Pathogenic role of interleukin-6 in the development of sepsis. Part I: Study in a standardized contact burn murine model.
OBJECTIVE
To establish a representative model for the evaluation of interleukin (IL)-6 and IL-6 receptor for pathogenicity and lethality in the postburn period.


METHODS
Ten-week-old C 57 BL/6J mice received a 20% body surface area contact burn and/or lipopolysaccharide (LPS) 48 hrs later. Standardized burns were created with a metal stamp of 150 degrees C of defined pressure and surface area (2.4525 Newton/0.00166 m2) over a period of 11 secs. The depth of dermal injury was verified histologically. The following groups were formed: I: no burn, no LPS (n = 35); II: burn, no LPS (n = 140); III, no burn, LPS (n = 56); and IV, burn, LPS (n = 80), to study the effect of burn alone, sepsis alone, or the combination. Lethal LPS dose (LD100) was determined by application of LPS in increasing doses (200, 300, 400, and 500 microg, n = 32) after burns.


METHODS
Concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), and leukocytes, platelets and organ pathology were evaluated.


METHODS
Research laboratory.


RESULTS
Burn and LPS showed an additive effect on the release of IL-6 but not of TNF-alpha and IFN-gamma. Leukocyte and platelet numbers decreased significantly (group IV) compared with the other groups (I-III). The maximal levels of IL-6 in group IV were reached earlier than those of TNF-alpha. The contact burn model has a mortality rate of 30%, which is close to clinical outcome. We found the model of contact burn superior to scald or flame burn models. A dose of 400-microg LPS was found to be the lethal LPS dose (LD100).


CONCLUSIONS
Our data suggest that preexisting burn injury increases the response to endotoxin. TNF-alpha is not involved in priming. IL-6 on the other hand is a very representative parameter for priming. Because TNF-alpha was obviously not the causative factor, it was concluded that the application of anti-IL-6-mAb should be of great value. Therefore, a therapeutic application was designed, see part II.
Pallua
Norbert
N
Department of Plastic Surgery and Hand Surgery--Burn Center, University Hospital of the Aachen University of Technology, Germany.
von Heimburg
Dennis
D
D000818:Animals; D001830:Body Surface Area; D002056:Burns / Q000097:blood / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D007249:Inflammation; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010976:Platelet Count; D011552:Pseudomonas Infections / Q000097:blood / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D018805:Sepsis / Q000097:blood / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D015850:Interleukin-6; D008070:Lipopolysaccharides; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma