Hyperoxia causes miR-34a-mediated injury via angiopoietin-1 in neonatal lungs

Syed, Mansoor Ali; Das, Pragnya; Pawar, Aishwarya; Aghai, Zubair H.; Kaskinen, Anu; Zhuang, Zhen W.; Ambalavanan, Namasivayam; Pryhuber, Gloria S.; Andersson, Sture; Bhandari, Vineet

doi:10.1038/s41467-017-01349-y

Cited by 106 publications

(119 citation statements)

References 79 publications

(87 reference statements)

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“…Ablation of miR-34a expression in PDGFRa + cells did not impact hyperoxia-provoked perturbations to septal thickness ( Fig 3K), which we attribute to the tamoxifen solvent, Miglyol, a complex fatty acid-derivative mixture, which we propose limited the impact of hyperoxia on septal thickening analogous to that reported for chemically related cottonseed oil (Nardiello et al, 2017b), since Miglyol alone is known to attenuate normal lung development (Fehl et al, 2019). Alternatively, it may be epithelial miR-34a that regulates septal thickening, since miR-34a regulates lung epithelial cell (notably, type II pneumocyte) apoptosis (Syed et al, 2017) in experimental BPD. These data validate a role for miR-34a in PDGFRa + cells in mediating the inhibitory effects of hyperoxia on alveolarization.…”

Section: Mir-34a In Pdgfra + Cells Contributes To Aberrant Lung Alveomentioning

confidence: 58%

“…lung development, which is relevant to BPD, several microRNA candidates have been proposed as pathogenic players, including miR-150(Narasaraju et al, 2015), miR-489(Olave et al, 2016), miR-29b(Durrani-Kolarik et al, 2017), the miR-19/72 cluster(Rogers et al, 2015;Robbins et al, 2016), and epithelial miR-34a(Syed et al, 2017), but transgenic mouse studies have only validated a causal role for epithelial miR-34a (most likely by targeting angiopoietin) in arrested alveolarization, where miR-34a levels were also documented to be elevated in the lungs of BPD patients(Syed et al, 2017). Ours is the first report of a causal role being validated for any microRNA/mRNA target interaction in aberrant lung alveolarization, as well as the first-in-mouse use of a TSB in vivo in an animal…”

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confidence: 99%

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Targeting miR‐34a/ Pdgfra interactions partially corrects alveologenesis in experimental bronchopulmonary dysplasia

et al. 2019

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Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth characterized by arrested lung alveolarization, which generates lungs that are incompetent for effective gas exchange. We report here deregulated expression of miR‐34a in a hyperoxia‐based mouse model of BPD, where miR‐34a expression was markedly increased in platelet‐derived growth factor receptor (PDGFR)α‐expressing myofibroblasts, a cell type critical for proper lung alveolarization. Global deletion of miR‐34a; and inducible, conditional deletion of miR‐34a in PDGFRα+ cells afforded partial protection to the developing lung against hyperoxia‐induced perturbations to lung architecture. Pdgfra mRNA was identified as the relevant miR‐34a target, and using a target site blocker in vivo, the miR‐34a/Pdgfra interaction was validated as a causal actor in arrested lung development. An antimiR directed against miR‐34a partially restored PDGFRα+ myofibroblast abundance and improved lung alveolarization in newborn mice in an experimental BPD model. We present here the first identification of a pathology‐relevant microRNA/mRNA target interaction in aberrant lung alveolarization and highlight the translational potential of targeting the miR‐34a/Pdgfra interaction to manage arrested lung development associated with preterm birth.

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Section: Mir-34a In Pdgfra + Cells Contributes To Aberrant Lung Alveomentioning

confidence: 58%

mentioning

confidence: 99%

Targeting miR‐34a/ Pdgfra interactions partially corrects alveologenesis in experimental bronchopulmonary dysplasia

et al. 2019

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“…; Syed et al. ). In our model system we did not find an increase in inflammatory mediators in animals ventilated with 15 cm H 2 O for 4 h at 100% FiO 2 versus 21% FiO 2 (see Fig.…”

Section: Discussionmentioning

confidence: 98%

“…All our mice received 100% FiO 2 during ventilation (both in the high and low peak inspiratory pressure). We are conscious of the fact, that most human patients do not receive 100% FiO 2 and that oxygen toxicity might be an additional factor in our modelhyperoxia is a well established model for neonatal lung injury, although the animals tend to be exposed to hyperoxia for days not hours (Cox et al 2015;Bao et al 2017;Syed et al 2017). In our model system we did not find an increase in inflammatory mediators in animals ventilated with 15 cm H 2 O for 4 h at 100% FiO 2 versus 21% FiO 2 (see Fig.…”

