A membrane TNF-alpha/TNFR ratio correlates to MODS score and mortality

This study hypothesizes that post-trauma elevated membrane-associated tumor necrosis factor-alpha (mTNF) and decreased TNF receptor shedding may be more related to development of multiple organ dysfunction syndrome (MODS) than elevated secreted TNF-alpha. We also address several of the possible reasons for the previous conflicting reports in studies correlating trauma patients' sera TNF-alpha levels to their clinical outcome. These are 1) the lack of an objective quantitative score of clinical illness severity, 2) the lack of multiple TNF-alpha measurements in one patient to allow for trend analysis, 3) the lack of analysis of membrane-associated as well as secreted TNF-alpha levels, 4) the lack of concomitant analysis of soluble TNF-alpha receptors which may bind TNF-alpha in the serum, and 5) the possible requirement for more than one dysfunction in monocyte (M phi) TNF-alpha production and regulation to initiate pathology. Here, the MODS score was used to quantitate patients' illness severity over the length of their intensive care unit (ICU) stay. Patients' and normals' monocytes (stimulated and unstimulated) were assessed for production of secreted as well as membrane-associated TNF-alpha (sTNF and mTNF) and for shed p75 TNF-alpha receptor (TNFR) levels. These parameters of M phi TNF-alpha production and regulation were correlated to the MODS score as an indicator of clinical outcome. There was no correlation between sTNF and MODS score (p = .9025). There was a correlation between increased mTNF (p = .057) or decreased TNFR shedding (p = .0021) to increased MODS, but this lacked specificity. However, when the stimulated M phi production of mTNF and TNFR are expressed as the mTNF/TNFR ratio, an increased ratio correlates with high specificity to development of organ failure (p = .0002). These data indicate that a dual deregulation in M phi TNF-alpha production reflects increasing mTNF-alpha levels concomitant to decreased M phi shedding of neutralizing TNFR and correlates with the development of MODS.