assays of ACE-2 enzymatic activity, mRNA, and immunoreactive protein. RESULTS Hyperoxia decreased ACE-2 immunoreactive protein and enzyme activity in IMR90 cells (both P < 0.01), but did not change ACE-2 mRNA. ACE-2 protein was increased in the cell supernatant, suggesting protease-mediated ectodomain shedding. TAPI-2, an inhibitor of TNF-α–converting enzyme (TACE/ADAM17), prevented both the decrease in cellular ACE-2 and the increase in soluble ACE-2 (both P < 0.05). CONCLUSION These data show that ACE-2 is expressed in fetal human lung fibroblasts but is significantly decreased by hyperoxic gas. They also suggest that hyperoxia decreases ACE-2 through a shedding mechanism mediated by ADAM17/TACE.

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Activation of the Renin-Angiotensin System in Hyperoxia-Induced Lung Fibrosis in Neonatal Rats

Cited by 23 publications

References 37 publications

Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system

Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system

Maternal Nicotine Exposure Exacerbates Neonatal Hyperoxia-Induced Lung Fibrosis in Rats

Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts

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