Metabolic Effects of Cytokines in Burns Trauma and Sepsis

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Proinflammatory Cytokines

TNF Primary mediator in inflammatory response, increase in acute phase proteins, reduction in skeletal muscle and diaphragm contractility

IL-1 Activation of T cells, iNOS expression, prostaglandin production, inhibition of lipoprotein lipase, procoagulant activity, increase in acute phase proteins

IL-6 Key later role in inflammatory cascade, activation of lymphocytes, increase in acute phase proteins, endogenous pyrogen

IL-8 Key later role in inflammatory cascade, regulates neutrophil activity

Anti-inflammatory Cytokines

IL-10 Feedback role in limiting inflammatory response; may lessen neutrophil activation; potent inhibitor of TNF-a, IL-1P, IL-6, and IL-8 production/release

TGF-P Downregulates proinflammatory cytokine production, lessens lymphocyte activation, stimulates extracellular matrix synthesis

IL-1ra IL-1 receptor antagonist

Ebb And Flow After Trauma

0 123456 78 (Weeks)

1 Ebb | Flow Phase

0 123456 78 (Weeks)

1 Ebb | Flow Phase

Injury Inflammation Proliferation Remodeling

FIGURE 11.2 Metabolic response to burns, trauma, and sepsis.

followed by immunodepression (Figure 11.2) with increased IL-4 and IL-10, reduced IL-2 [8], and decreased natural killer (NK) cell toxicity. This biphasic immune response may explain why the systemic inflammatory response occurs immediately after surgery, whereas infections occur later [9]. The immunosuppression that occurs post-burn or post-trauma increases with age. As shown in an animal model, there is an increase in the production of Th2 cytokines, particularly IL-4 and IL-10, and a reduction in Th1 cytokine IL-2 with advancing age [10].

Independent co-identification of a small polypeptide molecule present in the plasma of rabbits infected with Trypanosoma brucei which led to hypertriglyceridemia, hyperglycemia, and cachexia (hence, cachectin) [11] with the same molecule that induces hemorrhagic necrosis of tumors in animals after exposure of macrophages to endotoxin (tumor necrosis factor) has rapidly increased the understanding of metabolism following injury [12,13]. In healthy individuals, plasma TNF levels are less than 35 pg/ml; however, in both animals and humans, peak levels of TNF (240 pg/ml) occur after 90 to 120 min of exposure to endotoxin or Gram-negative bacteria and are positively correlated with mortality [14-16]. TNF induces hyper-triglyceridemia, weight loss, and cachexia, in part by inhibition of endothelial lipoprotein lipase, but also by increased lipolysis and mobilization of fat stores. Administration of TNF to animals and humans induces proteolysis, hepatocyte amino acid uptake, by increasing the number of transport protein molecules in the plasma membrane for amino acids, including glutamine and arginine, negative nitrogen balance, and suppressed dietary intake [17,18]. However, control of dietary intake in pair-fed animals exposed to TNF demonstrated that depletion of whole body protein stores is independent of nutritional intake. Studies in adrenalectomized animals given corticosterone suggest that glucocorticoids are involved in mediating the effects of TNF on muscle proteolysis [19,20].

Similar to TNF, IL-1 is produced by a wide variety of cell types as IL-1 or IL-1 with a somewhat slower rate of appearance and onset of action after bacteremia or endotoxin [21-23]. Both TNF and IL-1 can induce the production of the other [24] and can act synergistically in producing hypotension, thrombocytopenia, metabolic acidosis with increased lactate, anaerobic glycolysis, hyperglycemia, and hypertriglyceridemia [25]. There are beneficial effects of IL-1, however. Taros and colleagues [26] showed in an animal model that administration of IL-1 a lessened the mesenteric ischemia and reperfusion injury and reduced bacterial translocation after burn and sepsis.

