Kupffer-cell depletion attenuates colonic and extracolonic granulomatous inflammation in chronic colitis.
Intramural injection of peptidoglycan-polysaccharide polymers into the distal colon in rats induces granulomatous colitis associated with extracolonic manifestations. We sought to clarify the effects of Kupffer-cell depletion induced by the intravenous administration of gadolinium on colonic and extracolonic inflammation in this model. The effects of Kupffer-cell depletion on acute and chronic inflammation were evaluated 3 days and 3 weeks after injection of peptidoglycan-polysaccharide, respectively. We assessed the effects of gadolinium on colonic cytokine levels in vivo and the viability of elicited peritoneal macrophages and peptidoglycan-polysaccharide-induced production of nitrite, an indirect index of nitric oxide production, by these cells in vitro. A single injection of gadolinium caused a marked decrease in the number of Kupffer cells stained with antibodies within 3 days. Gadolinium treatment did not alter acute inflammation at 3 days. Repeated treatment with gadolinium dramatically attenuated grossly observed chronic inflammation, including thickening of colon wall, hepatic and splenic nodules, and swelling of foot joints; and significantly reduced the proportional areas occupied by granulomas in the colon, liver, and spleen at 3 weeks. These protective effects were reflected in significant reduction in colon and liver weights; gross scores; colonic myeloperoxidase activity, an indirect quantitative index of granulocyte infiltration; colonic interleukin-1beta levels; plasma nitrite and nitrate levels; and decreased tendency toward arthritis. Although gadolinium did not cause injury in elicited peritoneal macrophages in vitro, the compound dose-dependently attenuated peptidoglycan-polysaccharide-induced production of nitrite by these cells. Chronic Kupffer-cell depletion attenuates peptidoglycan-polysaccharide-induced granulomatous inflammation in the colon, liver, and spleen and reduces the incidence of arthritis, possibly by suppressing the production of interleukin-1beta and nitric oxide.
Yamada
Tamaki
T
Department of Comprehensive Medicine, Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan. yamtmaki@med.nagoya-cu.ac.jp
Takahashi
Satoru
S
Masuda
Kazuhiko
K
Ohara
Hirotaka
H
Nakazawa
Takahiro
T
Sano
Hitoshi
H
Ando
Tomoaki
T
Nakamura
Soichi
S
Kobayashi
Shinya
S
Kuno
Atsushi
A
Aoki
Shigeru
S
Nomura
Tomoyuki
T
Joh
Takashi
T
Itoh
Makoto
M
D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000473:pathology / Q000628:therapy*; D003106:Colon / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005682:Gadolinium / Q000627:therapeutic use*; D006099:Granuloma / Q000517:prevention & control*; D007249:Inflammation / Q000517:prevention & control*; D007375:Interleukin-1 / Q000032:analysis; D007728:Kupffer Cells / Q000502:physiology*; D008099:Liver / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis; D010457:Peptidoglycan / Q000633:toxicity; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007375:Interleukin-1; D010457:Peptidoglycan; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D005682:Gadolinium