In the field of forensic medicine,
shock has been identified as a cause of death owing to various kinds of exogenous insults. The etiology and pathogenesis of
shock cannot be explained well by the usual gross appearance in medicolegal autopsies, because it is now generally established that the
shock is a functional reaction of the vascular system to bodily injury, and that several organs are secondarily impaired during
shock. Thus it seemed to forensic pathologists that these morphological changes in several organs after
shock did not reveal any significant differences among the causes of death. We approached to the induction mechanism of
shock, and we investigated what etiology induced these morphological changes after
shock in order to identify
shock as the cause of death. It is now generally accepted that the kidney is a target organ of
shock, so we mainly investigated the cause of kidney disorder in a case of
burn shock and
hemorrhagic shock. 1. Consequences of bacterial translocation (BT) in the
shock. The concept of BT indicates that the beginning of
shock is induced by the loss of gut barrier function and consequent translocation of bacteria. In general, impaired gut barrier function can be caused either during the
shock period by decreased intestinal blood flow and reduced
oxygen delivery, resulting during reperfusion in a stage of increased intestinal blood flow, or at a later stage again by reduced flow. A variety of physiological stresses, such as
trauma,
hemorrhage, thermal
injury, surgical operation, various kinds of drags and mental stress, have been shown to cause failure of the gut mucosal barrier, with translocation of bacteria/
endotoxin from the gastrointestinal into the mesenteric lymph nodes, and translocation into remote organs and systemic circulation. 2.
Burn shock. We designed to evaluate the BT in a
burn shock rat model (following 20% full-thickness scald injury). The
p38 MAPK pathway is an important stress-responsive signal molecule pathway, and it is responsible for the production and signal transduction of
cytokines. This pathway is activated by the bacterial LPS or
ischemia, so we examined the effects of
FR167653, a specific inhibitor of
p38 MAPK, on the development of
renal failure after the
burn-induced intestinal barrier damage. Our study demonstrated that viable bacteria reached the remote organs after
burn by quantitative bacterial culture data and
FR167653 blocked the
burn-induced intestinal barrier damage, and the immunohistochemical data showed that
FR167653 prevented the accumulation of polymorphonuclear leukocytes (PMNs) in the glomerular capillaries after
burn, and blockaded the
burn-induced
renal failure by serum UN assay.
FR167653 especially decreased the phosphorylation levels of
p38 MAPK in the infant kidney after
burn, and
TNF-alpha and IL-1beta
mRNA decreased through the
p38 MAPK pathway. The above-mentioned facts do provide additional support for the hypothesis that postburn
renal failure is mediated by
endotoxin associated with the bacterial translocation, and we identified the pathophysiologic role of
p38 MAPK pathway in the development of
renal failure after the
burn-induced intestinal barrier damage. 3.
Hemorrhagic shock. We evaluated the role of endogenous
TNF-alpha in the
renal failure and gut bacterial translocation induced by mild
hemorrhagic shock (16.7%
bleeding of total body blood via a common carotid
catheter without fluid
resuscitation).
FR167653, a potent inhibitor of
TNF-alpha up regulation through
p38 MAPK pathway, significantly inhibited these increases of
TNF-alpha. Adding to this, our study demonstrated that
FR167653 prevented
renal failure, such as the infiltration of inflammatory cells and tubular cell
necrosis after
hemorrhage, and the intestinal barrier damage was also dramatically improved by
FR167653 treatment. These results show that derived endogenous
TNF-alpha plays a key role in
renal failure through
p38 MAPK activation during the early phase of mild
hemorrhagic shock, including the possible participation of BT. According to these results, we hypothesized that the invading leukocytes induced these organs failures after
hemorrhagic shock, so we examined the appearances of leukocytes by the immunohistochemical
myeloperoxidase (MPO) staining (marker staining for PMNs). The incidences of PMNs in these organs after mild
hemorrhagic shock increased significantly, and FR157653 prevented the appearance of PMNs. These results showed the possible effective role of the PMNs on the occurrence of organ failure caused by mild
hemorrhagic shock. 4. Forensic practice. Six hundred and seven forensic autopsy cases in our department of forensic medicine during the past 11 years between 1992 and 2002 were analyzed with regard to the cause of death.
Shock cases accounted for 18% of all forensic autopsy cases, and among them 65% of cases identified
hemorrhagic shock as the cause of death. So we investigated what good grounds to clearly identify the cause of death induced by
hemorrhagic shock. Our experimental
hemorrhagic shock data showed PMNs activation and priming during
hemorrhagic shock, and it might be closely related to BT and remote organ failure. Consequently, we used the MPO staining method, and we immunohistochemically investigated several organs of our practical autopsy cases to detect the appearance of PMNs as a marker of
shock induction. We compared the
hemorrhagic shock with other causes of death, such as blood loss,
asphyxia, drawing and
head injury (
intracranial hemorrhage). In every organ, a significant appearance of PMNs was observed in the
hemorrhagic shock compared to the other causes of death. Especially, the appearance of PMNs in the heart was clear than that of the other organs in the
hemorrhagic shock cases. Therefore, detecting the appearance of PMNs as a marker of
shock induction is a very useful and significant method forjudging the cause of death in forensic practice.