Experimental closed head injury: analysis of neurological outcome, blood-brain barrier dysfunction, intracranial neutrophil infiltration, and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines.
Cytokines are important mediators of intracranial inflammation following traumatic brain injury (TBI). In the present study, the neurological impairment and mortality, blood-brain barrier (BBB) function, intracranial polymorphonuclear leukocyte (PMN) accumulation, and posttraumatic neuronal cell death were monitored in mice lacking the genes for tumor necrosis factor (TNF)/lymphotoxin-alpha (LT-alpha) (TNF/LT-alpha-/-) and interleukin-6 (IL-6) and in wild-type (WT) littermates subjected to experimental closed head injury (total n = 107). The posttraumatic mortality was significantly increased in TNF/LT-alpha-/- mice (40%; P < 0.02) compared with WT animals (10%). The IL-6-/- mice also showed a higher mortality (17%) than their WT littermates (5.6%), but the difference was not statistically significant (P > 0.05). The neurological severity score was similar among all groups from 1 to 72 hours after trauma, whereas at 7 days, the TNF/LT-alpha-/- mice showed a tendency toward better neurological recovery than their WT littermates. Interestingly, neither the degree of BBB dysfunction nor the number of infiltrating PMNs in the injured hemisphere was different between WT and cytokine-deficient mice. Furthermore, the analysis of brain sections by in situ DNA nick end labeling (TUNEL histochemistry) at 24 hours and 7 days after head injury revealed a similar extent of posttraumatic intracranial cell death in all animals. These results show that the pathophysiological sequelae of TBI are not significantly altered in mice lacking the genes for the proinflammatory cytokines TNF, LT-alpha, and IL-6. Nevertheless, the increased posttraumatic mortality in TNF/LT-alpha-deficient mice suggests a protective effect of these cytokines by mechanisms that have not been elucidated yet.
Stahel
P F
PF
Department of Surgery, University Hospital, Zurich, Switzerland.
Shohami
E
E
Younis
F M
FM
Kariya
K
K
Otto
V I
VI
Lenzlinger
P M
PM
Grosjean
M B
MB
Eugster
H P
HP
Trentz
O
O
Kossmann
T
T
Morganti-Kossmann
M C
MC
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D016923:Cell Death; D016207:Cytokines / Q000235:genetics*; D004195:Disease Models, Animal; D016489:Head Injuries, Closed / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009460:Neurologic Examination; D009474:Neurons / Q000166:cytology; D009504:Neutrophils / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016207:Cytokines; D015850:Interleukin-6; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha