ADAM-17: A potential therapeutic target to prevent organ injury after hemorrhagic shock?

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To the Editor:
Peng et al.1 showed that, after severe hemorrhagic shock, intestinal intraluminal treatment with tranexamic acid (TXA) reduced intestinal and pulmonary injury associated with a decreased shedding of syndecan-1. Interestingly, the authors found that hemorrhagic shock increased the protein level and activity of A Disintegrin and Metalloproteinase-17 (ADAM-17). Following TXA treatment, protein levels and activity of ADAM-17 were both decreased along with reduced plasma levels of TNF-α and syndecan-1. ADAM-17 is an important protease that regulates many physiological and pathophysiological processes such as inflammation and coagulation and thus warrants special attention in studies related to hemorrhagic shock-induced organ injury. Therefore, we were particularly fascinated by the findings from Peng et al.1 that the severity of pulmonary and intestinal injury following hemorrhagic shock is correlated with ADAM-17, which might be a potential therapeutic target. On the basis of the results and conclusions presented, we have several comments for the authors.
Ischemia- or proteolysis-induced organ injury? Following severe (prolonged) hypovolemic shock, low oxygen and energy supply leads to ATP depletion and mitochondrial dysfunction, the key mechanisms for cell deterioration and apoptosis as well as subsequent organ injury. However, on the basis of the current study, enhanced proteolysis appears to be a fundamental mechanism, because TXA treatment (decreasing ADAM- 17) alone with no resuscitation significantly decreased organ injury. This raises a question whether TXA treatment or inhibition of ADAM-17 also improves cellular energy homeostasis and tissue oxygenation. In fact, there is evidence that inhibition of ADAM-17 leads to an increased metabolic rate because of elevated mitochondrial uncoupling protein,2 but such manipulation could be a fatal process after hemorrhagic shock because of a lower ATP production but a higher oxygen and energy expenditure. Notably, a recently study by Altshuler et al.3 addressed this question by showing that, following hemorrhagic shock, treatment with TXA alone failed to decrease intestinal injury, and reduced intestinal injury was not observed until rats were treated with a combination of glucose and TXA. In addition, after resuscitation, blood pressure was continuously decreased in the TXA and vehicle-treated groups, whereas in the animals treated with TXA and glucose combination, blood pressure appeared to be more stable.3 Although the mechanism underlying these beneficial effects is not thoroughly determined, this study provides direct evidence that metabolic support may still be a necessary therapeutic strategy following hemorrhagic shock. Because neither food intake nor intestinal content were controlled in the current study, the interpretation of the beneficial effect of TXA may need further clarification.
ADAM-17, a friend or foe? ADAM-17 is expressed in many types of tissues and plays various roles in multiple systems. More than just a TNF-α converting enzyme, ADAM-17 regulates immune responses at different levels and has both proinflammatory and anti-inflammatory effects. For example, the current study showed that ADAM-17 increased inflammation by enhancing TNF-α production, whereas other studies have suggested that ADAM-17 is an anti-inflammatory factor via its ability to cleave colony-stimulating factor-1, thereby decreasing monocyte/macrophage activation.4 In addition, after neutrophil attachment (to the vascular wall), increasing L-selectin shedding by ADAM-17 accelerates neutrophil infiltration, whereas cleavage occurring before neutrophil attachment actually blunts neutrophil transmigration and subsequently suppresses innate immune responses. These results might raise questions concerning the appropriate time interval between TXA treatment and initiation of inflammatory responses. Nevertheless, ADAM-17–deficient mice exhibit increased susceptibility to inflammation. Therefore, the net effect of ADAM-17 inhibition could be more than just anti-inflammation. ADAM-17 has also been recognized as a sheddase of many other proteins such as cell-junctional molecules and a number of adhesion molecules, inflammatory cytokines, as well as the corresponding receptors.5 These proteins are important mediators of inflammation and tissue permeability.
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