Impact of toll-like receptor 4 on the severity of acute pancreatitis and pancreatitis-associated lung injury in mice
Impact of toll-like receptor 4 on the severity of acute pancreatitis and pancreatitis-associated lung injury in mice
复制标题
DOI：
10.1136/gut.2008.170423
复制
发表时间：
2009-06-01
期刊：
影响因子：
24.5
通讯作者：
Saluja, A.
中科院分区：
文献类型：
--
作者：
Sharif, R.;Dawra, R.;Saluja, A.
背景与目的：急性胰腺炎是一种腺泡细胞损伤、炎性细胞因子快速产生和释放的炎症性疾病，在胰腺局部炎症和全身并发症中起主导作用。Toll样受体4(TLR4)与脂多糖(LPS)相互作用时，启动一条复杂的信号通路，最终导致促炎反应。我们假设TLR4在急性胰腺炎的病理生理学中是重要的，独立于内毒素。采用两种不同的急性胰腺炎模型，研究TLR4或其辅受体CD14基因缺失对急性胰腺炎进展和严重程度的影响。方法：分别给予野生型、TLR4(-/-)和CD14(-/-)小鼠雨蛙素或L精氨酸诱导急性胰腺炎。对照组小鼠接受生理盐水注射。通过检测血清淀粉酶活性、定量测定胰腺组织髓过氧化物酶活性和组织学评价腺泡细胞损伤程度来判断急性胰腺炎的严重程度。结果：野生型小鼠给予雨蛙素和L精氨酸可导致急性胰腺炎(表现为高淀粉酶血症、水肿、胰腺髓过氧化物酶活性升高和胰腺坏死)及相关的肺损伤。对TLR4(-/-)或CD14(-/-)小鼠进行同样的治疗，可以显著减轻严重的急性胰腺炎，并减少肺损伤。我们在血液或胰腺组织中没有发现细菌或内毒素的证据。结论：缺乏TLR4或CD14受体的小鼠急性胰腺炎的严重程度得到改善。此外，这些结果表明，在急性胰腺炎的发展过程中，TLR4在不依赖于内毒素的情况下具有显著的促炎作用。
Background and Aims: Acute pancreatitis is an inflammatory disease involving acinar cell injury, and the rapid production and release of inflammatory cytokines, which play a dominant role in local pancreatic inflammation and systemic complications. Toll-like receptor 4 (TLR4) initiates a complex signalling pathway when it interacts with lipopolysaccharide (LPS), which ultimately results in a proinflammatory response. We hypothesised that TLR4 is important in the pathophysiology of acute pancreatitis, independently of LPS. Using two different models of acute pancreatitis, we investigated how genetic deletion of TLR4 or its co-receptor CD14 effects its progression and severity.Methods: We induced acute pancreatitis by administering either caerulein or L-arginine to wild-type, TLR4(-/-), and CD14(-/-) mice. Control mice received normal saline injections. The severity of acute pancreatitis was determined by measuring serum amylase activity, quantifying myeloperoxidase (MPO) activity in the pancreatic tissue, and histologically assessing acinar cell injury.Results: It was found that administering caerulein and L-arginine to wild-type mice resulted in acute pancreatitis (as assessed by hyperamylasaemia, oedema, increased pancreatic MPO activity, and pancreatic necrosis) and associated lung injury. The same treatment to TLR4(-/-) or CD14(-/-) mice resulted in significantly less severe acute pancreatitis, and reduced lung injury. We found no evidence of either bacteria or LPS in the blood or in pancreatic tissue.Conclusions: The severity of acute pancreatitis is ameliorated in mice that lack either TLR4 or CD14 receptors. Furthermore, these results indicate that TLR4 plays a significant pro-inflammatory role independently of LPS in the progression of acute pancreatitis.