COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence
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 fibros...
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| creator | Zhang, Chen‐Yu Duan, Jia‐Xi Yang, Hui‐Hui Sun, Chen‐Chen Zhong, Wen‐Jing Tao, Jia‐Hao Guan, Xin‐Xin Jiang, Hui‐Ling Hammock, Bruce D. Hwang, Sung Hee Zhou, Yong Guan, Cha‐Xiang |
| description | 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 (p16Ink4a and p53‐p21Waf1/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.
Here, we observed a disorder in the cyclooxygenase‐2/cytochrome P450 (COX‐2/CYP) metabolism of arachidonic acid in the lungs of mice with pulmonary fibrosis (PF) induced by bleomycin. PTUPB, a dual COX‐2 and soluble epoxide hydrolase inhibitor, was used to restore the balance of COX‐2/CYP metabolism. Our findings showed that PTUPB alleviated bleomycin‐induced PF via inhibiting the cellular senescence in alveolar epithelial cells, indicating a potential therapeutic target for PF. |
| doi_str_mv | 10.1111/febs.15105 |
| format | Article |
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Here, we observed a disorder in the cyclooxygenase‐2/cytochrome P450 (COX‐2/CYP) metabolism of arachidonic acid in the lungs of mice with pulmonary fibrosis (PF) induced by bleomycin. PTUPB, a dual COX‐2 and soluble epoxide hydrolase inhibitor, was used to restore the balance of COX‐2/CYP metabolism. Our findings showed that PTUPB alleviated bleomycin‐induced PF via inhibiting the cellular senescence in alveolar epithelial cells, indicating a potential therapeutic target for PF.</description><identifier>ISSN: 1742-464X</identifier><identifier>EISSN: 1742-4658</identifier><identifier>DOI: 10.1111/febs.15105</identifier><identifier>PMID: 31646730</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>A549 Cells ; Aging - drug effects ; alveolar epithelial cells ; Alveoli ; Animals ; Arachidonic acid ; Arachidonic Acid - metabolism ; Bleomycin ; Cellular Senescence - drug effects ; Collagen ; Cyclin-dependent kinase inhibitor p21 ; Cyclooxygenase 2 - metabolism ; Cytochrome ; Cytochrome P450 ; Cytochromes P450 ; Disease Models, Animal ; Dose-Response Relationship, Drug ; dual COX‐2 and sEH inhibitor ; Enzyme Inhibitors - administration & dosage ; Enzyme Inhibitors - pharmacology ; Epithelial cells ; Epithelial Cells - drug effects ; Epithelial Cells - metabolism ; Epoxide hydrolase ; Epoxide Hydrolases - antagonists & inhibitors ; Epoxide Hydrolases - metabolism ; Fibrosis ; Humans ; Inhibitors ; Injections, Subcutaneous ; INK4a protein ; Lung diseases ; Lungs ; Male ; Metabolic disorders ; Metabolites ; Mice ; Mice, Inbred C57BL ; p16 Protein ; p53 Protein ; Pathogenesis ; Prostaglandin endoperoxide synthase ; Pulmonary fibrosis ; Pulmonary Fibrosis - chemically induced ; Pulmonary Fibrosis - drug therapy ; Pulmonary Fibrosis - metabolism ; Senescence ; Staphylococcal enterotoxin H ; Structure-Activity Relationship ; Therapeutic applications ; Tumor Cells, Cultured</subject><ispartof>The FEBS journal, 2020-04, Vol.287 (8), p.1666-1680</ispartof><rights>2019 Federation of European Biochemical Societies</rights><rights>2019 Federation of European Biochemical Societies.