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Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease
Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α i...
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| Published in: | American journal of physiology: Gastrointestinal and liver physiology 2016-10, Vol.311 (4), p.G688-G698 |
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| container_title | American journal of physiology: Gastrointestinal and liver physiology |
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| creator | Schmiedlin-Ren, Phyllissa Reingold, Laura J Broxson, Christopher S Rittershaus, Ahren C Brudi, Josh S Adler, Jeremy Owens, Scott R Zimmermann, Ellen M |
| description | Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α in a treatment paradigm. PG-PS or human serum albumin (HSA; control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNF-α or vehicle treatment was begun day (d)1, d7, or d14 postlaparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the percent decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as %decrease; gross abdominal score: d1 = 75% (P = 0.003), d7 = 57% (P = 0.18), d14 = no change (P = 0.99); histologic inflammation: d1 = 57% (P = 0.006), d7 = 50% (P = 0.019), d14 = no change (P = 0.99)]. This was also reflected in changes in IL-1β, IL-6, TNF-α, IGF-I, TGF-β1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNF-α beginning d1 or d7 compared with vehicle-treated rats; there was no effect if anti-TNF-α was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNF-α therapy is initiated early in the course of CD. |
| doi_str_mv | 10.1152/ajpgi.00216.2015 |
| format | article |
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However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α in a treatment paradigm. PG-PS or human serum albumin (HSA; control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNF-α or vehicle treatment was begun day (d)1, d7, or d14 postlaparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the percent decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as %decrease; gross abdominal score: d1 = 75% (P = 0.003), d7 = 57% (P = 0.18), d14 = no change (P = 0.99); histologic inflammation: d1 = 57% (P = 0.006), d7 = 50% (P = 0.019), d14 = no change (P = 0.99)]. This was also reflected in changes in IL-1β, IL-6, TNF-α, IGF-I, TGF-β1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNF-α beginning d1 or d7 compared with vehicle-treated rats; there was no effect if anti-TNF-α was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNF-α therapy is initiated early in the course of CD.</description><identifier>ISSN: 0193-1857</identifier><identifier>EISSN: 1522-1547</identifier><identifier>DOI: 10.1152/ajpgi.00216.2015</identifier><identifier>PMID: 27562059</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Antibodies, Monoclonal - therapeutic use ; Cecum - drug effects ; Cecum - metabolism ; Cecum - pathology ; Crohn Disease - drug therapy ; Crohn Disease - metabolism ; Crohn Disease - pathology ; Cytokines - metabolism ; Disease Models, Animal ; Fibrosis - drug therapy ; Fibrosis - metabolism ; Fibrosis - pathology ; Inflammation - drug therapy ; Inflammation - metabolism ; Inflammation - pathology ; Inflammation, Immunity, Fibrosis, and Infection ; Rats ; Time Factors ; Treatment Outcome ; Tumor Necrosis Factor-alpha - antagonists & inhibitors</subject><ispartof>American journal of physiology: Gastrointestinal and liver physiology, 2016-10, Vol.311 (4), p.G688-G698</ispartof><rights>Copyright © 2016 the American Physiological Society.</rights><rights>Copyright © 2016 the American Physiological Society 2016 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-1299a683e06522e81b7a2ada004adf55d01c2ea49e4c70ba2a2df7c925ca3a7a3</citedby><cites>FETCH-LOGICAL-c396t-1299a683e06522e81b7a2ada004adf55d01c2ea49e4c70ba2a2df7c925ca3a7a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27562059$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schmiedlin-Ren, Phyllissa</creatorcontrib><creatorcontrib>Reingold, Laura J</creatorcontrib><creatorcontrib>Broxson, Christopher S</creatorcontrib><creatorcontrib>Rittershaus, Ahren C</creatorcontrib><creatorcontrib>Brudi, Josh S</creatorcontrib><creatorcontrib>Adler, Jeremy</creatorcontrib><creatorcontrib>Owens, Scott R</creatorcontrib><creatorcontrib>Zimmermann, Ellen M</creatorcontrib><title>Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease</title><title>American journal of physiology: Gastrointestinal and liver physiology</title><addtitle>Am J Physiol Gastrointest Liver Physiol</addtitle><description>Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α in a treatment paradigm. PG-PS or human serum albumin (HSA; control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNF-α or vehicle treatment was begun day (d)1, d7, or d14 postlaparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the percent decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as %decrease; gross abdominal score: d1 = 75% (P = 0.003), d7 = 57% (P = 0.18), d14 = no change (P = 0.99); histologic inflammation: d1 = 57% (P = 0.006), d7 = 50% (P = 0.019), d14 = no change (P = 0.99)]. This was also reflected in changes in IL-1β, IL-6, TNF-α, IGF-I, TGF-β1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNF-α beginning d1 or d7 compared with vehicle-treated rats; there was no effect if anti-TNF-α was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNF-α therapy is initiated early in the course of CD.