Nitric oxide production during adjuvant‐induced and collagen‐induced arthritis

Abstract

Objective. To investigate the role of nitric oxide (NO) production and NO synthase (NOS) induction during adjuvant-induced arthritis (AIA) and collageninduced arthritis (CIA) in Dark Agouti rats.Methods. Urinary nitrate excretion and immune NOS (iNOS) messenger RNA (mRNA) expression were measured in the joint, lymph node, spleen, and liver tissues following the induction of either AIA or CIA.Results. Urinary nitrate excretion and iNOS mRNA expression increased substantially during joint inflammation in both models of arthritis. However, the increases in urinary nitrate excretion and iNOS mRNA expression observed in the joint, liver, and spleen tissues during AIA were greater than those observed during CIA, although iNOS induction in the lymph nodes was similar for both models. A prior injection with Mycobacterium bovis heat-shock protein resulted in suppression of arthritis and NO production in AIA, but not in CIA.Conclusion. Differences in NO production during AIA versus CIA are a reflection of the fundamental pathophysiologic differences between these 2 models of arthritis. Thus, NO production in these 2 models could not be merely a nonspecific reaction to the adjuvant injection, nor simply a byproduct of local inflammation in the joint.Adjuvant-induced arthritis (AIA) and collageninduced arthritis (CIA) are different models of experi-..Supported by the VA Medical Research Program, the NIH (grants HL-40665 and HL-37615), the Nora Eccles Treadwell Foundation, and a University of Utah Research Grant.Grant W. Cannon, MD, Scott J. Openshaw, BS, John B. Hibbs, Jr., MD, John R. Hoidal, MD, Thomas P. Huecksteadt, Marie M. Griffiths, PhD: VA Medical Center, and the University of Utah, Salt Lake City.Address correspondence to Grant W. Cannon, MD, VAMC (llE), 500 Foothill Drive, Salt Lake City, UT 84148.Submitted for publication September 11, 1995; accepted in revised form May 1, 1996. mental arthritis that are induced by the injection of Freund's complete adjuvant (FCA) (1-12) or type I1 collagen (CII) (13-21), respectively. Although these 2 models have many clinical similarities, fundamental differences in their pathophysiology and genetic control are clearly evident. AIA is a particularly informative model because it predominantly involves T cell-mediated mechanisms (1-8), in contrast to CIA, which requires both humoral (14-20) and cellular immunity (21).Nitric oxide (NO), an unstable radical produced by the action of the enzyme NO synthase (NOS) on 1.-arginine, is a mediator of multiple physiologic functions and may also mediate local inflammation and tissue destruction (22-25). After its production and local action, NO is eventually oxidized to nitrate, which is inactive and excreted in the urine. Urinary nitrate can be reduced to nitrite, which, when measured by the Griess reaction, serves as an indirect measure of NO production (22). The induction of immunehflammatory NOS (iNOS) messenger RNA (mRNA) can be detected by polymerase chain reaction (PCR).Recent evaluations of NO synthesis in streptococcal cell wall...

Effects of NO Synthase Inhibitors on the Synovial Microcirculation in the Mouse Knee Joint

“…Subsequent animal studies confirmed these observations by showing that chondrocytes and synovial fibroblasts as well as extravasated neutrophils and macrophages express iNOS in chronic inflammatory joint diseases [2, 3]. In patients with joint inflammation, induction of iNOS was demonstrated in neutrophils, synovial fibroblasts, and chondrocytes [4, 5].…”

“…This would be the assumption for the therapeutic use of an iNOS inhibitor, which is suggested to be sufficient in experimental arthritis by a number of studies [3, 6, 10]. One supposed mechanism is that L-NIL suppresses intra-articular NO synthesis by the synovium and the cartilage, and thus protects the joint possible inflammatory and erosive effects of prolonged, excessive local production of NO.…”

PPA250 [3-(2,4-Difluorophenyl)-6-{2-[4-(1H-imidazol-1-ylmethyl) Phenoxy]ethoxy}-2-phenylpyridine], a Novel Orally Effective Inhibitor of the Dimerization of Inducible Nitric-Oxide Synthase, Exhibits an Anti-Inflammatory Effect in Animal Models of Chronic Arthritis

“…Collagen-induced arthritis in mice and adjuvant arthritis in rats are typical animal models of human chronic arthritis. The development of arthritis is accompanied by the induction of iNOS and subsequent NO production in these models (Stefanovic-Racic et al, 1994Connor et al, 1995;Cannon et al, 1996;Vermeire et al, 2000). Earlier studies in animal models have demonstrated that NO inhibitors have little curative effect after rheumatoid arthritis has developed (Stefanovic-Racic et al, 1995;Fletcher et al, 1998).…”

The Effects of Enterococcus faecium and Selenium on Methotrexate Treatment in Rat Adjuvant‐induced Arthritis

“…NO is involved in both initiation and development of AA in rats (Oyanagui, 1994). Moreover, inhibitors of NOS have been shown to suppress arthritis in several animal models (Stefanovic-Racic et al, 1995;Cannon et al, 1996) and increased NO levels have been found in patients with RA (Ueki et al, 1996). Omata et al (1997) …”