Alterations of hepatic protein synthesis, such as reduction in albumin, transferrin, and pre-albumin production and dramatic rises in the acute phase proteins, a-1 antitrypsin, a-2 macroglobulin, procalcitonin, C-reactive protein (CRP), and fibrinogen were originally considered effects of IL-1 and TNF [27,28]. However, IL-6 has also been demonstrated to be a mediator of the hepatic acute phase response to trauma and infection [29-31]. Unlike TNF and IL-1, sustained elevations of IL-6 plasma levels have been found following major burn injury [32,33], sepsis [17,34-36], and trauma [37]. Other acute phase response proteins include lactoferrin leading to depressed serum iron concentration, which is inhibitory for growth of microorganisms [38], and ceruloplasmin and metallothionien with reduced serum zinc and copper in trauma and sepsis [38-42]. Serial measurement of prealbumin and CRP can be used to monitor nutritional status. For example, if prealbumin is not increasing and CRP is not decreasing, a low prealbumin may be due to inadequate nutrition vs. stress response [302].

Subsequently, glucagon, cortisol, and insulin are increased after major trauma, such as thermal injury [23,43]. Also, in the acute phase of the stress response, there is a tenfold increase in the catecholamines epinephrine and norepinephrine produced endogenously [23]. During shock, catecholamines dopamine, dobutamine, epineph-rine, and norepinephrine are also administered exogenously as vasopressors to restore arterial pressure, with differential effects on metabolism. Dobutamine [44] and norepinephrine [45] result in greater improvements in splanchnic blood flow than other catecholamines, and dopamine and dobutamine have less of an inhibitory effect on intestinal motility than do norepinephrine and epinephrine [46]. Epinephrine in comparison to norepinephrine is associated with increased lactate levels (an indicator of tissue hypoxia), decreased pH, and higher blood glucose levels [47], and it is an immunosuppressant. Based on an animal model of the effects of catecholamines on small bowel peristalsis, Fruhwald [48] indicated that epinephrine, especially in combination with the anesthetic, sufentanil, should not be used in the intensive care setting. Furthermore, administration of a vasoconstrictor, such as epinephrine, without sufficient volume therapy can lead to temporary reduction of skin perfusion and progression of burn necrosis [49]. Dopamine impairs mucosal blood flow, worsens reduced gastric motility, and suppresses the secretion of anterior pituitary hormones, increasing catabolism and immune dysfunction [50]. Given the potential deleterious effects of large amounts of vasopressors, studies are investigating the potential to reduce vasopressor requirements by administering corticosteriods [51].

Sepsis is the systemic response to infection. Early studies suggested that sepsis and, subsequently, multiple organ dysfunction syndrome (MODS) were caused by uncontrolled infection and bacteria or endotoxins. However, some patients with adequately controlled infection and those without sepsis develop MODS and signs of systemic inflammation. This discrepancy led to investigations of systemic activation of inflammation by a wider variety of biological modulators than just infection. Activators of the inflammatory response include surgical trauma, blood loss or transfusion, and hypothermia. Despite the apparent involvement of biological modulators and cytokines such as TNF, and IL-1 receptor in MODS, agents that neutralize these modulators have failed to attenuate the progression of sepsis, septic shock, and organ failure. The failure of anti-cytokine therapy may be due to the complexity of septic shock, the heterogeneity of patients with septic shock, the timing of interventions, and interventions that reduce the immune response and may reduce clearance of the primary infection and exacerbate the immunosuppression [52]. In contrast, more success has been found manipulating the clotting cascade as compared with the immune system in ameliorating sepsis. Recombinant human activated protein C, an anticoagulant that inactivates clotting factors Va and Villa, preventing the formation of thrombin, resulted in a 16% decrease in mortality in patients with sepsis [53].

As part of the inflammatory phase of wound healing, the complement cascade and immune cells such as neutrophils are involved in the removal of debris and bacteria. In burn patients and trauma patients with wounds, it is important to limit the extent and duration of the inflammatory process by early debridement and removing infected and necrotic material as soon as possible to minimize inflammation by early closure of wounds [54]. Debridement of wounds removes burn eschar and can prevent invasive wound infections. Hydrotherapy should not be used due to the propensity for contamination with Pseudomonas aeruginosa and subsequent increased mortality [1].

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Your Metabolism - What You Need To Know

Your Metabolism - What You Need To Know

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