Sharif R, Dawra R, Wasiluk K, Phillips P, Dudeja V, Kurt-Jones E, Finberg R, Saluja A
Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA.
Gut. 2009 Jun;58(6):813-9. doi: 10.1136/gut.2008.170423. Epub 2009 Feb 6.
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.
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.
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.
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.
急性胰腺炎是一种涉及腺泡细胞损伤以及炎症细胞因子快速产生和释放的炎症性疾病，这些细胞因子在局部胰腺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）相互作用时会启动一条复杂的信号通路，最终导致促炎反应。我们推测TLR4在急性胰腺炎的病理生理学中起重要作用，且独立于LPS。我们使用两种不同的急性胰腺炎模型，研究了TLR4或其共受体CD14的基因缺失如何影响其进展和严重程度。
我们通过向野生型、TLR4基因敲除小鼠和CD14基因敲除小鼠注射雨蛙素或L-精氨酸来诱导急性胰腺炎。对照小鼠注射生理盐水。通过测量血清淀粉酶活性、定量胰腺组织中的髓过氧化物酶（MPO）活性以及组织学评估腺泡细胞损伤来确定急性胰腺炎的严重程度。
发现向野生型小鼠注射雨蛙素和L-精氨酸会导致急性胰腺炎（通过高淀粉酶血症、水肿、胰腺MPO活性增加和胰腺坏死评估）及相关的肺损伤。对TLR4基因敲除小鼠或CD14基因敲除小鼠进行相同处理后，急性胰腺炎的严重程度明显减轻，肺损伤也减轻。我们在血液或胰腺组织中未发现细菌或LPS的证据。
缺乏TLR4或CD14受体的小鼠急性胰腺炎严重程度有所改善。此外，这些结果表明TLR4在急性胰腺炎进展过程中独立于LPS发挥显著的促炎作用。
