Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis
Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice...
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| creator | Nakanishi, Takeo Hasegawa, Yoshitaka Mimura, Reo Wakayama, Tomohiko Uetoko, Yuka Komori, Hisakazu Akanuma, Shin-Ichi Hosoya, Ken-Ichi Tamai, Ikumi |
| description | Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis. |
| doi_str_mv | 10.1371/journal.pone.0123895 |
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The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0123895</identifier><identifier>PMID: 25923111</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alveoli ; Animal models ; Animal tissues ; Animals ; Bleomycin ; Bronchoalveolar Lavage Fluid ; Bronchus ; Cell surface ; Cells, Cultured ; Collagen ; Connective tissues ; Dinoprostone - analysis ; Dinoprostone - immunology ; Epithelial cells ; Fibrosis ; Gene Deletion ; Gene Expression Regulation ; Immunohistochemistry ; Inflammation ; Lung - drug effects ; Lung - immunology ; Lung - pathology ; Lung diseases ; Male ; Mice ; Mice, Inbred C57BL ; Organic Anion Transporters - analysis ; Organic Anion Transporters - genetics ; Organic Anion Transporters - immunology ; Phosphates ; Prostaglandin E2 ; Protein kinase C ; Pulmonary Fibrosis - chemically induced ; Pulmonary Fibrosis - genetics ; Pulmonary Fibrosis - immunology ; Pulmonary Fibrosis - pathology ; Rats, Wistar ; Respiratory tract ; RNA, Messenger - genetics ; Signaling ; Smad3 protein ; Substrates ; Transcription ; Transforming growth factor-b1 ; Transporter</subject><ispartof>PloS one, 2015-04, Vol.10 (4), p.e0123895-e0123895</ispartof><rights>2015 Nakanishi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Nakanishi et al 2015 Nakanishi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-8993d18d7eb6ce02387488c7d2711432ee063555a99b1a62388419e87ea381f93</citedby><cites>FETCH-LOGICAL-c592t-8993d18d7eb6ce02387488c7d2711432ee063555a99b1a62388419e87ea381f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414486/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414486/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25923111$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nakanishi, Takeo</creatorcontrib><creatorcontrib>Hasegawa, Yoshitaka</creatorcontrib><creatorcontrib>Mimura, Reo</creatorcontrib><creatorcontrib>Wakayama, Tomohiko</creatorcontrib><creatorcontrib>Uetoko, Yuka</creatorcontrib><creatorcontrib>Komori, Hisakazu</creatorcontrib><creatorcontrib>Akanuma, Shin-Ichi</creatorcontrib><creatorcontrib>Hosoya, Ken-Ichi</creatorcontrib><creatorcontrib>Tamai, Ikumi</creatorcontrib><title>Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.</description><subject>Alveoli</subject><subject>Animal models</subject><subject>Animal tissues</subject><subject>Animals</subject><subject>Bleomycin</subject><subject>Bronchoalveolar Lavage Fluid</subject><subject>Bronchus</subject><subject>Cell surface</subject><subject>Cells, Cultured</subject><subject>Collagen</subject><subject>Connective tissues</subject><subject>Dinoprostone - analysis</subject><subject>Dinoprostone - immunology</subject><subject>Epithelial cells</subject><subject>Fibrosis</subject><subject>Gene Deletion</subject><subject>Gene Expression Regulation</subject><subject>Immunohistochemistry</subject><subject>Inflammation</subject><subject>Lung - drug effects</subject><subject>Lung - immunology</subject><subject>Lung - pathology</subject><subject>Lung diseases</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Organic Anion Transporters - analysis</subject><subject>Organic Anion Transporters - genetics</subject><subject>Organic Anion Transporters - immunology</subject><subject>Phosphates</subject><subject>Prostaglandin E2</subject><subject>Protein kinase C</subject><subject>Pulmonary Fibrosis - chemically induced</subject><subject>Pulmonary Fibrosis - genetics</subject><subject>Pulmonary Fibrosis - immunology</subject><subject>Pulmonary Fibrosis - pathology</subject><subject>Rats, Wistar</subject><subject>Respiratory tract</subject><subject>RNA, Messenger - genetics</subject><subject>Signaling</subject><subject>Smad3 