PubMed · 11555941
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T Murakami. 2001. [Hypersensitivity vasculitis].. https://pubmed.ncbi.nlm.nih.gov/11555941/
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BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may modulate cellular inflammatory functions independent of serum cholesterol. We tested the hypothesis that statins decrease respiratory burst activity of human polymorphonuclear neutrophils (PMN) in response to anti-neutrophil cytoplasmic antibodies (ANCA). METHODS: Neutrophils were isolated from healthy human volunteers, human immunoglobulins were isolated from patients with proteinase-3 (PR3)- and myeloperoxidase (MPO)-ANCA. Superoxide generation was measured by the ferricytochrome C assay and the nitro blue tetrazolium (NBT) test. ANCA antigen expression was measured by flow cytometry and phosphorylation of mitogen-activated protein kinase (MAPK) was assessed by Western blotting. RESULTS: Cerivastatin and simvastatin inhibited respiratory burst activity to ANCA dose-dependently (1 to 25 micromol/L). Tumor necrosis factor-alpha (TNF-alpha)-primed neutrophils released 26.7 +/- 2.8 nmol O2-/0.75 x 106 PMN/45 min and 10 micromol/L simvastatin reduced this amount to 18.0 +/- 2.1 nmol. The inhibitory effect was confirmed by the NBT test. The respiratory burst decrease could not be reversed by 500 micromol/L mevalonic acid (MVA). In this assay, both statins also inhibited the response to human ANCA. PR3-ANCA resulted in 19.4 +/- 2.0 nmol O2- nmol. This amount was decreased to 6.0 +/- 1.2 nmol by preincubation with 10 micromol/L simvastatin (P < 0.01). For MPO-ANCA, the values were 22.6 +/- 2.8 nmol for controls versus 16.7 +/- 3.1 nmol with statin (P < 0.01). By FACS, simvastatin decreased TNF-alpha-mediated ANCA antigen translocation (from 219 +/- 33 to 180 +/- 35 MFI for PR3 and 24.0 +/- 2.4 to 18.3 +/- 1.1 for MPO). Finally, since p38 MAPK and ERK control TNF-alpha priming, we studied the effects of both statins on MAPK. Western blotting showed that statins inhibited TNF-alpha-induced ERK phosphorylation in a dose dependent fashion, but had no effect on p38. CONCLUSION: These findings demonstrate that HMG-CoA reductase inhibitors decrease respiratory burst activity of human PMN in response to ANCA. This effect was independent of mevalonate, but involved inhibition of ERK activation during TNF-alpha priming. Our data suggest that HMG-CoA reductase inhibitors may help limit inflammatory responses.
This chapter is an overview of the literature on serological markers of inflammatory bowel diseases (IBD), focusing on anti-neutrophil cytoplasm autoantibodies (ANCA) and anti- Saccharomyces cerevisiae mannan antibodies (ASCA). The methodology for ANCA and ASCA testing is first introduced. The value of these markers as diagnostic tools is then discussed. Other chapters are devoted to the potential role of ANCA and ASCA in disease monitoring, disease stratification and as subclinical markers in families. Finally reviewed are other antibodies recently tested in clinical trials such as pancreatic antibodies and antibodies directed against bacterial antigens. The role of these antibodies in the pathophysiology of IBD still needs to be assessed. We also need to identify the ASCA immunogen(s) eliciting the antibody response.
Vasculitis is histologically defined by the presence of blood vessel inflammation. It can be observed in a wide variety of settings, either occurring secondarily to another process or as the pathologic foundation of a primary vasculitic disease. The primary systemic vasculitides comprise a broad group of disease entities that are uniquely identified by the nature of their clinical, histopathologic, or therapeutic characteristics. Individual diseases often predominantly affect blood vessels of a particular size, the pattern of which influences their clinical manifestations and has been used in their classification. The vasculitides span a wide range of disease severity, extending from illnesses that rarely produce death to those almost universally fatal before the introduction of effective therapy. Immunosuppressive and cytotoxic agents are used to treat many vasculitic diseases. Although such approaches can be effective, long-term treatment may be complicated by chronic sequelae from organ damage, disease relapses, and medication side effects. Recent investigations have focused on understanding the pathophysiology of these diseases, which may lead to more efficacious and less toxic therapeutic options.