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
Main Authors: Schmiedlin-Ren, Phyllissa, Reingold, Laura J, Broxson, Christopher S, Rittershaus, Ahren C, Brudi, Josh S, Adler, Jeremy, Owens, Scott R, Zimmermann, Ellen M
Format: Article
Language:English
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
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Summary: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.
ISSN:0193-1857
1522-1547
DOI:10.1152/ajpgi.00216.2015