As 2018 draws to a close, this issue of Shock offers another 17 excellent reports on the Basic Science Aspects of shock, injury, inflammation, and sepsis. An important theme this month is related to the role of the heart in shock-related injury. As more patients survive severe sepsis, the recovery phase after clearance of the infection is of great importance. Cardiac failure is a common finding in sepsis that potentiates the onset of shock. Crowell et al.(1) investigated the different regulation of protein balance in the heart during the acute and recovery phases of sepsis in a mouse cecal ligation and puncture (CLP) model. They found that the acute phase was characterized by proteostasis with increased apoptosis, inflammasome activation and autophagy. During recovery, protein synthesis was increased along with pyroptosis via the noncanonical pathway. Further studies are needed to determine whether these changes in protein balance lead to physiological changes.
In addition to being a target for organ failure in sepsis, the heart is a common site of ischemia leading to infarct. Stem cell therapy, in particular the use of induced pluripotent stem cells (iPSC) has shown promise in mitigating injury following myocardial infarction. Xuan et al. examined (2) the use of a cardiogenic small molecule isoxazole (ISX-9) to drive differentiation of human iPSCs to be used therapeutically. ISX upregulated multiple differentiation pathways in iPSCs in vitro. When these cells were transplanted into the infarct area of immunodeficient mice after left anterior descending artery ligation, they inhibited fibrosis and enhance healing. This suggests potential promise for therapeutic approaches using ISX-9 to differentiate iPSCs. In addition to stem cell therapy, various pharmacological interventions including the use of compounds from traditional herbs have been shown to benefit following myocardial ischemia. Guo et al.(3) examined the potential mechanisms by which matrine, a quinolizodine alkaloid isolated from a traditional Chinese herb protects cardiomyocytes from ischemia/reperfusion injury. They found the matrine protected against cardiac hypoxia/reoxygenation injury in vitro and ischemia reperfusion injury in vivo. It also activated the JAK2/STAT3 pathway and expression of heat shock protein (HSP)70. Inhibition of JAK2/STAT3 or knock down of HSP70 abrogated the protection indicating that these factors are at least largely responsible for the protective effects of matrine.
In addition to serving as an end target for injury, failure of the heart leads to impairment of other organs. Wei et al.(4) examined the potential role of rho kinase (ROCK) in the genesis of ischemic lung injury following resuscitation from cardiac arrest. The ROCK pathway activates a myriad of potentially damaging pathways including reactive oxygen production and vasoconstriction. They used fasudil to inhibit ROCK and showed that it improved gas exchange and decreased reactive oxygen and inflammation in the lung following return of spontaneous circulation after cardiac arrest indicating that activation of ROCK is a contributor to injury and inhibiting it may have potential for therapeutic intervention. The lung is also a target for injury following blunt thoracic trauma. Although pulmonary embolus is commonly considered to result primarily secondary to deep venous thrombosis, its incidence in trauma suggests other sources as well. Brown et al.(5) tested whether thromboses may also originate in the lungs following trauma. They used a thoracic blunt trauma model in mice caused by dropping a 50 g weight on the chest. The blunt trauma resulted in elevated markers of tissue injury as well as lung contusion with the development of pulmonary artery fibrin deposits and CD41 cell accumulation indicating pulmonary thrombosis of lung origin. This model may be useful in further study of pulmonary emboli following trauma; however, it would be interesting to know whether trauma to areas other than the lung also predispose to pulmonary emboli of lung origin.
Another theme in this month's issue is in the use of H2 as a therapy for sepsis or ischemia. H2 gas either inhaled or in solution, has been shown to have beneficial effects in inflammation and ischemia. Ikeda et al.(6) used a murine CLP model of sepsis to study the effects of gavage with H2-rich saline daily for 7 days following CLP on increased gut permeability. H2-rich saline decreases gut permeability, markers of inflammation and expansion of facultative anaerobes and increased survival. The authors conclude that the use of H2-rich saline oral administration may have therapeutic potential in sepsis. In addition to being administered in saline, H2 can also be inhaled. Chen et al.(7) compared H2 gas inhalation to mild hypothermia in attenuating the neurologic damage that follows cardiac arrest. They compared control versus hypothermia (33°C) alone or with 2% H2 inhalation or H2 at normothermia. Although all treatments improved indicators of cardiac injury compared to control, only treatments with H2 improved neurologic score or survival. In another report examining the effect of hypothermia on neurologic injury Lee et al.(8) tested the effects of targeted temperature measurement at either 33°C or 36°C in a rat model of ischemic stroke. While targeted temperature management (TTM) is accepted as an effective treatment to minimize neurologic deficits following cardiac arrest, the degree of hypothermia has been the subject of some controversy. Generally, lowering temperature below 36°C does not appear to confer additional benefit following cardiac arrest. Here Lee et al.(8) examined whether this was also true in a stroke model. They created a stroke by middle cerebral artery occlusion in a rat model and compared outcome following TTM at 36°C or 33°C. Both conditions attenuated TNF-α induction as well as protected against neurologic deficits suggesting that in stroke, similar to cardiac arrest TTM at 36°C provides adequate protection without the additional deficits that may be induced by lower temperatures.
