Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis
Bleomycin (BLM) induced lung injury is detectable in C57BL/6 mice using magnetic resonance imaging (MRI). We investigated the effects of the fibroblast activation protein (FAP) inhibitor, PT100, in this model. BLM (0.5mg/kg/day) was administered on days −7, −6, −5, −2, −1, 0 in the nostrils of male...
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| description | Bleomycin (BLM) induced lung injury is detectable in C57BL/6 mice using magnetic resonance imaging (MRI). We investigated the effects of the fibroblast activation protein (FAP) inhibitor, PT100, in this model. BLM (0.5mg/kg/day) was administered on days −7, −6, −5, −2, −1, 0 in the nostrils of male mice. PT100 (40µg/mouse) or vehicle (0.9%NaCl) was dosed per os twice daily from day 1–14. MRI was performed before BLM and at days 0, 7 and 14. After the last MRI acquisition, animals were euthanised and the lungs harvested for histological and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. As evidenced longitudinally by MRI, the BLM-elicited lesions in the lungs of vehicle-treated mice progressed over time. In contrast, responses elicited by BLM did not progress in animals receiving PT100. Histology demonstrated significant less fibrosis in PT100- than in vehicle-treated, BLM-challenged mice. Significant correlation (R=0.91, P |
| doi_str_mv | 10.1016/j.ejphar.2017.05.022 |
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Lung MRI of spontaneously breathing mice to assess the effect of the fibroblast activation protein inhibitor, PT100. Axial multislice images through the chest of a saline-challenged, vehicle-treated animal and two bleomycin (BLM)-challenged mice, treated either with vehicle or PT100 from day 1 until the end of the study. Images were acquired at day 14 after last saline or BLM dosing. Vessels are indicated by white arrows, and BLM-induced lesions by red arrows. [Display omitted]</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2017.05.022</identifier><identifier>PMID: 28506908</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Animals ; Bleomycin (BLM) ; Bleomycin - adverse effects ; Body Weight - drug effects ; Boronic Acids - pharmacology ; Boronic Acids - therapeutic use ; Dipeptides - pharmacology ; Dipeptides - therapeutic use ; Disease Models, Animal ; Fibroblast activation protein (FAP) ; Fibrosis ; Gelatinases - antagonists & inhibitors ; Gene Expression Regulation - drug effects ; Lung ; Magnetic Resonance Imaging ; Magnetic resonance imaging (MRI) ; Male ; Membrane Proteins - antagonists & inhibitors ; Mice, Inbred C57BL ; PT100 ; Pulmonary Fibrosis - diagnostic imaging ; Pulmonary Fibrosis - drug therapy ; Pulmonary Fibrosis - genetics ; Serine Endopeptidases</subject><ispartof>European journal of pharmacology, 2017-08, Vol.809, p.64-72</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-6b2995997297ddcb699bd46b34a8f3869a18f7b30d0c377028a479090b36c9cf3</citedby><cites>FETCH-LOGICAL-c362t-6b2995997297ddcb699bd46b34a8f3869a18f7b30d0c377028a479090b36c9cf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0014299917303424$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28506908$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Egger, Christine</creatorcontrib><creatorcontrib>Cannet, Catherine</creatorcontrib><creatorcontrib>Gérard, Christelle</creatorcontrib><creatorcontrib>Suply, Thomas</creatorcontrib><creatorcontrib>Ksiazek, Iwona</creatorcontrib><creatorcontrib>Jarman, Elizabeth</creatorcontrib><creatorcontrib>Beckmann, Nicolau</creatorcontrib><title>Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>Bleomycin (BLM) induced lung injury is detectable in C57BL/6 mice using magnetic resonance imaging (MRI). We investigated the effects of the fibroblast activation protein (FAP) inhibitor, PT100, in this model. BLM (0.5mg/kg/day) was administered on days −7, −6, −5, −2, −1, 0 in the nostrils of male mice. PT100 (40µg/mouse) or vehicle (0.9%NaCl) was dosed per os twice daily from day 1–14. MRI was performed before BLM and at days 0, 7 and 14. After the last MRI acquisition, animals were euthanised and the lungs harvested for histological and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. As evidenced longitudinally by MRI, the BLM-elicited lesions in the lungs of vehicle-treated mice progressed over time. In contrast, responses elicited by BLM did not progress in animals receiving PT100. Histology demonstrated significant less fibrosis in PT100- than in vehicle-treated, BLM-challenged mice. Significant correlation (R=0.91, P<0.001, N=24) was found between the volumes of BLM-induced lesions detected in vivo by MRI and the collagen content determined histologically (picrosirius staining). FAP was overexpressed in the lungs of BLM-challenged mice. Upon PT100 treatment, FAP expression was reduced. Significant differences in the MMP-12, MIP-1α, and MCP-3 mRNA expression levels in the lungs of PT100- compared to vehicle-treated mice were also revealed by qRT-PCR. The IBA-1 level determined histologically was higher in the lungs of PT100- compared to vehicle-treated mice. Taken together, these observations suggest that treatment with PT100 in this murine model of pulmonary fibrosis had an anti-fibro-proliferative effect and increased macrophage activation.
