This Article Full Text Full Text (PDF) All Versions of this Article: 2005-0272OCv1 35/2/198    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matsuda, N. Articles by Hattori, Y. Search for Related Content PubMed PubMed Citation Articles by Matsuda, N. Articles by Hattori, Y.

Role of Macrophage Migration Inhibitory Factor in Acute Lung Injury in Mice with Acute Pancreatitis Complicated by Endotoxemia

Department of Pharmacology, School of Medicine, University of Toyama, Toyama; Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo; and GeneticLab Company, Limited, Sapporo, Japan

Correspondence and requests for reprints should be addressed to Yuichi Hattori, M.D., Ph.D., Department of Pharmacology, School of Medicine, University of Toyama, Toyama 930-0194, Japan. E-mail: yhattori{at}med.u-toyama.ac.jp

Acute pancreatitis accompanied by a subsequent infectious attack can often lead to multisystem organ dysfunction, including acute lung injury (ALI), but the molecular mechanisms are poorly defined. In this study, we explored the role of the priming insult by induction of cerulein pancreatitis, which was followed by the second attack due to endotoxemia, in the development of ALI in mice. Experiments revealed that LPS injection in mice with acute pancreatitis caused the development of ALI, as indicated by blood-gas derangements, pulmonary vascular hyperpermeability, increased inflammatory cell counts in bronchoalveolar lavage, and histologic lung damage. This was associated with the pancreatitis-induced increase in expression of macrophage migration inhibitory factor (MIF) in the lungs, together with elevated expression of Toll-like receptor (TLR)-4, both of which were inhibited by administration of anti–protease-activated receptor (PAR)-2 antibody. Furthermore, anti-MIF antibody treatment suppressed the pancreatitis-induced elevation of TLR-4 pulmonary expression. Genetic removal of MIF from mice resulted in less development of ALI in the setting of acute pancreatitis complicated by endotoxemia. These findings demonstrate that activation of protease-activated receptor–2 with trypsin, which can be released after pancreatitis induction, positively regulates the transcript level of MIF, and increased MIF results in exaggerated pulmonary expression of TLR-4, leading to the development of ALI with a subsequent infectious attack. We thus suggest that interventions designed to modulate MIF may have therapeutic advantages in treating ALI in patients with acute pancreatitis complicated by bacterial infection.

Key Words: acute lung injury • acute pancreatitis • macrophage migration inhibitory factor • protease-activated receptor–2 • Toll-like receptor–4

This article has been cited by other articles:

				L. Moussa, J. Apostolopoulos, P. Davenport, J. Tchongue, and P. G. Tipping Protease-Activated Receptor-2 Augments Experimental Crescentic Glomerulonephritis Am. J. Pathol., September 1, 2007; 171(3): 800 - 808. [Abstract] [Full Text] [PDF]