Section: Discussionmentioning

confidence: 99%

Capturing the multifactorial nature of ARDS - “Two-hit” approach to model murine acute lung injury

et al. 2018

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Severe acute respiratory distress syndrome (ARDS) presents typically with an initializing event, followed by the need for mechanical ventilation. Most animal models of ALI are limited by the fact that they focus on a singular cause of acute lung injury (ALI) and therefore fail to mimic the complex, multifactorial pathobiology of ARDS. To better capture this scenario, we provide a comprehensive characterization of models of ALI combining two injuries: intra tracheal (i.t.) instillation of LPS or hypochloric acid (HCl) followed by ventilator‐induced lung injury (VILI). We hypothesized, that mice pretreated with LPS or HCl prior to VILI and thus receiving a (“two‐hit injury”) will sustain a superadditive lung injury when compared to VILI. Mice were allocated to following treatment groups: control with i.t. NaCl, ventilation with low peak inspiratory pressure (PIP), i.t. HCl, i.t. LPS, VILI (high PIP), HCl i.t. followed by VILI and LPS i.t. followed by VILI. Severity of injury was determined by protein content and MPO activity in bronchoalveolar lavage (BAL), the expression of inflammatory cytokines and histopathology. Mice subjected to VILI after HCl or LPS instillation displayed augmented lung injury, compared to singular lung injury. However, mice that received i.t. LPS prior to VILI showed significantly increased inflammatory lung injury compared to animals that underwent i.t. HCl followed by VILI. The two‐hit lung injury models described, resulting in additive but differential acute lung injury recaptures the clinical relevant multifactorial etiology of ALI and could be a valuable tool in translational research.

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“…Abnormal miRNA expression has been reported in a number of diseases, including cystic fibrosis, asthma, ALI and ARDS (12,13). MiR-34a levels are significantly higher in the lungs of neonatal rats exposed to hyperoxia compared with normal controls and miR-34a suppression improves the pulmonary phenotype and bronchopulmonary dysplasia-associated pulmonary arterial hypertension (14). Furthermore, plasma miR-200c-3p levels are much higher in patients with severe pneumonia compared with healthy controls (15).…”

Section: Introductionmentioning

confidence: 77%

Reduced peripheral blood miR‑140 may be a biomarker for acute lung injury by targeting Toll‑like receptor4 (TLR4)

Wang

Guo

et al. 2018

Exp Ther Med

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Abstract. Acute lung injury (ALI) is a common complication of sepsis to which patients often succumb due to poor effective pharmacological interventions. Recent studies have focused on the potential application of circulating microRNAs (miRs or miRNAs) as novel prognostic and therapeutic biomarkers. The present study focuses mainly on miR-140, the role of which is poorly understood in the progression of ALI. The results of the present study revealed that toll-like receptor 4 (TLR4) expression was upregulated the lungs of rats with ALI. Meanwhile, serum levels of tumor necrosis factor-α, interleukin (IL)-6 and IL-1β were significantly increased in rats with ALI compared with normal control rats. These data indicated the successful establishment of LPS-induced ALI. Furthermore, miR-140 was decreased in the peripheral blood of patients with ALI compared with control subjects. Receiver operator characteristic analysis indicated that miR-140 could be used to screen ALI patients and distinguish them from healthy controls. MiR-140 was demonstrated to be downregulated in the plasma and lungs of rats with ALI compared with the normal control group. A dual luciferase reporter assay indicated that TLR4 was a target gene of miR-140. To investigate whether miR-140 exerted its role via TLR4, a specific TLR4-targeting small interfering RNA was selected. It was revealed that TLR4 silencing was able to suppress the phosphorylation of NF-κB even in cells transfected with miR-140 inhibitor. In summary, reduced miR-140 expression and increased TLR4 signaling activation may serve a key role in the progression of ALI.

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Hyperoxia causes miR-34a-mediated injury via angiopoietin-1 in neonatal lungs

Cited by 106 publications

References 79 publications

Targeting miR‐34a/ Pdgfra interactions partially corrects alveologenesis in experimental bronchopulmonary dysplasia

Targeting miR‐34a/ Pdgfra interactions partially corrects alveologenesis in experimental bronchopulmonary dysplasia

Capturing the multifactorial nature of ARDS - “Two-hit” approach to model murine acute lung injury

Reduced peripheral blood miR‑140 may be a biomarker for acute lung injury by targeting Toll‑like receptor4 (TLR4)

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