| Lupus nephritis (immune-mediated nephritis) is a common complication of systemic lupus erythematosus (SLE). It is now clear that multiple and independent mechanisms contribute to disease onset and pathogenesis, which may explain the remarkable phenotypic and histopathological heterogeneity observed in human SLE. Identification and characterization of disease-relevant autoantibodies, cellular effectors, and soluble immune elements have provided crucial insight into the immunologic interactions that promote renal immune injury. It is now clear that nephritogenic autoantibodies of diverse specificity localize to the kidney by a variety of mechanisms. They are accompanied by activated macrophages and T cells recruited in part through enhanced and abnormal production of macrophage growth factors and cytokines. These pathways provide novel targets for therapeutic intervention to prevent or amelioratethe aggressive autoimmune nephritis that characterizes SLE.The enzyme cyclooxygenase ( COX ) catalyzes the first step of the synthesis of prostanoids by converting arachidonic acid into prostaglandin H2, which is the common substrate for specific prostaglandin synthases. COX consists of two distinct isoforms: constitutive COX-1, constitutively expressed as a "housekeeping" enzyme in most tissues, mediates physiological responses (e.g., cytoprotection of the stomach, platelet aggregation) and inducible COX-2, expressed by cells that are involved in inflammation(e.g., macrophages, monocytes, synoviocytes), which can be up-regulated by various proinflammatory agents, including lipopolysaccharide, cytokines, and growth factors. In renal cortex, COX-2 expression is localized in the macula densa and the cortical thick ascending limb of Henle (cTALH) cells. COX-2 plays a role in physiological renal functions. It regulates glomerular blood flow and rennin release and becomes up-regulated by sodium restriction. In kidneies of patients with active lupus nephritis, the expression of COX-2 isoenzyme is selectively up-regulated. Glomerular mesangial cells are key modulators of the inflammatory response in lupus nephritis. When activated, these cells secrete inflammatory mediators including NO and products of cyclooxygenase perpetuating the local inflammatory response. Alterations in PG production are known to occur in human and murine lupus nephritis. PGE2 and PGI2, vasodilators that increase glomerular filtration rate (GFR),are decreased in lupus nephritis, whereas thromboxane A2 which reduces GFR, is elevated. Thromboxane A2 (TXA2) has been implicated as a major mediator in that in mice as well as in patients with active lupus nephritis, renal TXA2 production increased and correlated with both proteinuria and the severity of renal pathological changes. This discloses a novel pathway of inflammatory injury in LN. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been commonly used to manage joint and muscle pain, fatigue, serositis, fevers and headache in patients with SLE since 1966. But for their potential heightened allergic responses, renal and GI toxicity, patients with SLE can be safely and effectively treated with COX-2 inhibitor. The rationale of using the COX-2 inhibitor is offered by findings of an increased production of TXB2 in kidney homogenate. The treatment of the COX-2 inhibitor remarkably affords preservation of renal function and structural injury, and delays the onset of proteinuria and ameliorats animal survival.Approaches to the treatment of lupus nephritis include immunosuppressants associated with anti-inflammatory drugs, mainly steroids, which, however, cause major side effects. COX-2 inhibitor will be effective in preventing progressive nephritis in LN. So COX-2 inhibitor can be an effective treatment of LN, with the obvious advantage of avoiding steroid-related toxicity. |
