Breakdown of Epithelial Barrier Integrity and Overdrive Activation of Alveolar Epithelial Cells in the Pathogenesis of Acute Respiratory Distress Syndrome and Lung Fibrosis

Yanagi, Shigehisa; Tsubouchi, Hironobu; Miura, Ayako; Matsumoto, Nobuhiro; Nakazato, Masamitsu

doi:10.1155/2015/573210

Cited by 64 publications

(56 citation statements)

References 92 publications

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“…The accelerated senescence of AECs is one of the mechanisms that aggravate the aberrant activation of AECs . Abnormally activated cells activate fibroblasts and myofibroblasts to secrete excess extracellular matrix, leading to the deposition of collagen and destruction of the lung architecture.…”

Section: Resultsmentioning

confidence: 99%

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

et al. 2019

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Pulmonary fibrosis (PF) is a senescence-associated disease with poor prognosis. Currently, there is no effective therapeutic strategy for preventing and treating the disease process. Mounting evidence suggests that arachidonic acid (ARA) metabolites are involved in the pathogenesis of various fibrosis. However, the relationship between the metabolism of ARA and PF is still elusive. In this study, we observed a disorder in the cyclooxygenase-2/cytochrome P450 (COX-2/CYP) metabolism of ARA in the lungs of PF mice induced by bleomycin (BLM). Therefore, we aimed to explore the role of COX-2/CYP-derived ARA metabolic disorders in PF. PTUPB, a dual COX-2 and soluble epoxide hydrolase (sEH) inhibitor, was used to restore the balance of COX-2/CYP metabolism. sEH is an enzyme hydrolyzing epoxyeicosatrienoic acids derived from ARA by CYP. We found that PTUPB alleviated the pathological changes in lung tissue and collagen deposition, as well as reduced senescence marker molecules (p16 Ink4a and p53-p21 Waf1/Cip1 ) in the lungs of mice treated by BLM. In vitro, we found that PTUPB pretreatment remarkably reduced the expression of senescence-related molecules in the alveolar epithelial cells (AECs) induced by BLM. In conclusion, our study supports the notion that the COX-2/CYP-derived ARA metabolic disorders may be a potential therapeutic target for PF via inhibiting the cellular senescence in AECs.

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Section: Resultsmentioning

confidence: 99%

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

et al. 2019

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“…These findings also highlight the possibility that administration of therapeutic agents that promote barrier protective responses in the developing fetal lung may help alleviate the effects of maternal smoke exposure. Additionally, resident progenitor cell populations may play a role in reestablishing barrier integrity in fetal lungs after injury by tobacco smoke (58).…”

Section: Discussionmentioning

confidence: 99%

Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho‐GTPase‐dependent actin cytoskeletal signaling in fetal lungs

et al. 2017

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The present study tested the hypothesis that maternal smoke exposure results in fetal lung growth retardation due to dysregulation in various signaling pathways, including the Wnt (wingless-related integration site)/β-catenin pathway. Pregnant female C57BL/6J mice were exposed to cigarette smoke (100-150 mg/m) or room air, and offspring were humanely killed on 12.5, 14.5, 16.5, and 18.5 d (dpc). We assessed lung stereology with Cavalieri estimation; apoptosis with proliferating cell nuclear antigen, TUNEL, and caspase assays; and gene expression with quantitative PCR (qPCR) and RNA sequencing on lung epithelium and mesenchyme retrieved by laser capture microdissection. Results demonstrated a significant decrease in body weight and lung volume of smoke-exposed embryos. At 16.5 dpc, the reduction in lung volume was due to loss of lung mesenchymal tissue correlating with a decrease in cell proliferation ( = 10; air: 61.65% smoke: 44.21%, < 0.05). RNA sequence analysis demonstrated an alteration in the Wnt pathway, and qPCR confirmed an increased expression of secreted frizzled-related protein 1 (sFRP-1) [ = 12; relative quantification (RQ) 1 2.33, < 0.05] and down-regulation of Cyclin D1 ( = 7; RQ 1 0.61, < 0.05) in mesenchymal tissue. Furthermore, genome expression studies revealed a smoke-induced up-regulation of Rho-GTPase-dependent actin cytoskeletal signaling that can lead to loss of tissue integrity.-Unachukwu, U., Trischler, J., Goldklang, M., Xiao, R., D'Armiento, J. Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho-GTPase-dependent actin cytoskeletal signaling in fetal lungs.

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“…Moreover, AKT is generally recognized as a key factor in PI3K (phosphatidylinositol 3-kinase) /AKT pathway and acts as a crucial role in cell differentiation, proliferation, metabolism, apoptosis, protein synthesis and transcription [11]. Previous studies have indicated that ARDS can be treated by the inhibition of PI3K/AKT signaling pathway [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

miR-146b-3p regulates PI3K/AKT signaling pathway in septic mice with acute respiratory distress syndrome

Liu¹,

Zhu²,

Jin³

et al. 2020

Preprint

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Background: This study aimed to explore the effect of miR-146b-3p on acute respiratory distress syndrome in septic mice by regulating PI3K/AKT signaling pathway. Methods: Seventy C57BL/6 mice were divided into normal group ( n = 10) and modeling group ( n = 60, mice for constructing septic mice models with acute respiratory distress syndrome). Model mice were subdivided into model group (without any treatment), negative control (NC) mimic group (injection with miRNA NC), miR-146b-3p mimic group (injection with miR-146b-3p mimic), si-NC group (injection with PI3Kγ siRNA NC), si-PI3Kγ group (injection with PI3Kγ interference sequence), and miR-146b-3p mimic + oe-PI3Kγ group (injection with miR-146b-3p mimic + PI3Kγ overexpression plasmid). Dual-luciferase reporter assay was conducted to determine the target relationship between miR-146b-3p and PI3Kγ. Wet weight/dry weight (W/D) ratio of the left lung was measured. Hematoxylin and eosin stain was used to detect the pathological change of mouse lung. ELISA was employed to measure serum interleukin (IL) -1β and IL-18 levels. miR-146b-3p and PI3Kγ expressions were detected by qRT-PCR. PI3Kγ, AKT, NLRP3, apoptosis-associated speck-like protein caspase recruitment domain (ASC) and Caspase-1 protein expressions were detected by Western blotting. Results: miR-146b-3p negatively regulated PI3Kγ. The lung tissues in other groups compared with normal group had down-regulated miR-146b-3p, up-regulated PI3Kγ, p-AKT, ASC, NLRP3 and Caspase-1 proteins, higher W/D ratio, and more serum IL-1β and IL-18 (all P < 0.05). All indicators in miR-146b-3p mimic group and si-PI3Kγ group were significantly improved as compared to model group (all P < 0.05). Up-regulated PI3Kγ, p-AKT, ASC, NLRP3 and Caspase-1 proteins and higher W/D ratio and IL-1β and IL-18 levels in serum existed in miR-146b-3p mimic + oe-PI3Kγ group compared with miR-146b-3p mimic group (all P < 0.05). Conclusions: Up-regulation of miR-146b-3p can restrain PI3K/AKT signaling pathway, thereby improving acute respiratory distress syndrome in septic mice.

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Breakdown of Epithelial Barrier Integrity and Overdrive Activation of Alveolar Epithelial Cells in the Pathogenesis of Acute Respiratory Distress Syndrome and Lung Fibrosis

Cited by 64 publications

References 92 publications

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho‐GTPase‐dependent actin cytoskeletal signaling in fetal lungs

miR-146b-3p regulates PI3K/AKT signaling pathway in septic mice with acute respiratory distress syndrome

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