René G Holzheimer

Circadian rhythm of cytokine secretion following thermal injury in mice: implications for burn and trauma research.

Although there are many reports of circadian variation in hormone secretion, there are only a few reports on the relationship between circadian rhythm and cytokine production. The aim of the present studies was to investigate whether there is a circadian effect on cytokine production of splenic lymphocytes and adherent splenocytes in mice after burn or sham injury. We selected day 7 after injury for our determinations because we have previously shown day 7 is the time of maximal suppression of T cell IL-2 and IFN&ggr; production and maximal increase in adherent cell proinflammatory cytokine secretion in this model. IL-2 and TNF&agr; were chosen as reference cytokines since the former is known to be produced by T cells and the latter by adherent cells of the innate immune system. The results showed that seven days after sham or thermal injury both T cell IL-2 and adherent cell TNF&agr; production were altered by time of injury or time of cell harvest. IL-2 secretion was significantly decreased in burn compared to sham animals when splenocytes were harvested in the morning; the decrease was non-significant when splenocytes were harvested in the afternoon. TNF&agr; secretion was significantly increased in burn vs. sham adherent cells only when injury took place in the morning. The observed circadian variations in cytokine production could have a significant effect on cytokine levels measured in clinical and animal studies of injury and may explain some of the reported discrepancies among these studies.

Long-term immunotherapeutic intervention with pentoxifylline in a mouse model of thermal injury and infection.

Major thermal or traumatic injury often results in abnormalities of immune function, and these abnormalities contribute to the increased susceptibility to infection observed in these patients. Abnormalities of T-cell function, including decreased proliferation and secretion of cytokines are observed following major injury and, conversely, there is markedly increased monokine production. Thus, therapy of this syndrome might logically be aimed at modulating the immune system to upregulate T-cell function and downregulate monocyte hyperactivation. Pentoxifylline (PTX), a methylxanthine derivative, has been shown to be therapeutically effective in several animal models. The purpose of this study was to evaluate PTX and its effect on cytokine production in a mouse model of thermal injury and to study its effect on survival after septic challenge. The results show that PTX therapy after injury can restore T-cell production of IL-2 and downregulate the hyperactive macrophage secretion of proinflammatory cytokines. However, improvement in survival resulting from this therapy following thermal injury and septic challenge depends on timing of dosage.