Anti-placental growth factor antibody ameliorates hyperoxia-mediated impairment of lung development in neonatal rats

Zhang, Zuo‐Feng; Zhong, Yigang; Li, Xiaoxia; Huang, Xu; Du, Lizhong

doi:10.1590/1414-431x20198917

Cited by 5 publications

(5 citation statements)

References 35 publications

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“…Abnormal lipid metabolism in CF HBEC correlated with enhanced shedding of cytokines and growth factors to the basal medium ( Table 2 , Supplementary Table S1 ). The data highlight the enhanced inducible cytokine CXCL5 involved in neutrophil recruitment, tissue remodeling and COPD ( Chen et al, 2019 ), and placental growth factor (PGF) which is induced in the lung hyperoxia response, involved in macrophage polarization and angiogenesis, and exacerbates pulmonary fibrosis ( Zhao et al, 2019 ; Zhang et al, 2020 ). Both proteins correlated with oxidative stress markers, inflammation, and lung CT scores in CF infant BALF ( Horati et al, 2020 ), consistent with a role of these epithelial factors in early CF lung disease.…”

Section: Discussionmentioning

confidence: 99%

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

et al. 2021

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A deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) function in CF leads to chronic lung disease. CF is associated with abnormalities in fatty acids, ceramides, and cholesterol, their relationship with CF lung pathology is not completely understood. Therefore, we examined the impact of CFTR deficiency on lipid metabolism and pro-inflammatory signaling in airway epithelium using mass spectrometric, protein array. We observed a striking imbalance in fatty acid and ceramide metabolism, associated with chronic oxidative stress under basal conditions in CF mouse lung and well-differentiated bronchial epithelial cell cultures of CFTR knock out pig and CF patients. Cell-autonomous features of all three CF models included high ratios of ω-6- to ω-3-polyunsaturated fatty acids and of long- to very long-chain ceramide species (LCC/VLCC), reduced levels of total ceramides and ceramide precursors. In addition to the retinoic acid analog fenretinide, the anti-oxidants glutathione (GSH) and deferoxamine partially corrected the lipid profile indicating that oxidative stress may promote the lipid abnormalities. CFTR-targeted modulators reduced the lipid imbalance and oxidative stress, confirming the CFTR dependence of lipid ratios. However, despite functional correction of CF cells up to 60% of non-CF in Ussing chamber experiments, a 72-h triple compound treatment (elexacaftor/tezacaftor/ivacaftor surrogate) did not completely normalize lipid imbalance or oxidative stress.Protein array analysis revealed differential expression and shedding of cytokines and growth factors from CF epithelial cells compared to non-CF cells, consistent with sterile inflammation and tissue remodeling under basal conditions, including enhanced secretion of the neutrophil activator CXCL5, and the T-cell activator CCL17. However, treatment with antioxidants or CFTR modulators that mimic the approved combination therapies, ivacaftor/lumacaftor and ivacaftor/tezacaftor/elexacaftor, did not effectively suppress the inflammatory phenotype.We propose that CFTR deficiency causes oxidative stress in CF airway epithelium, affecting multiple bioactive lipid metabolic pathways, which likely play a role in CF lung disease progression. A combination of anti-oxidant, anti-inflammatory and CFTR targeted therapeutics may be required for full correction of the CF phenotype.

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Section: Discussionmentioning

confidence: 99%

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

et al. 2021

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“…CD34 + cells maintain tissue homeostasis [71] and are activated during tissue injury, increasing the expression of growth repair tissue factors such as Areg [72]. CD34 is also an angiogenic marker, and HO exposure has dual effects on the expression of this protein [73,74]. Our findings indicate that HO but not Areg increases CD34 expression in fetal murine lung ECs.…”