</rights><rights>Copyright © 2020 Federation of European Biochemical Societies</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4485-82130631d26e07b6eb3462ec6b33b63dd564f42ccf4285eecf55f2f5263bbdc43</citedby><cites>FETCH-LOGICAL-c4485-82130631d26e07b6eb3462ec6b33b63dd564f42ccf4285eecf55f2f5263bbdc43</cites><orcidid>0000-0002-8505-8724 ; 0000-0002-7348-2376</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Ffebs.15105$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Ffebs.15105$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31646730$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Chen‐Yu</creatorcontrib><creatorcontrib>Duan, Jia‐Xi</creatorcontrib><creatorcontrib>Yang, Hui‐Hui</creatorcontrib><creatorcontrib>Sun, Chen‐Chen</creatorcontrib><creatorcontrib>Zhong, Wen‐Jing</creatorcontrib><creatorcontrib>Tao, Jia‐Hao</creatorcontrib><creatorcontrib>Guan, Xin‐Xin</creatorcontrib><creatorcontrib>Jiang, Hui‐Ling</creatorcontrib><creatorcontrib>Hammock, Bruce D.</creatorcontrib><creatorcontrib>Hwang, Sung Hee</creatorcontrib><creatorcontrib>Zhou, Yong</creatorcontrib><creatorcontrib>Guan, Cha‐Xiang</creatorcontrib><title>COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence</title><title>The FEBS journal</title><addtitle>FEBS J</addtitle><description>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 (p16Ink4a and p53‐p21Waf1/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.
Here, we observed a disorder in the cyclooxygenase‐2/cytochrome P450 (COX‐2/CYP) metabolism of arachidonic acid in the lungs of mice with pulmonary fibrosis (PF) induced by bleomycin. PTUPB, a dual COX‐2 and soluble epoxide hydrolase inhibitor, was used to restore the balance of COX‐2/CYP metabolism. Our findings showed that PTUPB alleviated bleomycin‐induced PF via inhibiting the cellular senescence in alveolar epithelial cells, indicating a potential therapeutic target for PF.</description><subject>A549 Cells</subject><subject>Aging - drug effects</subject><subject>alveolar epithelial cells</subject><subject>Alveoli</subject><subject>Animals</subject><subject>Arachidonic acid</subject><subject>Arachidonic Acid - metabolism</subject><subject>Bleomycin</subject><subject>Cellular Senescence - drug effects</subject><subject>Collagen</subject><subject>Cyclin-dependent kinase inhibitor p21</subject><subject>Cyclooxygenase 2 - metabolism</subject><subject>Cytochrome</subject><subject>Cytochrome P450</subject><subject>Cytochromes P450</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>dual COX‐2 and sEH inhibitor</subject><subject>Enzyme Inhibitors - administration & dosage</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epithelial cells</subject><subject>Epithelial Cells - drug effects</subject><subject>Epithelial Cells - metabolism</subject><subject>Epoxide hydrolase</subject><subject>Epoxide Hydrolases - antagonists & inhibitors</subject><subject>Epoxide Hydrolases - metabolism</subject><subject>Fibrosis</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Injections, Subcutaneous</subject><subject>INK4a protein</subject><subject>Lung diseases</subject><subject>Lungs</subject><subject>Male</subject><subject>Metabolic disorders</subject><subject>Metabolites</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>p16 Protein</subject><subject>p53 Protein</subject><subject>Pathogenesis</subject><subject>Prostaglandin endoperoxide synthase</subject><subject>Pulmonary fibrosis</subject><subject>Pulmonary Fibrosis - chemically induced</subject><subject>Pulmonary Fibrosis - drug therapy</subject><subject>Pulmonary Fibrosis - metabolism</subject><subject>Senescence</subject><subject>Staphylococcal