Lung MRI of spontaneously breathing mice to assess the effect of the fibroblast activation protein inhibitor, PT100. Axial multislice images through the chest of a saline-challenged, vehicle-treated animal and two bleomycin (BLM)-challenged mice, treated either with vehicle or PT100 from day 1 until the end of the study. Images were acquired at day 14 after last saline or BLM dosing. Vessels are indicated by white arrows, and BLM-induced lesions by red arrows. [Display omitted]</description><subject>Animals</subject><subject>Bleomycin (BLM)</subject><subject>Bleomycin - adverse effects</subject><subject>Body Weight - drug effects</subject><subject>Boronic Acids - pharmacology</subject><subject>Boronic Acids - therapeutic use</subject><subject>Dipeptides - pharmacology</subject><subject>Dipeptides - therapeutic use</subject><subject>Disease Models, Animal</subject><subject>Fibroblast activation protein (FAP)</subject><subject>Fibrosis</subject><subject>Gelatinases - antagonists & inhibitors</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Lung</subject><subject>Magnetic Resonance Imaging</subject><subject>Magnetic resonance imaging (MRI)</subject><subject>Male</subject><subject>Membrane Proteins - antagonists & inhibitors</subject><subject>Mice, Inbred C57BL</subject><subject>PT100</subject><subject>Pulmonary Fibrosis - diagnostic imaging</subject><subject>Pulmonary Fibrosis - drug therapy</subject><subject>Pulmonary Fibrosis - genetics</subject><subject>Serine Endopeptidases</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1r3DAQxUVJabZp_4MSdMwhdkfyhzyXQgjbDwi0h_QsJFlitdjWRpID_e-rxWmPOQ0Mb9578yPkE4OaAes_H2t7PB1UrDkwUUNXA-dvyI4NAisQjF-QHQBrK46Il-R9SkcA6JB378glHzroEYYdcXvnrMmJBkfzwVLndQx6UilTZbJ_VtmHhZ5iyNYv1C8Hr30O8Zb-emQAt2VDFZ3X6BdL5zDa6Wx0Wqc5LCr-2eySTx_IW6emZD--zCvy--v-8f579fDz24_7u4fKND3PVa9L2w5RcBTjaHSPqMe2102rBtcMPSo2OKEbGME0QgAfVCsQEHTTGzSuuSI3m29p_LTalOXsk7HTpBYb1iTZgNhCW0KKtN2kpjRM0Tp5in4upSUDeSYsj3IjLM-EJXSyEC5n1y8Jq57t-P_oH9Ii-LIJbPnz2dsok_F2MXb0sZCWY_CvJ_wFekWOAw</recordid><startdate>20170815</startdate><enddate>20170815</enddate><creator>Egger, Christine</creator><creator>Cannet, Catherine</creator><creator>Gérard, Christelle</creator><creator>Suply, Thomas</creator><creator>Ksiazek, Iwona</creator><creator>Jarman, Elizabeth</creator><creator>Beckmann, Nicolau</creator><general>Elsevier B.V</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>7X8</scope></search><sort><creationdate>20170815</creationdate><title>Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis</title><author>Egger, Christine ; Cannet, Catherine ; Gérard, Christelle ; Suply, Thomas ; Ksiazek, Iwona ; Jarman, Elizabeth ; Beckmann, Nicolau</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-6b2995997297ddcb699bd46b34a8f3869a18f7b30d0c377028a479090b36c9cf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Bleomycin (BLM)</topic><topic>Bleomycin - adverse effects</topic><topic>Body Weight - drug effects</topic><topic>Boronic Acids - pharmacology</topic><topic>Boronic Acids - therapeutic use</topic><topic>Dipeptides - pharmacology</topic><topic>Dipeptides - therapeutic use</topic><topic>Disease Models, Animal</topic><topic>Fibroblast activation protein (FAP)</topic><topic>Fibrosis</topic><topic>Gelatinases - antagonists & inhibitors</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Lung</topic><topic>Magnetic Resonance Imaging</topic><topic>Magnetic resonance imaging (MRI)</topic><topic>Male</topic><topic>Membrane Proteins - antagonists & inhibitors</topic><topic>Mice, Inbred C57BL</topic><topic>PT100</topic><topic>Pulmonary Fibrosis - diagnostic imaging</topic><topic>Pulmonary Fibrosis - drug therapy</topic><topic>Pulmonary Fibrosis - genetics</topic><topic>Serine