Section: Discussionmentioning

confidence: 66%

Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs

Thapa,

Shankar,

Shrestha

et al. 2024

Antioxidants

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Interrupted lung angiogenesis is a hallmark of bronchopulmonary dysplasia (BPD); however, druggable targets that can rescue this phenotype remain elusive. Thus, our investigation focused on amphiregulin (Areg), a growth factor that mediates cellular proliferation, differentiation, migration, survival, and repair. While Areg promotes lung branching morphogenesis, its effect on endothelial cell (EC) homeostasis in developing lungs is understudied. Therefore, we hypothesized that Areg promotes the proangiogenic ability of the ECs in developing murine lungs exposed to hyperoxia. Lung tissues were harvested from neonatal mice exposed to normoxia or hyperoxia to determine Areg expression. Next, we performed genetic loss-of-function and pharmacological gain-of-function studies in normoxia- and hyperoxia-exposed fetal murine lung ECs. Hyperoxia increased Areg mRNA levels and Areg+ cells in whole lungs. While Areg expression was increased in lung ECs exposed to hyperoxia, the expression of its signaling receptor, epidermal growth factor receptor, was decreased, indicating that hyperoxia reduces Areg signaling in lung ECs. Areg deficiency potentiated hyperoxia-mediated anti-angiogenic effects. In contrast, Areg treatment increased extracellular signal-regulated kinase activation and exerted proangiogenic effects. In conclusion, Areg promotes EC tubule formation in developing murine lungs exposed to hyperoxia.

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“…PlGF is a member of the VEGF family and is minimally expressed in the mature lung under homeostatic conditions. 47,48 This cytokine has been studied most commonly in pathologic lung diseases, such as bronchopulmonary dysplasia, 49,50 lung cancer, [51][52][53][54] and hyperoxia-induced lung injury. 50,55 More recently, investigators have identified PlGF as a key signaling cytokine in hepatopulmonary syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…47,48 This cytokine has been studied most commonly in pathologic lung diseases, such as bronchopulmonary dysplasia, 49,50 lung cancer, [51][52][53][54] and hyperoxia-induced lung injury. 50,55 More recently, investigators have identified PlGF as a key signaling cytokine in hepatopulmonary syndrome. 56,57 Unlike VEGF-A, which regulates angiogenesis in homeostasis as well as during lung development, PlGF exclusively regulates angiogenesis in pathologic conditions.…”

Section: Discussionmentioning

confidence: 99%

Acute cytotoxicity and increased vascular endothelial growth factor after in vitro nitrogen mustard vapor exposure

McGraw

Kim

White

et al. 2020

Annals of the New York Academy of Sciences

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Nitrogen mustard (NM) is a highly toxic alkylating agent. Inhalation exposure can cause acute and chronic lung injury. This study's aims were to develop an in vitro coculture model of mustard-induced airway injury and to identify growth factors contributing to airway pathology. Primary human bronchial epithelial cells cultured with pulmonary endothelial cells were exposed to NM (25, 50, 100, 250, or 500 µM) or PBS (control) for 1 hour. Lactate dehydrogenase (LDH) and transepithelial electrical resistance (TEER) were measured before and 24 h after NM exposure. Fixed cultures were stained for hematoxylin and eosin or live/dead staining. Culture media were analyzed for 11 growth factors. A 1-h vapor exposure to greater than or equal to 50 µM NM increased supernatant LDH, decreased TEER, and caused airway epithelial cell detachment. Endothelial cell death occurred at 500 µM NM. Vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF) expression increased in 500 µM NM−exposed cultures compared with PBS-exposed control cultures. NM vapor exposure causes differential cytotoxicity to airway epithelial and endothelial injury in culture. Increased VEGF-A and PlGF expression occurred acutely in airway cocultures. Future studies are required to validate the role of VEGF signaling in mustardinduced airway pathology.

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Anti-placental growth factor antibody ameliorates hyperoxia-mediated impairment of lung development in neonatal rats

Cited by 5 publications

References 35 publications

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs

Acute cytotoxicity and increased vascular endothelial growth factor after in vitro nitrogen mustard vapor exposure

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