An important event that can lead to circulatory collapse is an increase in vascular permeability. For decades, the use of intravital microscopy has been a valuable tool to assess vascular permeability with high resolution. However, this requires exposure of the tissues to be measured and is thus, not easily used for sequential studies. Shimazui et al.(9) describe a technique using and in vivo imaging system in-vivo fluorescence technique to estimate changes in vascular permeability noninvasively. They used the near infrared fluorescence marker Genhance 750 to maximize tissue penetration, and compared foot pad fluorescence as measured by in vivo imaging system to fluorescence in lung homogenate. Both footpad and lung fluorescence increased following CLP and correlated well with each other and with permeability estimated using the conventional Evans blue. This suggests that noninvasive imaging of footpad vascular permeability may be an adequate surrogate for lung permeability.
There are many potential mediators of increased vascular permeability in sepsis and inflammation. One of these is adrenomedulin (ADM). Geven et al.(10) tested whether pretreatment with an antibody to ADM might attenuate increased vascular permeability in a rat endotoxemia model. They treated rat with the antibody against the N-terminus of ADM (HAM8101) immediately before LPS injection. HAM8101 pretreatment decreased renal albumin leakage as well as decreasing levels of vascular endothelial growth factor and increasing levels of angiopoietin. It would be important to repeat these studies with a posttreatment model in a more relevant sepsis model, but these preliminary findings suggest some potential for the use of ADM inhibition in sepsis.
Coagulopathy is a common and complex event in sepsis. Proper coagulation regulation is dependent on the proper balance between fibrin clot formation and dissolution via fibrinolysis. These are regulated by the balance between tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI). Although high levels of PAI are associated with poor outcome, the source of PAI remains controversial. Huebner et al.(11) hypothesized that it may come from thrombin-induced degranulation of platelets. Platelets from healthy apheresis donors were stimulated with thrombin and PAI and PAI–tPA complexes measured in the supernatant by enzyme linked immunosorbent assay. Thrombin caused a rapid release of PAI which complexed with and inhibited tPA. These results suggest that thrombin-stimulated platelets may be an important source of PAI released from α granules.
Malaria remains a significant cause of mortality and morbidity worldwide accounting for over 400,000 deaths in 2016. Beyond its direct effect on mortality, the malarial parasite may enhance susceptibility to bacterial infection. Patel et al.(12) examined the effect of coinfection with Plasmodium and S. enterica. Coinfected mice failed to respond to respond to Ofloxocin with a decrease in bacterial burden, markers of inflammation or liver injury. In contrast, pretreatment with antimalarials to control the Plasmodium infection restored responsiveness to Ofloxicin. These results indicate the importance of malarial infection as a preexisting condition for bacterial sepsis.
Hypertonic saline (HS) has shown some benefit in resuscitation, but the potential for hypernatremia and acidosis can limit its use. These effects can be particularly problematic in the kidney. Ergin et al.(13) examined the balance of beneficial and deleterious effect in a lower body ischemia model. HS treatment decreased systemic markers of inflammation and improved both systemic and renal hemodynamics and oxygen delivery; however, HS caused decreased sodium reabsorption, acidosis and increased renal tubular injury indicating that, although HS had beneficial effects, it is potentially injurious to ischemic kidneys. An important role for the kidneys is in regulation of plasma K+. Either elevated K+ release or inadequate renal excretion can lead to hyperkalemia requiring renal replacement therapy; however, such therapy is not always available, especially in disaster or combat settings. Base on this, Hoareau et al.(14) developed a novel perfusion system that circumvents some of the limitations of renal replacement therapy, at least for short-term damage control. They evaluated and extracorporeal sorbent system for binding K+ in a swine model of hyperkalemia. This system effectively lowered serum K+ levels without affecting Ca2+or platelets. Two of 5 animals in control group developed arrhythmias while none of the treated ones did. This suggests that this approach may be effective for short-term treatment of hyperkalemia when standard renal replacement therapy is not available.
