Expression of p38 mitogen-activated protein kinases, glycogen synthase kinase, c-Jun NH2-terminal kinase, extracellular signal-regulated kinase signaling: Can it be used as molecular markers among trauma-hemorrhagic shock patients?

Hemorrhagic shock (HS) is the third leading cause of death in trauma.[1] HS induces an excessive release of inflammatory cytokines which lead to the multi-organ failure and death. A recent study showed that in vitro release of inflammatory mediators is affected by mitogen-activated protein kinases (MAPKs), such as p38MAPK, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK).[2,3,4] After trauma/HS (T/HS), the phosphorylation of MAPKs, namely, p38, ERK1/2, and JNK in Kupffer cells increase. Kupffer cells are the major source for the production of interleukin (IL)-6, tumor necrosis factor (TNF-α), and IL-10. These cells contribute to increased level of circulatory cytokines. Cytokines expression is regulated by MAPKs both at the transcriptional level and at the posttranscriptional level. Earlier studies have indicated that activation of p38 is required for IL-6, TNF-α, and IL-10 expression. ERK pathway has been shown to control TNF-α expression. Previous studies also indicated that neither IL-6 nor IL-10 is ERK-independent. JNK is also involved in expression of IL-6 and TNF-α.[5] Among these MAPK groups, p38MAPK is believed to be the most important kinase in stress signaling which can be activated by various cellular stresses such as ischemia-reperfusion and causes inflammatory response as well as apoptosis.[2,3,4] To our knowledge, expression of p38MAPK, JNK, glycogen synthase kinase (GSK), and ERK has not been previously reported in patients with T/HS.

Cell signaling (CS) is a complex system of communication. Basic cellular activities and coordination of cell's action are governed by CS. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, immunity, tissue repair, as well as normal tissue homeostasis. Dysregulation of CS is responsible for diseases such as diabetes, autoimmunity, and cancer.[6]

p38MAPK signaling pathway leads to the multi-organ injury caused by ischemia-reperfusion in animal models. Increased expression of p38MAPK is seen in ischemia-reperfusion models of kidney, liver, vascular and myocardial cells, and lung.[7] Yang et al. showed that in HS rats, MAPK's signaling pathways indirectly regulate vascular activity.[8] A recent study reported that nuclear factor-kappa B is one of the key players that are involved in the regulation of hypoxic inflammation after HS following resuscitation (H/R).[9,10] McCloskey investigated that the activation of JNK in the liver as an early response to tissue hypoxia soon after the initiation of hemorrhage.[11] A recent study has shown that GSK-3β inhibitor modulates the inflammatory response to stress and may be protective in condition with sepsis inflammation and shock.[12] Multiple signaling pathways including the Akt pathway regulates GSK-3, inactivates it by causing Ser9 phosphorylation. There is a consistent decline in the activation of Akt pathway during the hemorrhage and resuscitation. This indicates an excessive activation of GSK-3β, which leads to both inflammation and tissue injury.[13]

Wu et al. showed that TNF-α-mediated-p38-dependent signaling pathway contributes to posttraumatic myocyte apoptosis of rats undergoing surgical trauma.[13,14] Hence, the author felt that expression of p38MAPK, GSK, JNK, and ERK should be studied on patients with T/HS.