Endopeptidases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Egger, Christine</creatorcontrib><creatorcontrib>Cannet, Catherine</creatorcontrib><creatorcontrib>Gérard, Christelle</creatorcontrib><creatorcontrib>Suply, Thomas</creatorcontrib><creatorcontrib>Ksiazek, Iwona</creatorcontrib><creatorcontrib>Jarman, Elizabeth</creatorcontrib><creatorcontrib>Beckmann, Nicolau</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Egger, Christine</au><au>Cannet, Catherine</au><au>Gérard, Christelle</au><au>Suply, Thomas</au><au>Ksiazek, Iwona</au><au>Jarman, Elizabeth</au><au>Beckmann, Nicolau</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2017-08-15</date><risdate>2017</risdate><volume>809</volume><spage>64</spage><epage>72</epage><pages>64-72</pages><issn>0014-2999</issn><eissn>1879-0712</eissn><abstract>Bleomycin (BLM) induced lung injury is detectable in C57BL/6 mice using magnetic resonance imaging (MRI). We investigated the effects of the fibroblast activation protein (FAP) inhibitor, PT100, in this model. BLM (0.5mg/kg/day) was administered on days −7, −6, −5, −2, −1, 0 in the nostrils of male mice. PT100 (40µg/mouse) or vehicle (0.9%NaCl) was dosed per os twice daily from day 1–14. MRI was performed before BLM and at days 0, 7 and 14. After the last MRI acquisition, animals were euthanised and the lungs harvested for histological and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. As evidenced longitudinally by MRI, the BLM-elicited lesions in the lungs of vehicle-treated mice progressed over time. In contrast, responses elicited by BLM did not progress in animals receiving PT100. Histology demonstrated significant less fibrosis in PT100- than in vehicle-treated, BLM-challenged mice. Significant correlation (R=0.91, P<0.001, N=24) was found between the volumes of BLM-induced lesions detected in vivo by MRI and the collagen content determined histologically (picrosirius staining). FAP was overexpressed in the lungs of BLM-challenged mice. Upon PT100 treatment, FAP expression was reduced. Significant differences in the MMP-12, MIP-1α, and MCP-3 mRNA expression levels in the lungs of PT100- compared to vehicle-treated mice were also revealed by qRT-PCR. The IBA-1 level determined histologically was higher in the lungs of PT100- compared to vehicle-treated mice. Taken together, these observations suggest that treatment with PT100 in this murine model of pulmonary fibrosis had an anti-fibro-proliferative effect and increased macrophage activation.
Lung MRI of spontaneously breathing mice to assess the effect of the fibroblast activation protein inhibitor, PT100. Axial multislice images through the chest of a saline-challenged, vehicle-treated animal and two bleomycin (BLM)-challenged mice, treated either with vehicle or PT100 from day 1 until the end of the study. Images were acquired at day 14 after last saline or BLM dosing. Vessels are indicated by white arrows, and BLM-induced lesions by red arrows. [Display omitted]</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>28506908</pmid><doi>10.1016/j.ejphar.2017.05.022</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Bleomycin (BLM) Bleomycin - adverse effects Body Weight - drug effects Boronic Acids - pharmacology Boronic Acids - therapeutic use Dipeptides - pharmacology Dipeptides - therapeutic use Disease Models, Animal Fibroblast activation protein (FAP) Fibrosis Gelatinases - antagonists & inhibitors Gene Expression Regulation - drug effects Lung Magnetic Resonance Imaging Magnetic resonance imaging (MRI) Male Membrane Proteins - antagonists & inhibitors Mice, Inbred C57BL PT100 Pulmonary Fibrosis - diagnostic imaging Pulmonary Fibrosis - drug therapy Pulmonary Fibrosis - genetics Serine Endopeptidases |
| title | Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis |
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