Journal of Surgical Research 128, 1–2 (2005)doi:10.1016/j.jss.2005.07

EDITORIAL

Neutral Endopeptidase Determines the Severityof Pancreatitis-Associated Lung Injury

In this issue of the Journal of Surgical Research, Kirkwood et al., fromthe University of California at San Francisco examine the anti-inflammatory effects of the ubiquitous cell surface protease, neutral endo-peptidase (NEP). The authors specifically examined the ability of NEP toinhibit the pulmonary inflammatory response in pancreatitis associatedlung injury, or PALI, when induced by elastase.

Pulmonary insufficiency is a common and relentless morbidity seen inpatients with severe acute pancreatitis and a primary cause of theirmortality. The pulmonary histology from affected patients commonly re-veals inflammatory cell sequestration and microvascular injury. Activatedinflammatory cells in the lung lead, via both direct and indirect means, tothe release of a cascade of pro-inflammatory mediators [1]. The mecha-nisms by which pancreatitis activates this pulmonary inflammatory re-sponse are incompletely understood but candidate etiologies include noci-ceptive neuronal activation [2], interleukins 6 and 10 [3] heat shockprotein 60 [4], nitric oxide [5], and TNF-� and STAT-3 [6]. These authorsalso propose IL1-�, oxygen free radicals, and platelet-activating factor aspotential biological mediators [7].

NEP is a cell-surface metalloprotease that catalyzes and deactivatesproinflammatory peptides and is an appealing therapeutic target for thetreatment of the lung injury associated with pancreatitis or sepsis.Neutralization of NEP worsens both experimental pancreatitis and thecoupled lung injury. In this study, the authors used a murine model ofPALI to test their hypothesis: that NEP antagonism, or its geneticdeletion, would enhance inflammation and pulmonary damage irrespec-tive of the extent of pancreatitic inflammation. Using NEP knockoutmice, the investigators were able to show conclusively that NEP is aninhibitor of pancreatic elastase-induced lung injury, in all probabilityvia degradation of pro-inflammatory mediators, in both models. Theseresults also support the effectiveness of the elastase-induced lung in-jury model in studying respiratory insufficiency associated with acutepancreatitis.

This manuscript is important as it describes NEPs ability to degrade avariety of pro-inflammatory mediators thereby underpinning the salientrole of NEP in PALI. These experiments portend a therapeutic role forneutral endopeptidase in improving the relentless lung injury seen inacute pancreatitis.

David McFadden, M.D.Editor

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1 0022-4804/05 $30.00© 2005 Elsevier Inc. All rights reserved.

2 JOURNAL OF SURGICAL RESEARCH: VOL. 128, NO. 1, SEPTEMBER 2005

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5. Boer, C., Groenveld, A. B., Scheffer, G. J., deLange, J. J., Westerhof, N., and Sipkema, P.Induced nitric oxide impairs relaxation but not contraction in endotoxin-exposed ratpulmonary arteries. J. Surg. Res. 2005 May 24; [Epub ahead of print.

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7. Day, A.L., Wick, E., Jordan, T.H., et al. Neural endopeptidase determines the severity ofpancreatitis-associated lung injury. J. Surg. Res. 128: 21, 2005.