Br. vet..[. (1995). 151,469

GUEST EDITORIAL

ENDOTOXAEMIA: WHERE DO WE GO FROM HERE?

In the past decade, there has been a virtual explosion of information on the pathophysiology of endotoxaemia. Because endotoxin must interact with mam- malian cells to exert biological activity, most recent research efforts have focused attention on the interaction of endotoxin with host inflammatoi 3, cells and the subsequent production of secondary endogenous mediators. The article by Pro- fessor Neil Olson and his colleagues in this issue gives a detailed review of cur- rently available information on the interaction of endotoxin with host cells (Olson et al., 1995). Although it is generally accepted that endotoxin interacts with mam- malian cells through surface receptors, little is known about the events that cause cellular activation and mediator synthesis (Morrison et al., 1994).

Despite the plethora of new information, little progress has been made in the development of specific therapies to combat endotoxaemia in the clinical setting. The therapeutic challenge of endotoxaelnia stems from the rapid physiological response to the endotoxin and the subsequent production and complex inter- action of a diverse array of secondary endogenous mediators. The authors' dis- cussion on therapeutic options for endotoxaemia is directed primarily at neu- tralization of endotoxin through the use of antibodies or compounds that bind endotoxin, thereby decreasing plasma concenu'ations of endotoxin, and endo- toxin analogues or receptor antagonists that interfere with cellular binding. Only some of these therapies have been investigated in clinical trials and most with con- flicting results. Although it seems logical to neutralize endotoxin or prevent its interaction with host cells, the lack of conclusive efficacy of these types of treat- ment stems fronl the fact that the interaction of endotoxin with cells is a rapid event, thus presenting an extremely narrow therapeutic window. There is little controversy that these types of therapeutics are beneficial when administered prior to the onset of endotoxaemia, a situation rarely available clinically. Nonethe- less, treatments aimed at neutralizing the release and /o r interaction of endotoxin with host cells can serve some degree of benefit, especially when used in con- ditions characterized by delayed onset of endotoxaemia or prolonged endo- toxaemia.

Once host cells have been activated by endotoxin, remaining therapeutic options are targeted toward prevention of endogenous mediator synthesis, release or action. As examples, the authors discuss the use of antibodies directed against cytokines, platelet activating factor and leukotriene receptor antagonists, inhibi-

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470 BRITISH \rETERINARY JOURNAL, 151, 5

tors of arachidonic acid metabolism, and nitric oxide synthase inhibitors. Additional therapeutics also may be directed against free radicals, procoagulants, and vasoactive amines. Although these types of therapeutics can provide evidence for the role of a specific mediator in endotoxaemia, blockade of a single class of mediators-is unlikely to affect the production or action of other types of mediators. A possible exception is blockade of 'proximal mediators', such as the cytokines, that are released earl), in the course of endotoxaemia and initiate the production of additional mediators. Continued research delineating the inter- action of endotoxin with mammalian cells, the mechanisms responsible for cellu- lar activation, and the role of mediator synthesis and activity is essential in identifi- cation of specific pharmacological targets for improving management of endotoxic shock. Clinically available and affordable treatments for endotoxaemia are largely limited to the provision of supportive care and the use of non-steroidal mati-inflammatory drugs targeting cyclo-oxygenase inhibition. Because the biologi- cal response to endotoxin is driven collectively by a diverse array of endogenous mediators, furore pharmacological studies should be aimed at neutralization of more than a single class of mediators.

Another factor that has hindered therapeutic progress is the lack of a reliable experimental model. In addition to the tremendous variation in the response to endotoxin between species, inconsistency in response also exists within the same species. Only some of these inconsistencies can be explained by genetic resistance, tolerance, hypersensitivity or priming, or differences in cellular receptor concen- tration or type, or mediator response. Interpretation of experimental data is further confounded by differences in the source (Gram-negative bacteria vs puri- fied lipopolysaccharide) and concentration of endotoxin used and the route and rate of administration. The article in this issue focuses on porcine models as examples of the pathophysiological response to endotoxin. As with all models of endotoxaemia, caution must be exercised in the interpretation of experimental results in a species in which little is known about the relevancy of the concen- tration of endotoxin used experimentally vs that which exists in naturally occur- ring diseases affecting that particular model species. However, determination of a clinically relevant experimental challenge dose of endotoxin is not an easy task in any species. Measurement of blood endotoxin concentration is primarily limited to the use of assays which only detect the endotoxin concentration in plasma. Because endotoxin rapidly interacts with cells, the plasma concentration of endo- toxin greatly underestimates the concentration of endotoxin responsible for the evoked path ophysiological response (Steckel & Smith, 1991; Tasmura et al., 1991). Currently, new whole blood assays that purported detect both cellular bound and unbound endotoxin are under clinical investigation (Steckel & Smith, 1991). The results of these clinical trials will hopefully guide experimental research.

M. H. BAa'rON, Department of Large Animal Medicine,

College of Veterina U Medicine, University of Georgia,

Athens, GA 30602, USA

EN DOTOXAEM IA 471

REFERENCES

MORRISON, D. C., DINARELLO, C. A., MUNFORD, R. D., NATANSEN, C., DANNER, R., POLLACK, M., SPITZER, J. J., ULEVITCH, R.J., VOGEL, S. N. 8c McSwEE(;AN, E. (1994). Current status of bac- terial endotoxins. Amet~can Society of Microbiolo~, News 60, 479-84.

OLSON, N. C., HELL',a~2R, P. W. 8g DODAM, J. R. Mediators and vascular effects in response to endotoxin. British Veterinao, Journa1151, 489-5 22.

STECKEL, R. R. & S~xlm-t, N. L. (1991). Identification of endotoxin in equine colic patients: a preliminary study. Proceedings of the 37th Annual Convention of the American Assodalion of Equine Practitioners, pp. 265-73.

TAMVR..\, H., TANAr~X, S., OBAVASHI, T., YOSHmA, M. & ILxw~xa, T. (1991). A new sensitive method for determining endotoxin in whole blood. Clinica Chimica Acta 200, 35--42.