PMID- 33921872 OWN - NLM STAT- MEDLINE DCOM- 20211020 LR - 20240226 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 10 IP - 4 DP - 2021 Apr 19 TI - Clusterin Deficiency Exacerbates Hyperoxia-Induced Acute Lung Injury. LID - 10.3390/cells10040944 [doi] LID - 944 AB - Exposure to high oxygen concentrations leads to generation of excessive reactive oxygen species, causing cellular injury and multiple organ dysfunctions and is associated with a high mortality rate. Clusterin (CLU) is a heterodimeric glycoprotein that mediates several intracellular signaling pathways, including cell death and inflammation. However, the role of CLU in the pathogenesis of hyperoxic acute lung injury (HALI) is unknown. Wild-type (WT) and CLU-deficient mice and cultured human airway epithelial cells were used. Changes in cell death- and inflammation-related molecules with or without hyperoxia exposure in cells and animals were determined. Hyperoxia induced an increase in CLU expression in mouse lungs and human airway epithelial cells. Mice lacking CLU had increased HALI and mortality rate compared with WT mice. In vitro, CLU-disrupted cells showed enhanced release of cytochrome c, Bax translocation, cell death and inflammatory cytokine expression. However, treatment with recombinant CLU attenuated hyperoxia-induced apoptosis. Moreover, the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses revealed metabolic pathways, hematopoietic cell lineage, response to stress and localization and regulation of immune system that were differentially regulated between WT and CLU(-/-) mice. These results demonstrate that prolonged hyperoxia-induced lung injury is associated with CLU expression and that CLU replenishment may alleviate hyperoxia-induced cell death. FAU - Hong, Jung Yeon AU - Hong JY AUID- ORCID: 0000-0003-0406-9956 AD - Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea. FAU - Kim, Mi Na AU - Kim MN AUID- ORCID: 0000-0002-1675-0688 AD - Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea. FAU - Kim, Eun Gyul AU - Kim EG AD - Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea. FAU - Lee, Jae Woo AU - Lee JW AD - Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea. FAU - Kim, Hye Rin AU - Kim HR AD - Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea. FAU - Kim, Soo Yeon AU - Kim SY AD - Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea. FAU - Lee, Soon Min AU - Lee SM AUID- ORCID: 0000-0003-0174-1065 AD - Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea. FAU - Kim, Yoon Hee AU - Kim YH AD - Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea. FAU - Kim, Kyung Won AU - Kim KW AUID- ORCID: 0000-0003-4529-6135 AD - Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea. FAU - Sohn, Myung Hyun AU - Sohn MH AD - Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea. LA - eng GR - 2011-0024036, 2016R1D1A1B03931794/National Research Foundation of Korea (NRF) funded by the Ministry of Education/ GR - 2018R1A5A2025079 2020R1A2B5B02001713/National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210419 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Clusterin) RN - 0 (RNA, Messenger) RN - 0 (bcl-2-Associated X Protein) RN - 9007-43-6 (Cytochromes c) SB - IM MH - Acute Lung Injury/*etiology/genetics/pathology/prevention & control MH - Animals MH - Apoptosis MH - Clusterin/*deficiency/metabolism MH - Cytochromes c/metabolism MH - Epithelial Cells/metabolism/pathology MH - Gene Expression Profiling MH - Gene Expression Regulation MH - Humans MH - Hyperoxia/*complications MH - Inflammation/pathology MH - Lung/metabolism/pathology MH - Male MH - Membrane Potential, Mitochondrial MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Microarray Analysis MH - RNA, Messenger/genetics/metabolism MH - bcl-2-Associated X Protein/metabolism MH - Mice PMC - PMC8073575 OTO - NOTNLM OT - acute lung injury OT - apoptosis OT - clusterin OT - hyperoxia OT - inflammation COIS- The authors declare that they have no conflict of interest. EDAT- 2021/05/01 06:00 MHDA- 2021/10/21 06:00 PMCR- 2021/04/19 CRDT- 2021/04/30 01:20 PHST- 2021/02/08 00:00 [received] PHST- 2021/04/07 00:00 [revised] PHST- 2021/04/16 00:00 [accepted] PHST- 2021/04/30 01:20 [entrez] PHST- 2021/05/01 06:00 [pubmed] PHST- 2021/10/21 06:00 [medline] PHST- 2021/04/19 00:00 [pmc-release] AID - cells10040944 [pii] AID - cells-10-00944 [pii] AID - 10.3390/cells10040944 [doi] PST - epublish SO - Cells. 2021 Apr 19;10(4):944. doi: 10.3390/cells10040944.