</description><subject>Animals</subject><subject>Antibodies, Monoclonal - therapeutic use</subject><subject>Cecum - drug effects</subject><subject>Cecum - metabolism</subject><subject>Cecum - pathology</subject><subject>Crohn Disease - drug therapy</subject><subject>Crohn Disease - metabolism</subject><subject>Crohn Disease - pathology</subject><subject>Cytokines - metabolism</subject><subject>Disease Models, Animal</subject><subject>Fibrosis - drug therapy</subject><subject>Fibrosis - metabolism</subject><subject>Fibrosis - pathology</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - metabolism</subject><subject>Inflammation - pathology</subject><subject>Inflammation, Immunity, Fibrosis, and Infection</subject><subject>Rats</subject><subject>Time Factors</subject><subject>Treatment Outcome</subject><subject>Tumor Necrosis Factor-alpha - antagonists & inhibitors</subject><issn>0193-1857</issn><issn>1522-1547</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNpVkU9v1DAQxS0EapfSOyfkGxyaxePE-XNBqlaUVqrgUs7WJJlsXGXtxXZK92PxRfhMeNttVU6WZt57nqcfY-9BLAGU_Iy327VZCiGhXEoB6hVbpLHMQBXVa7YQ0OQZ1Ko6Zm9DuBVCKAlwxI5lpUopVLNg9-c2muzm-8XfPxynSD7wOBK3GGePEx9NiM7vuBs43W_Jmw3ZmOYr70b7MfDeBMJA3FjuMQb-eyTLW1rPlhP6aXfG2zly6yKfMNLZXnewvGNvBpwCnR7eE_bz4uvN6jK7_vHtanV-nXV5U8YMZNNgWeckylSMamgrlNijEAX2g1K9gE4SFg0VXSXatJP9UHWNVB3mWGF-wr485m7ndkN9l-5PxfQ2VUG_0w6N_n9jzajX7k4rKCQ0MgV8OgR492umEPXGhI6mCS25OWioc5VXqqjLJBWP0s67EDwNz9-A0Htg-gGYfgCm98CS5cPL854NT4Tyf78KlVQ</recordid><startdate>20161001</startdate><enddate>20161001</enddate><creator>Schmiedlin-Ren, Phyllissa</creator><creator>Reingold, Laura J</creator><creator>Broxson, Christopher S</creator><creator>Rittershaus, Ahren C</creator><creator>Brudi, Josh S</creator><creator>Adler, Jeremy</creator><creator>Owens, Scott R</creator><creator>Zimmermann, Ellen M</creator><general>American Physiological Society</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><scope>5PM</scope></search><sort><creationdate>20161001</creationdate><title>Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease</title><author>Schmiedlin-Ren, Phyllissa ; Reingold, Laura J ; Broxson, Christopher S ; Rittershaus, Ahren C ; Brudi, Josh S ; Adler, Jeremy ; Owens, Scott R ; Zimmermann, Ellen M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-1299a683e06522e81b7a2ada004adf55d01c2ea49e4c70ba2a2df7c925ca3a7a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antibodies, Monoclonal - therapeutic use</topic><topic>Cecum - drug effects</topic><topic>Cecum - metabolism</topic><topic>Cecum - pathology</topic><topic>Crohn Disease - drug therapy</topic><topic>Crohn Disease - metabolism</topic><topic>Crohn Disease - pathology</topic><topic>Cytokines - metabolism</topic><topic>Disease Models, Animal</topic><topic>Fibrosis - drug therapy</topic><topic>Fibrosis - metabolism</topic><topic>Fibrosis - pathology</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - metabolism</topic><topic>Inflammation - pathology</topic><topic>Inflammation, Immunity, Fibrosis, and Infection</topic><topic>Rats</topic><topic>Time Factors</topic><topic>Treatment Outcome</topic><topic>Tumor Necrosis Factor-alpha - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schmiedlin-Ren, Phyllissa</creatorcontrib><creatorcontrib>Reingold, Laura J</creatorcontrib><creatorcontrib>Broxson, Christopher S</creatorcontrib><creatorcontrib>Rittershaus, Ahren C</creatorcontrib><creatorcontrib>Brudi, Josh S</creatorcontrib><creatorcontrib>Adler, Jeremy</creatorcontrib><creatorcontrib>Owens, Scott R</creatorcontrib><creatorcontrib>Zimmermann, Ellen M</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of physiology: Gastrointestinal and liver physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schmiedlin-Ren, Phyllissa</au><au>Reingold, Laura J</au><au>Broxson, Christopher S</au><au>Rittershaus, Ahren C</au><au>Brudi, Josh S</au><au>Adler, Jeremy</au><au>Owens, Scott R</au><au>Zimmermann, Ellen M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease</atitle><jtitle>American journal of physiology: Gastrointestinal and liver physiology</jtitle><addtitle>Am J Physiol Gastrointest Liver Physiol</addtitle><date>2016-10-01</date><risdate>2016</risdate><volume>311</volume><issue>4</issue><spage>G688</spage><epage>G698</epage><pages>G688-G698</pages><issn>0193-1857</issn><eissn>1522-1547</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α in a treatment paradigm. PG-PS or human serum albumin (HSA; control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNF-α or vehicle treatment was begun day (d)1, d7, or d14 postlaparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the percent decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as %decrease; gross abdominal score: d1 = 75% (P = 0.003), d7 = 57% (P = 0.18), d14 = no change (P = 0.99); histologic inflammation: d1 = 57% (P = 0.006), d7 = 50% (P = 0.019), d14 = no change (P = 0.99)]. This was also reflected in changes in IL-1β, IL-6, TNF-α, IGF-I, TGF-β1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNF-α beginning d1 or d7 compared with vehicle-treated rats; there was no effect if anti-TNF-α was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNF-α therapy is initiated early in the course of CD.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>27562059</pmid><doi>10.1152/ajpgi.00216.2015</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | American journal of physiology: Gastrointestinal and liver physiology, 2016-10, Vol.311 (4), p.G688-G698 |
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| subjects | Animals Antibodies, Monoclonal - therapeutic use Cecum - drug effects Cecum - metabolism Cecum - pathology Crohn Disease - drug therapy Crohn Disease - metabolism Crohn Disease - pathology Cytokines - metabolism Disease Models, Animal Fibrosis - drug therapy Fibrosis - metabolism Fibrosis - pathology Inflammation - drug therapy Inflammation - metabolism Inflammation - pathology Inflammation, Immunity, Fibrosis, and Infection Rats Time Factors Treatment Outcome Tumor Necrosis Factor-alpha - antagonists & inhibitors |
| title | Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease |
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