Hyperoxia Induced Bronchopulmonary Dysplasia-Like Inflammation via miR34a-TNIP2-IL-1β Pathway

Abstract

Lung injury induced by oxygen is a key contributor to the pathogenesis of preterm infant bronchopulmonary dysplasia (BPD). To date, there are comprehensive therapeutic strategy for this disease, but the underlying mechanism is still in progress. By using lentivirus, we constructed microRNA34a (miR34a)-overexpressing or knockdown A549 cell lines, and exposure to hyperoxia to mimic oxygen induce lung injury. In this study, we investigated 4 proinflammatory cytokines, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), angiopoietin-1 (Ang-1), and Cyclooxygenase-2 (COX-2) in the secreted sputum of infants who received mechanical ventilation, and found that IL-1β was substantially elevated in the first week after oxygen therapy and with no significant decrease until the fourth week, while TNF-α, Ang-1, and COX-2 were increased in the first week but decreased quickly in the following weeks. In addition, in vitro assay revealed that hyperoxia significantly increased the expression of miR-34a, which positively regulated the proinflammatory cytokine IL-1β in a time- and concentration-dependent manner in A549 cells. Overexpressing or knockdown miR34 would exacerbate or inhibit production of IL-1β and its upstream NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway. Mechanically, it’s found that TNFAIP3 interacting protein 2 (TNIP2), an inhibitor of nuclear factor κB (NF-κB), is a direct target of miR34a, negatively regulated activation of NLRP3 inflammasome and the production of IL-1β. Overexpressing TNIP2 ameliorated hyperoxia-induced production of IL-1β and cell apoptosis. Our findings suggest that TNIP2 may be a potential clinical marker in the diagnosis of BPD.

Hsa_circ_0001359 in Serum Exosomes: A Promising Marker to Predict Bronchopulmonary Dysplasia in Premature Infants

“… 19 It was also demonstrated that serum levels of IL-1β, IL-6, IL-8, IL-33, and TNF-α were significantly increased in the early postnatal period of BPD infants. 3 , 4 , 20 However, the above classic markers are mostly non-specific indicators such as inflammatory factors, making it difficult to distinguish between primary disease and BPD in infants with acute respiratory distress syndrome. 2 Therefore, serum IL-6 and IL-33 21 , 22 as inflammatory cytokines, serum ET-1 and KL-6 23 , 24 as lung injury markers were measured, and compared between BPD and non-BPD infants.…”

“… 1 However, the early clinical manifestations of BPD are often non-specific. 2 Though several inflammatory factors (such as IL-1β, IL-6, and IL-8) have been reported to be associated with BPD, 3 , 4 these markers lack tissue and disease specificity. Meanwhile, some clinical prediction models have also been developed, but these models contain too many variables, which limits their usability in clinical practice.…”

ETS1 Ameliorates Hyperoxia-Induced Bronchopulmonary Dysplasia in Mice by Activating Nrf2/HO-1 Mediated Ferroptosis

“…Human alveolar basal epithelial cells (A549, AW-CCH011, Abiowell, China) were cultured in DMEM containing 10% FBS, 100 U/ml penicillin, and 100 μg/ml streptomycin, at 37 °C in 95% air and 5% CO 2 . Cultured A549 cells were subjected to hyperoxia induction and ETS1 overexpression assays [ 22 ]. To conduct the hyperoxia experiments, we used subconfluent cells (at 70% with approximately 350–400 cells/mm 2 ) and placed them in sealed glass chambers filled with a gas mixture of 95% O 2 and 5% CO 2 .…”