Low-dose radiotherapy (LD-RT) and the modulation of iNOS expression in adjuvant-induced arthritis in rats.
OBJECTIVE
Low-dose radiotherapy (LD-RT) of arthritic joints applied during the peak of the acute inflammatory response improves the clinical and histomorphological development of adjuvant arthritis. The study was undertaken to investigate the cellular composition of the inflammatory infiltrate and the expression of the pro-inflammatory and anti-inflammatory enzymes, inducible nitric oxide synthase (iNOS), cyclo-oxygenase 2 (COX-2) and haem-oxygenase 1 (HO-1), in response to LD-RT.


METHODS
Adjuvant arthritis in female Lewis rats was induced by intradermal injection of heat-inactivated mycobacterium tuberculosis on day 0. Both arthritic hind paws were sham irradiated (group 1) or X-irradiated with either 5 x 1.0 Gy (group 2) or 5 x 0.5 Gy (group 3) from days 15 to 19 after induction (15 animals/group). On days 21 (n=12 joints/group) and 30 (n=18 joints/group), cryostat sections were analysed histologically and immunohistologically after specific staining for macrophages, iNOS, COX-2 and HO-1.


RESULTS
A total of 5 x 1.0 Gy or 5 x 0.5 Gy led to a significant reduction of clinical symptoms from days 21 to 29, and a highly significant reduction of cartilage and bone destruction on day 30. Macrophage-positive areas could be detected continuously throughout the periarticular infiltrate, and were slightly reduced after LD-RT on days 21 and 30. This reduction was more pronounced after 5 x 1.0 Gy. Following LD-RT, the iNOS score was reduced by about 45-50% on days 21 (p<0.05) and 30 (p<0.001). In contrast, the HO-1 score was increased by about 50% on days 21 (p=0.08) and 30 (p=0.03).


CONCLUSIONS
The clinically and histologically observed prevention of the progression of adjuvant arthritis after LD-RT given during the peak of the acute inflammatory response and the reduction of cartilage and bone destruction in the chronic phase appears to be related to the modulation of iNOS activity by low X-ray doses.
Hildebrandt
G
G
Department of Radiotherapy and Radiooncology, University of Leipzig, Stephanstrasse 9a, D-04103 Leipzig, Germany. hilg@medizin.uni-leipzig.de
Radlingmayr
A
A
Rosenthal
S
S
Rothe
R
R
Jahns
J
J
Hindemith
M
M
Rödel
F
F
Kamprad
F
F
D000818:Animals; D000843:Ankle Joint / Q000201:enzymology* / Q000473:pathology / Q000528:radiation effects*; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy*; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy; D051546:Cyclooxygenase 2; D004307:Dose-Response Relationship, Radiation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007527:Isoenzymes / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011829:Radiation Dosage; D051381:Rats; D011917:Rats, Inbred Lew; D016896:Treatment Outcome
D007527:Isoenzymes; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases