Ho-Sam Chung

Metallothionein suppresses collagen‐induced arthritis via induction of TGF‐β and down‐regulation of proinflammatory mediators

Metallothionein is a low molecular weight, cysteine‐rich, stress response protein that can act as an antioxidant and as an immunosuppressive agent in instances of antigen‐dependent adaptive immunity. In this context, we assessed the therapeutic potential and mechanisms of action of metallothionein in a collagen‐induced arthritis model. Repeated administration of metallothionein‐I + II during the course of disease dramatically reduced the incidence and severity of the disease. Joint tissues isolated from boostered paws of metallothionein‐I + II‐treated mice expressed significantly reduced levels of proinflammatory mediators, such as tumour necrosis factor (TNF)‐α and cyclooxygenase‐2, when compared with those of control‐treated mice. Lymph node cells obtained from metallothionein‐I + II ‐injected mice exhibited a significant decrease in the proliferative response and a remarkable increase in tumour growth factor (TGF)‐β production in response to type II collagen. Taken together, these results suggest that metallothionein‐I + II promote the development of type II collagen‐specific, TGF‐β‐producing cells to antagonize the expansion of arthritogenic cells. This could lead to local suppression of inflammatory responses by inhibiting the expression of proinflammatory molecules. Thus, this study demonstrates the suppressive effects of metallothionein on collagen‐induced arthritis, and indicates that there may be a potential therapeutic application for manipulation of metallothionein during the treatment of autoimmune disorders.

Combined Therapy of Cilazapril and Losartan Has No Additive Effects in Ameliorating Adriamycin-Induced Glomerulopathy

Aims: Effects of the blockade of renin-angiotensin system (RAS), by angiotensin-converting enzyme inhibitor (ACEi), type 1 angiotensin II receptor blocker (ARB), or a combination of both, were evaluated in Adriamycin (ADR)-induced glomerulopathy. Methods: Male Sprague-Dawley rats (180–250 g) were induced of glomerulopathy by treatment with ADR (2 mg/kg, i.v.). Six weeks later, they were treated with cilazapril (1 mg/kg/day) and/or losartan (10 mg/kg/day) for an additional 6 weeks. Results: The urinary excretion of protein progressively increased following the treatment with ADR, which was prevented by ACEi, ARB, and a combination of both. Similarly, the glomerulopathy assessed by glomerulosclerosis index was also ameliorated by ACEi or ARB. However, combined therapy of both ACEi and ARB was without an additional effect (Control 1.4 ± 0.4%, ADR 10.7 ± 2.7%**, ACEi 0.8 ± 0.4%, ARB 2.6 ± 1.0%, ACEi+ARB 1.7 ± 1.5%, ** p < 0.01 vs. Control). The expression of transforming growth factor-β1 was increased following the treatment with ADR (1.4 ± 0.07-fold, p < 0.05 vs. Control), however, the degree of which was similarly blunted by either ACEi, ARB, or the combination of both. The expression of type 1 angiotensin II receptor mRNA increased following the treatment with ADR, the degree of which was further upregulated by ACEi and decreased by ARB to the control level (ADR 1.3 ± 0.06-fold*, ACEi 1.8 ± 0.05-fold***, ARB 1.0 ± 0.04-fold, * p < 0.05 and *** p < 0.001 vs. Control). The combined therapy of ACEi and ARB still showed an upregulation of type 1 angiotensin II receptor mRNA, however, of which degree was mitigated compared with that induced by ACEi alone (ACEi+ARB 1.5 ± 0.04-fold, ** p < 0.01 vs. Control). On the contrary, the expression of type 2 angiotensin II receptor mRNA was downregulated following the treatment with ADR, which was similarly restored to the control level by ACEi, ARB, and a combination of both (ADR 0.5 ± 0.08-fold**, ACEi 1.0 ± 0.06-fold, ARB 1.0 ± 0.05-fold, ACEi+ARB 1.0 ± 0.05-fold, ** p < 0.01 vs. Control). Conclusion: It is suggested that combined therapy of ACEi and ARB with relatively high or maximal doses of each drug has no additive or synergistic benefits on the progression of ADR-induced glomerulopathy. Effects of RAS blockade may in part be related to differential regulation of type 1 and type 2 angiotensin II receptors.