Joseph Cuschieri, MD
Associate Professor, Department of Surgery
Severe injury is associated with increased susceptibility to life-threatening infections and sepsis, leading to the development of MODS. Severely injured patients appear to have a dysregulated innate immune response following injury, which appears to be central to the development of these clinical syndromes. The effect of trauma on mononuclear cell phagocytosis, killing of microorganisms, antigen presentation, cytokine production, and induction of cytotoxic effector cells has been characterized. However, the mechanisms responsible remain unknown due to both exaggerated pro- and anti-inflammatory responses. Insight into the mechanisms involved, however, can be determined through in vitro modeling of factors induced by severe injury, including PAF, oxidant stress and C5a, and through the induction of tolerance.
Treatment of mononuclear cells with various agents, including PAF, oxidant stress and C5a, results in a heightened responsiveness to subsequently encountered stimuli such as LPS. Critical to this reprogramming is cellular adherence. This is fortunate, since it is difficult to envision an in vivo situation where local tissue injury might occur from stimulation of suspension phase cells.
Common to these various agents is the mobilization of calcium and subsequent activation of CaMK II that we have demonstrated to occur following exposure to each of the reprogramming conditions. Although the cellular source of calcium varies, each factor results in the autophosphorylation and sustained activation of CaMK II. Sustained activation had been previously demonstrated in a number of cell types during sepsis, including cardiac myocytes and smooth muscle cells. Recently, we have demonstrated a similar sustained activation of CaMK II in bronchoalveolar macrophages obtained from injured patients that have gone on to develop ARDS. This is the first example of increased activation of CaMK II following injury, and provides support that cellular alteration of calcium may be an important event in immune cell reprogramming.
In addition to the activation of the regulatory kinase, CaMK II, recent evidence has suggested that sphingomyelinase activation and ceramide production may play additional regulatory roles. In fact, intracellular ceramide levels along with serum TNF-α have been demonstrated to be elevated in patients suffering from severe sepsis. This strong correlation between cell-associated ceramide and serum TNF-α supports the hypothesis that ceramide, along with sphingomyelinase, plays a role in sepsis and subsequent organ dysfunction. Although sphingomyelinase activation and ceramide production may prove to be important following acute injury, this exploration has only just begun.