enterotoxin H</subject><subject>Structure-Activity Relationship</subject><subject>Therapeutic applications</subject><subject>Tumor Cells, Cultured</subject><issn>1742-464X</issn><issn>1742-4658</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1KAzEUhYMo_lQ3PoAE3AnV_He6EWypVigoqNBdmGTu1MhMpk5mlO58BJ_RJzG1WnRjFsmFnPvdkxyEDik5pXGd5WDCKZWUyA20S3uCdYWSyea6FtMdtBfCEyFcin5_G-1wqoTqcbKLmuHN9OPtnZ2F0RhnbVpg5x-dcU1V49v7h9sBTosCXlzaQMCmgKpcWOdjh_NZayHD87YoK5_WC5w7U1fBhUjApbOAY9cPzfkZDuAhWPAW9tFWnhYBDr7PDnq4HN0Px93JzdX18GLStUIkspswyoniNGMKSM8oMFwoBlYZzo3iWSaVyAWzNm6JBLC5lDnLJVPcmMwK3kHnK-68NSVkcXZTp4We166MhnWVOv33xrtHPatedC_-HBUsAo6_AXX13EJo9FPV1j561oz3GSEkETyqTlYqG98fasjXEyjRy4T0MiH9lVAUH_32tJb-RBIFdCV4dQUs_kHpy9HgbgX9BBPun48</recordid><startdate>202004</startdate><enddate>202004</enddate><creator>Zhang, Chen‐Yu</creator><creator>Duan, Jia‐Xi</creator><creator>Yang, Hui‐Hui</creator><creator>Sun, Chen‐Chen</creator><creator>Zhong, Wen‐Jing</creator><creator>Tao, Jia‐Hao</creator><creator>Guan, Xin‐Xin</creator><creator>Jiang, Hui‐Ling</creator><creator>Hammock, Bruce D.</creator><creator>Hwang, Sung Hee</creator><creator>Zhou, Yong</creator><creator>Guan, Cha‐Xiang</creator><general>Blackwell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8505-8724</orcidid><orcidid>https://orcid.org/0000-0002-7348-2376</orcidid></search><sort><creationdate>202004</creationdate><title>COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence</title><author>Zhang, Chen‐Yu ; Duan, Jia‐Xi ; Yang, Hui‐Hui ; Sun, Chen‐Chen ; Zhong, Wen‐Jing ; Tao, Jia‐Hao ; Guan, Xin‐Xin ; Jiang, Hui‐Ling ; Hammock, Bruce D. ; Hwang, Sung Hee ; Zhou, Yong ; Guan, Cha‐Xiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4485-82130631d26e07b6eb3462ec6b33b63dd564f42ccf4285eecf55f2f5263bbdc43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>A549 Cells</topic><topic>Aging - drug effects</topic><topic>alveolar epithelial cells</topic><topic>Alveoli</topic><topic>Animals</topic><topic>Arachidonic acid</topic><topic>Arachidonic Acid - metabolism</topic><topic>Bleomycin</topic><topic>Cellular Senescence - drug effects</topic><topic>Collagen</topic><topic>Cyclin-dependent kinase inhibitor p21</topic><topic>Cyclooxygenase 2 - metabolism</topic><topic>Cytochrome</topic><topic>Cytochrome P450</topic><topic>Cytochromes P450</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>dual COX‐2 and sEH inhibitor</topic><topic>Enzyme Inhibitors - administration & dosage</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Epithelial cells</topic><topic>Epithelial Cells - drug effects</topic><topic>Epithelial Cells - metabolism</topic><topic>Epoxide hydrolase</topic><topic>Epoxide Hydrolases - antagonists & inhibitors</topic><topic>Epoxide Hydrolases - metabolism</topic><topic>Fibrosis</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Injections, Subcutaneous</topic><topic>INK4a protein</topic><topic>Lung diseases</topic><topic>Lungs</topic><topic>Male</topic><topic>Metabolic disorders</topic><topic>Metabolites</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>p16 Protein</topic><topic>p53 Protein</topic><topic>Pathogenesis</topic><topic>Prostaglandin endoperoxide synthase</topic><topic>Pulmonary fibrosis</topic><topic>Pulmonary Fibrosis - chemically induced</topic><topic>Pulmonary Fibrosis - drug therapy</topic><topic>Pulmonary Fibrosis - metabolism</topic><topic>Senescence</topic><topic>Staphylococcal enterotoxin H</topic><topic>Structure-Activity Relationship</topic><topic>Therapeutic applications</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Chen‐Yu</creatorcontrib><creatorcontrib>Duan, Jia‐Xi</creatorcontrib><creatorcontrib>Yang, Hui‐Hui</creatorcontrib><creatorcontrib>Sun, Chen‐Chen</creatorcontrib><creatorcontrib>Zhong, Wen‐Jing</creatorcontrib><creatorcontrib>Tao, Jia‐Hao</creatorcontrib><creatorcontrib>Guan, Xin‐Xin</creatorcontrib><creatorcontrib>Jiang, Hui‐Ling</creatorcontrib><creatorcontrib>Hammock, Bruce D.