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Jeffrey L. Johnson, MD; Ernest E. Moore, MD; David A. Patrick, MD; Douglas Y. Tamura, MD; Garret Zallen, MD; David J. Elzi; Christopher C. Silliman, MD, PhD

Arch Surg. 1999;134:1074-1078.

Background  Inflammatory stimuli rapidly activate mitogen-activated protein kinases (MAPKs) in neutrophils (PMNs). However, their role in cytotoxic function remains unknown. Elucidating the signals involved in release of cytotoxic agents from PMNs may provide new avenues for therapy in diseases of diminished or excessive PMN function.

Hypothesis  The p38 MAPK and extracellular signal-related kinase 1/2 (ERK1/2) modulate superoxide generation and elastase release in activated human PMNs.

Study Design  Isolated human PMNs were incubated with specific inhibitors of MAPK pathways, or vehicle control solution, before activation with the bacterial peptide f-Met-Leu-Phe.

Main Outcome Measures  The rate of superoxide release from activated PMNs was measured by the superoxide dismutase–inhibitable reduction of cytochrome-c. Elastase release from PMNs was determined by cleavage of the substrate Ala-Ala-Pro-Val-pNA.

Results  Superoxide release from activated PMNs was inhibited by blockade of p38 MAPK activation but unaffected by blockade of ERK1/2. Conversely, elastase release was unaffected by p38 MAPK inhibition and increased by ERK1/2 inhibition.

Conclusions  Activation of p38 MAPK promotes superoxide release from PMNs activated by f-Met-Leu-Phe. The ERK1/2 pathway may serve as a negative feedback mechanism for granule exocytosis.

From the Departments of Surgery (Drs Johnson, Moore, Tamura, and Zallen and Mr Patrick) and Pediatrics (Mr Elzi and Dr Silliman), Denver Health Medical Center, University of Colorado Health Sciences Center; and the Bonfils Blood Center (Mr Elzi and Dr Silliman), Denver.

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