Prophylactic inhibition of neutrophil elastase prevents the development of chronic neuropathic pain in osteoarthritic mice

被引:49
作者
Muley, Milind M.
Krustev, Eugene
Reid, Allison R.
McDougall, Jason J. [1 ]
机构
[1] Dalhousie Univ, Dept Pharmacol, 5850 Coll St,POB 15000, Halifax, NS B3H 4R2, Canada
来源
JOURNAL OF NEUROINFLAMMATION | 2017年 / 14卷
基金
加拿大健康研究院;
关键词
Neutrophil elastase; Proteinase-activated receptor-2; Inflammation; Osteoarthritis; Pain; Peripheral neuropathy; PROTEINASE-ACTIVATED RECEPTOR-2; CELL-ADHESION MOLECULE-1; THROMBIN RECEPTOR; MASS-SPECTROMETRY; NEURONAL INJURY; RAT MODEL; EXPRESSION; INFLAMMATION; CARTILAGE; DISEASE;
D O I
10.1186/s12974-017-0944-0
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background: A subset of osteoarthritis (OA) patients experience joint pain with neuropathic characteristics. Mediators such as neutrophil elastase, a serine proteinase, may be released during acute OA inflammatory flares. We have previously shown that local administration of neutrophil elastase causes joint inflammation and pain via activation of proteinase-activated receptor-2 (PAR2). The aim of this study was to examine the contribution of endogenous neutrophil elastase and PAR2 to the development of joint inflammation, pain, and neuropathy associated with monoiodoacetate (MIA)-induced experimental OA. Methods: MIA (0.3 mg/10 mu l) was injected into the right knee joint of male C57BL/6 mice (20-34 g). Joint inflammation (edema, leukocyte kinetics), neutrophil elastase proteolytic activity, tactile allodynia, and saphenous nerve demyelination were assessed over 14 days post-injection. The effects of inhibiting neutrophil elastase during the early inflammatory phase of MIA (days 0 to 3) were determined using sivelestat (50 mg/kg i.p.)and serpinA1 (10 mu g i.p.). Involvement of PAR2 in the development of MIA-induced joint inflammation and pain was studied using the PAR2 antagonist GB83 (5 mu g i.p. days 0 to 1) and PAR2 knockout animals. Results: MIA caused an increase in neutrophil elastase proteolytic activity on day 1 (P < 0.0001), but not on day 14. MIA also generated a transient inflammatory response which peaked on day 1 (P < 0.01) then subsided over the 2-week time course. Joint pain appeared on day 1 and persisted to day 14 (P < 0.0001). By day 14, the saphenous nerve showed signs of demyelination. Early treatment with sivelestat and serpinA1 blocked the proteolytic activity of neutrophil elastase on day 1 (P < 0.001), and caused lasting improvements in joint inflammation, pain, and saphenous nerve damage (P < 0.05). MIA-induced synovitis was reversed by early treatment with GB83 and attenuated in PAR2 knockout mice (P < 0.05). PAR2 knockout mice also showed reduced MIA-induced joint pain (P < 0.0001) and less nerve demyelination (P = 0.81 compared to saline control). Conclusions: Neutrophil elastase and PAR2 contribute significantly to the development of joint inflammation, pain, and peripheral neuropathy associated with experimental OA, suggesting their potential as therapeutic targets.
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页数:12
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