The Effects of Heme Oxygenase-1 on Collagen Induced Arthritis Model / 대한해부학회지

Heme oxygenase-1 (HO-1), an inducible heme-degrading enzyme, is expressed by macrophages and endothelial cells in response to inflammatory stresses. It has been known to show strong immunosuppressive properties although its mechanisms are not completely understood. This study was designed to determine the effects of HO-1 modulation on collagen induced arthritis (CIA) model. CIA model was induced by subcutaneous injection of collagen on tail of DBA/1J mice. For evaluation of HO-1 effects, an inducer of HO-1, cobalt protoporphyrin IX (CoPPIX), or an inhibitor of HO-1, tin protoporphyrin IX (SnPPIX), were administered every other days into peritoneal cavity from day 1 to day 42 after CIA induction. The macrocopic clinical findings of CIA were evaluated and histo-pathologic findings and radiographic analysis were carried out. The expressions of TNF-alpha, IL-6, and VEGF which have important roles in pathogenesis of rheumatoid arthritis were observed by immuno-histochemical staining. Collagen on DBA/1J mice induced arthritis at knee joint and ankle joint. Administration of CoPPIX significantly aggravated the severity of arthritis while SnPPIX protected collagen induced arthritis. SnPPIX strongly suppressed inflammatory cell infiltration, swelling of synovial membrane, and erosion and destruction of bone on CIA mice. Furthermore subcutaneous injection of collagen also increased expression of TNF-alpha, IL-6, and VEGF which are important pro-inflammatory mediators in rheumatoid arthritis. SnPPIX suppressed expression of the pro-inflammatory mediators on CIA mice. Finally, we suggest that HO-1 mediates the expression of pro-inflammatory mediators and bone destruction during pathogenesis of CIA, which indicates modulation of HO-1 can be a new therapeutic target of rheumatoid arthritis.

CoPPIX Protects against TNBS Induced Colitis Through HO-1 Induction / 대한해부학회지

Crohn`s disease is a severe chronic inflammation that is treated mainly by immunosuppression, which often has serious side effects. There is a need to develop new drugs for treating this disease that have few side effects. Heme oxygenase-1 (HO-1) has immunosuppressive properties, but the mechanism of its anti-inflammatory actions is unclear. We investigated the protective effects of HO-1 on trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. An HO-1 inducer, cobalt protoporphyrin IX (CoPPIX), dramatically improved the clinical and histopathological symptoms in TNBS-induced colitis. CoPPIX suppressed tumor necrosis factor-alpha and interleukin-1beta expression and down-regulated the nuclear transcription factor kappa B activity caused by TNBS. The vehicle copper protoporphyrin IX (CuPPIX) failed to duplicate the protective effects seen with CoPPIX. Moreover, an inhibitor of HO-1 activity-zinc protoporphyrin IX-reversed the protective effects of CoPPIX on TNBS-induced colitis. In conclusion CoPPIX protects against TNBS-induced colonic damage by inducing HO-1, which might be an important target in the treatment of Crohn`s disease.