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Impact of Toll-like Receptor 4 on the Severity of Acute Pancreatitis and Pancreatitis-Associated Lung Injury in Mice
  1. Rifat Sharif (ashok.saluja{at}
  1. University of Minnesota, United States
    1. Rajinder K Dawra (dawra001{at}
    1. University of Minnesota, United States
      1. Karen Wasiluk (wasil002{at}
      1. University of Minnesota, United States
        1. Phoebe Phillips (phillipsp{at}
        1. University of Minnesota, United States
          1. Vikas Dudeja (dudej001{at}
          1. University of Minnesota, United States
            1. Evelyn Kurt-Jones (evelyn.kurt-jones{at}
            1. Univ Mass Medical School, United States
              1. Robert Finberg (robert.finberg{at}
              1. Univ Mass Medical School, United States
                1. Ashok K Saluja (asaluja{at}
                1. University of Minnesota, United States


                  Background and aims: Acute pancreatitis (AP) 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 signaling pathway when it interacts with lipopolysaccharide (LPS), which ultimately results in a proinflammatory response. We hypothesized that TLR4 is important in the pathophysiology of AP, 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 AP by administering either caerulein or L-arginine to wild-type, TLR4 -/-, and CD14 -/- mice. Control mice received normal saline injections. The severity of AP was determined by measuring serum amylase activity, quantitating 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 (WT) mice resulted in AP (as assessed by hyperamylasemia, edema, increased pancreatic MPO activity, and pancreatic necrosis) and associated lung injury. The same treatment to TLR4 -/- or CD14 -/- mice resulted in significantly less severe AP, and reduced lung injury. We found no evidence of either bacteria or LPS in the blood or in pancreatic tissue.

                  Conclusions: The severity of AP 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 AP.

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