EDITORIAL FOCUS
Use of knockouts to define sequential steps on a pathway to organ injury
Focus on "Essential role for IL-6 in postresuscitation inflammation in hemorrhagic shock"

Joseph S. Solomkin

Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0558


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A VARIETY of both pro- and anti-inflammatory mediators can be detected in plasma taken from otherwise healthy individuals suffering any one of a variety of acute conditions, including major injury with hemorrhagic shock (3). Recent attention has focused on interleukin (IL)-6 because of the known effects of IL-6 on the function of inflammatory cells and because IL-6 levels correlate with subsequent clinical course (5). An understanding of the biological effects of IL-6 is complicated by the role of soluble IL-6Ralpha in conferring responsiveness to cells that do not ordinarily express this receptor.

There are several difficulties in establishing cause-effect relationships for these events. Binding to various proteins or cell receptors may modulate bioactivity of the mediator under study. One function of shed receptors in the vascular space or site of inflammation may be to serve as a sink for its ligand, abrogating ligand bioactivity by binding. Furthermore, infusion of mediators may actually downregulate the inflammatory response to subsequently encountered stimuli. This has, for example, been well studied with IL-8 (3). This may occur through a variety of mechanisms, including loss of cell surface receptors for the ligand under study and induction of anti-inflammatory mediators (1). In experiments in which mediator infusion induces organ injury, it often is not known whether this is a direct effect of the specific mediator or a more distal effect of sequential mediator and cellular activation.

A study by Meng et al., the current article in focus (Ref. 4, see p. C343 in this issue), provides a template for addressing the role of specific mediators in the evolution of systemic inflammatory disease. The basis for their research was the paradoxical observation that locally applied IL-6 induced neutrophil infiltration and lung injury, while systemic infusion of IL-6 reduced inflammation and injury. With the use of IL-6 knockouts and histological and functional assays of lung and liver, they demonstrated that knockout animals experienced less organ injury than wild-type animals. This supports the notions that the proinflammatory consequences of locally generated IL-6 are central to organ injury in this model of hemorrhagic shock and that this local effect predominates over the anti-inflammatory effects of intravascular IL-6.

Meng et al. used specific assays of hepatocyte activation, Stat3 activation, and increased nuclear factor- kappa B activity to identify at least one element of the reduced organ injury seen in the knockouts. The finding of these events in wild-type animals but not in the knockouts provides a mechanistic connection between IL-6 activity and the cellular activation required for organ injury.

These findings also implicate IL-6 as a proximal mediator of injury. The next step in this work would be to demonstrate that more distal elements are persistently functional. This will serve to further clarify the participation of local IL-6 as a neutrophil activating substance.


    FOOTNOTES

Address for reprint requests and other correspondence: J. S. Solomkin, Dept. of Surgery, Univ. of Cincinnati College of Medicine, 231 Bethesda Ave., Cincinnati, OH 45267-0558 (E-mail: joseph.solomkin{at}uc.edu).


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1.   Ahmed, N, Thorley R, Xia D, Samols D, and Webster RO. Transgenic mice expressing rabbit C-reactive protein exhibit diminished chemotactic factor-induced alveolitis. Am J Respir Crit Care Med 153: 1141-1147, 1996[Abstract].

2.   Hechtman, DH, Cybulsky MI, Fuchs HJ, Baker JB, and Gimbrone MA, Jr. Intravascular IL8. Inhibitor of polymorphonuclear leukocyte accumulation at sites of acute inflammation. J Immunol 147: 883-892, 1991[Abstract/Free Full Text].

3.   Hoch, RC, Rodriguez R, Manning T, Bishop M, Mead P, Shoemaker WC, and Abraham E. Effects of accidental trauma on cytokine and endotoxin production. Crit Care Med 21: 839-845, 1993[ISI][Medline].

4.   Meng, ZH, Dyer K, Billiar TR, and Tweardy DJ. Essential role for IL-6 in postresuscitation inflammation in hemorrhagic shock. Am J Physiol Cell Physiol 280: C343-C351, 2001[Abstract/Free Full Text].

5.   Nast-Kolb, D, Waydhas C, Gippner-Steppert C, Schneider I, Trupka A, Ruchholtz S, Zettl R, Schweiberer L, and Jochum M. Indicators of the posttraumatic inflammatory response correlate with organ failure in patients with multiple injuries. J Trauma 42: 446-454, 1997[ISI][Medline].


Am J Physiol Cell Physiol 280(2):C237-C238
0363-6143/01 $5.00 Copyright © 2001 the American Physiological Society




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