Progression and variability of TNBS colitis-associated inflammation in rats assessed by contrast-enhanced and T2-weighted MRI.
BACKGROUND
A common feature of preclinical models of colitis is that the time-course, magnitude, and persistence of inflammation vary considerably within the experimental animal group. Accordingly, noninvasive, serial quantification of colonic inflammation could advantageously guide dosing regimens and assess drug efficacy, thus enhancing the value of colitis models in research. This investigation using magnetic resonance imaging (MRI) was therefore undertaken to objectively determine inflammatory progression, variability, and response to therapy associated with trinitrobenzene sulfonic acid (TNBS)-induced colitis in Wistar rats.


METHODS
Rats underwent TNBS treatment on Day 0 and received sulfasalazine or vehicle (methylcellulose) orally, daily, from Day -1 (prophylactically) or Day 2 (therapeutically). T2-weighted and semidynamic T1-weighted contrast-enhanced MRI (CE-MRI) was repeated over 7-10 days to measure colon wall thickness and perfusion-related aspects of inflammation. Rectal bleeding, stool consistency, and disease activity were scored throughout and colon pathology determined terminally.


RESULTS
Principal component analysis of the CE-MRI time-series highlighted colon wall and mesenteric inflammation, which increased by 6-8x naïve values. Peristaltic artifacts were distinguished from perfusion changes using the normalized temporal standard deviation. MRI correlated strongly with terminal colon weight (mean correlation r = 0.8), well with body weight change (r = -0.7), but little with conventional clinical scores. Sulfasalazine reduced inflammation administered prophylactically and therapeutically.


CONCLUSIONS
Inflammation and therapeutic efficacy can be sensitively quantified noninvasively using MRI in TNBS-treated rats. This methodology provides unique and objective in vivo measures of inflammation that can guide dosing strategies, enhancing colitis research effectiveness and the assessment of potential IBD therapeutics.
Pohlmann
Andreas
A
Preclinical MRI Centre, Immuno-Inflammation Centre of Excellence in Drug Discovery, GlaxoSmithKline R&D, Harlow, UK.
Tilling
Lorna C
LC
Robinson
Alison
A
Woolmer
Olga
O
McCleary
Scott
S
Kruidenier
Laurens
L
Warnock
Linda C
LC
Lewis
Huw D
HD
Hobson
Anthony R
AR
James
Michael F
MF
D018685:Anesthetics, Inhalation; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D003106:Colon / Q000276:immunology* / Q000473:pathology*; D003287:Contrast Media; D004195:Disease Models, Animal; D018450:Disease Progression; D005765:Gastrointestinal Agents / Q000494:pharmacology; D007530:Isoflurane; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D012460:Sulfasalazine / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D018685:Anesthetics, Inhalation; D003287:Contrast Media; D005765:Gastrointestinal Agents; D012460:Sulfasalazine; D014302:Trinitrobenzenesulfonic Acid; D007530:Isoflurane