</creatorcontrib><creatorcontrib>Hwang, Sung Hee</creatorcontrib><creatorcontrib>Zhou, Yong</creatorcontrib><creatorcontrib>Guan, Cha‐Xiang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The FEBS journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Chen‐Yu</au><au>Duan, Jia‐Xi</au><au>Yang, Hui‐Hui</au><au>Sun, Chen‐Chen</au><au>Zhong, Wen‐Jing</au><au>Tao, Jia‐Hao</au><au>Guan, Xin‐Xin</au><au>Jiang, Hui‐Ling</au><au>Hammock, Bruce D.</au><au>Hwang, Sung Hee</au><au>Zhou, Yong</au><au>Guan, Cha‐Xiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence</atitle><jtitle>The FEBS journal</jtitle><addtitle>FEBS J</addtitle><date>2020-04</date><risdate>2020</risdate><volume>287</volume><issue>8</issue><spage>1666</spage><epage>1680</epage><pages>1666-1680</pages><issn>1742-464X</issn><eissn>1742-4658</eissn><abstract>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 (p16Ink4a and p53‐p21Waf1/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.
Here, we observed a disorder in the cyclooxygenase‐2/cytochrome P450 (COX‐2/CYP) metabolism of arachidonic acid in the lungs of mice with pulmonary fibrosis (PF) induced by bleomycin. PTUPB, a dual COX‐2 and soluble epoxide hydrolase inhibitor, was used to restore the balance of COX‐2/CYP metabolism. Our findings showed that PTUPB alleviated bleomycin‐induced PF via inhibiting the cellular senescence in alveolar epithelial cells, indicating a potential therapeutic target for PF.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>31646730</pmid><doi>10.1111/febs.15105</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-8505-8724</orcidid><orcidid>https://orcid.org/0000-0002-7348-2376</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | A549 Cells Aging - drug effects alveolar epithelial cells Alveoli Animals Arachidonic acid Arachidonic Acid - metabolism Bleomycin Cellular Senescence - drug effects Collagen Cyclin-dependent kinase inhibitor p21 Cyclooxygenase 2 - metabolism Cytochrome Cytochrome P450 Cytochromes P450 Disease Models, Animal Dose-Response Relationship, Drug dual COX‐2 and sEH inhibitor Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - pharmacology Epithelial cells Epithelial Cells - drug effects Epithelial Cells - metabolism Epoxide hydrolase Epoxide Hydrolases - antagonists & inhibitors Epoxide Hydrolases - metabolism Fibrosis Humans Inhibitors Injections, Subcutaneous INK4a protein Lung diseases Lungs Male Metabolic disorders Metabolites Mice Mice, Inbred C57BL p16 Protein p53 Protein Pathogenesis Prostaglandin endoperoxide synthase Pulmonary fibrosis Pulmonary Fibrosis - chemically induced Pulmonary Fibrosis - drug therapy Pulmonary Fibrosis - metabolism Senescence Staphylococcal enterotoxin H Structure-Activity Relationship Therapeutic applications Tumor Cells, Cultured |
| title | COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence |
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