protein</subject><subject>Substrates</subject><subject>Transcription</subject><subject>Transforming growth factor-b1</subject><subject>Transporter</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptUk1v1DAUjBCIlsI_QBCJSzlk66_444JUVrSstFIrsRw4WY79ss0qsRc7Qeq_x-2mVYs42fKbN2_meYriPUYLTAU-24UpetMv9sHDAmFCpapfFMdYUVJxgujLJ_ej4k1KO4RqKjl_XRyRWhGKMT4ufl3HkEaz7Y13nS830fi0D3GEWJ5eX27OfqyXV-Qcfy4zbgQ7pnK8gXI9-W3ZxjCUX3sIw63tfLXybrLgyouuyZRdelu8ak2f4N18nhQ_L75tlt-r9dXlanm-rmwWMVZSKeqwdAIabgFlG4JJaYUjAmNGCQDitK5ro1SDDc91ybACKcBQiVtFT4qPB959H5Ket5I05oJzQghHGbE6IFwwO72P3WDirQ6m0_cPIW61iWNne9C0xrQluKmZsiwPaSQSDjVMAneAoM5cX-ZpUzOAs-DHaPpnpM8rvrvR2_BHM4YZkzwTnM4EMfyeII166JKFPn8AhOlet5BSEiEz9NM_0P-7YweUzWtPEdpHMRjpu6Q8dOm7pOg5Kbntw1Mjj00P0aB_AW2Jugk</recordid><startdate>20150429</startdate><enddate>20150429</enddate><creator>Nakanishi, Takeo</creator><creator>Hasegawa, Yoshitaka</creator><creator>Mimura, Reo</creator><creator>Wakayama, Tomohiko</creator><creator>Uetoko, Yuka</creator><creator>Komori, Hisakazu</creator><creator>Akanuma, Shin-Ichi</creator><creator>Hosoya, Ken-Ichi</creator><creator>Tamai, Ikumi</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150429</creationdate><title>Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis</title><author>Nakanishi, Takeo ; Hasegawa, Yoshitaka ; Mimura, Reo ; Wakayama, Tomohiko ; Uetoko, Yuka ; Komori, Hisakazu ; Akanuma, Shin-Ichi ; Hosoya, Ken-Ichi ; Tamai, Ikumi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-8993d18d7eb6ce02387488c7d2711432ee063555a99b1a62388419e87ea381f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alveoli</topic><topic>Animal models</topic><topic>Animal tissues</topic><topic>Animals</topic><topic>Bleomycin</topic><topic>Bronchoalveolar Lavage Fluid</topic><topic>Bronchus</topic><topic>Cell surface</topic><topic>Cells, Cultured</topic><topic>Collagen</topic><topic>Connective tissues</topic><topic>Dinoprostone - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nakanishi, Takeo</au><au>Hasegawa, Yoshitaka</au><au>Mimura, Reo</au><au>Wakayama, Tomohiko</au><au>Uetoko, Yuka</au><au>Komori, Hisakazu</au><au>Akanuma, Shin-Ichi</au><au>Hosoya, Ken-Ichi</au><au>Tamai, Ikumi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-04-29</date><risdate>2015</risdate><volume>10</volume><issue>4</issue><spage>e0123895</spage><epage>e0123895</epage><pages>e0123895-e0123895</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25923111</pmid><doi>10.1371/journal.pone.0123895</doi><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_1676622260 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alveoli Animal models Animal tissues Animals Bleomycin Bronchoalveolar Lavage Fluid Bronchus Cell surface Cells, Cultured Collagen Connective tissues Dinoprostone - analysis Dinoprostone - immunology Epithelial cells Fibrosis Gene Deletion Gene Expression Regulation Immunohistochemistry Inflammation Lung - drug effects Lung - immunology Lung - pathology Lung diseases Male Mice Mice, Inbred C57BL Organic Anion Transporters - analysis Organic Anion Transporters - genetics Organic Anion Transporters - immunology Phosphates Prostaglandin E2 Protein kinase C Pulmonary Fibrosis - chemically induced Pulmonary Fibrosis - genetics Pulmonary Fibrosis - immunology Pulmonary Fibrosis - pathology Rats, Wistar Respiratory tract RNA, Messenger - genetics Signaling Smad3 protein Substrates Transcription Transforming growth factor-b1 Transporter |
| title | Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-18T12%3A44%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Prostaglandin%20Transporter%20(PGT/SLCO2A1)%20Protects%20the%20Lung%20from%20Bleomycin-Induced%20Fibrosis&rft.jtitle=PloS%20one&rft.au=Nakanishi,%20Takeo&rft.date=2015-04-29&rft.volume=10&rft.issue=4&rft.spage=e0123895&rft.epage=e0123895&rft.pages=e0123895-e0123895&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0123895&rft_dat=%3Cproquest_plos_%3E3669859111%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1676622260&rft_id=info:pmid/25923111&rft_doaj_id=oai_doaj_org_article_3513f21b549c4e87b807d0b48e6de0e5&rfr_iscdi=true |