Disruption of splanchnic circulation leads to tissue ischemia, edema, and in the case of portal hypertension can give rise to lethal hemorrhage. An important factor in regulation of splanchnic circulation is intra-abdominal pressure, but this is often difficult to measure clinically. Bloch et al.(15) report a proof of concept for the use of ultrasound guided tonometry for measurement of intra-abdominal pressure (IAP). IAP was modified in swine by fluid infusion and IAP estimated using an ultrasound probe with a pressure sensing flexible chamber filled with ultrasound translucent at its tip. Increasing IAP resulted in decreased splanchnic blood flow and increased IAP as estimated by the ultrasound. These results suggest that this approach may constitute a simple noninvasive method for estimating IAP. This approach is important since fluid accumulation in the abdomen may result from over resuscitation. The changes in blood flow from increased IAP may affect intestinal motility. Gorrasi et al.(16) examined the relative effects of endotoxemia, peritonitis, and perioperative fluid accumulation resulting from aggressive fluid therapy on intestinal contractility in a swine model. Although gut perfusion was maintained in all groups, both endotoxemia and peritonitis decreased intestinal motility as assessed in a tissue bath to a similar extent. In addition, high volume but not moderate resuscitation decreased intestinal motility to an extent similar to endotoxemia and peritonitis.
Cirrhosis severely disrupts both splanchnic and systemic circulations. Moreover, the development of varices with portal hypertension can lead to bleeding and hemorrhagic shock. This can be potentiated by the impairment of adrenal function that accompanies the hepato-adrenal syndrome. Since the adrenal can be a source of androgens important for normal blood flow regulation, Huang et al.(17) examined the effect of androgen replacement with dihydroepiandosterone (DHEA) on vascular response in cirrhotic rats exposed to hemorrhagic shock. At baseline, cirrhotic rats showed typical systemic and splanchnic hyperdynamic circulation. After hemorrhage, vehicle-treated rats failed to respond appropriately to pressor therapy while DHEA-treated rats showed improved systemic and splanchnic circulation. These results suggest that androgen replacement may be useful in treating cirrhotic patients experience variceal bleeds.
1. Crowell KT, Moreno S, Steiner JL, Coleman CS, Soybel DI, Lang CH. Temporally distinct regulation of pathways contributing to cardiac proteostasis during the acute and recovery phases of sepsis. Shock
2. Xuan W, Wang Y, Tang Y, Ali A, Hu H, Maienschein-Cline M, Ashraf M. Cardiac progenitors induced from human induced pluripotent stem cells with cardiogenic small molecule effectively regenerate infarcted hearts and attenuate fibrosis. Shock
3. Guo S, Gao C, Xiao W, Zhang J, Qu Y, Li J, Ye F. Matrine protects cardiomyocytes from ischemia/reperfusion injury by regulating HSP70 expression via activation of the JAK2/STAT3 pathway. Shock
4. Wei J, Wang P, Li Y, Dou Q, Lin J, Tao W, Lin J, Fu X, Huang Z, Zhang W. Inhibition of Rho kinase by fasudil attenuates ischemic lung injury after cardiac arrest in rats. Shock
5. Brown IE, Rigor RR, Schutzman LM, Khosravi N, Chung K, Becker JA, Pivetti CD, Best GT, Chavez JC, Galante JM. Pulmonary arterial thrombosis in a murine model of blunt thoracic trauma. Shock
6. Ikeda M, Shimizu K, Ogura H, Kurakawa T, Umemoto E, Motooka D, Nakamura S, Ichimaru N, Takeda K, Takahara S, et al. Hydrogen-rich saline regulates intestinal barrier dysfunction, dysbiosis, and bacterial translocation in a murine model of sepsis. Shock
7. Chen G, Chen B, Dai C, Wang J, Wang J, Huang Y, Li Y. Hydrogen inhalation is superior to mild hypothermia for improving neurological outcome and survival in a cardiac arrest model of spontaneously hypertensive rat. Shock
8. Lee JH, Lim J, Chung YE, Chung SP, Park I, Kim CH, You JS. Targeted temperature management at 33°C or 36°C produces equivalent neuroprotective effects in the middle cerebral artery occlusion rat model of ischemic stroke. Shock
9. Shimazui T, Nakada T-a, Fujimura L, Sakamoto A, Hatano M, Oda S. Development of noninvasive in vivo
approach to assess vascular permeability in inflammation using fluorescence imaging. Shock
10. Geven C, Peters E, Schroedter M, Struck J, Bergmann A, McCook O, Radermacher P, Kox M, Pickkers P. Effects of the humanized anti-adrenomedullin antibody adrecizumab (HAM8101) on vascular barrier function and survival in rodent models of systemic inflammation and sepsis. Shock
11. Huebner BR, Moore EE, Moore HB, Stettler GR, Nunns GR, Lawson P, Sauaia A, Kelher M, Banerjee A, Silliman CC. Thrombin provokes degranulation of platelet α-granules leading to the release of active plasminogen activator inhibitor-1 (PAI-1). Shock
12. Patel DK, Mittal S, Tiwari N, Maurya AK, Singh D, Pandey AK, Pal A. Plasmodium-salmonella
coinfection induces intense inflammatory response, oxidative stress, and liver damage: a mice model study for therapeutic strategy. Shock
13. Ergin B, Zuurbier CJ, Kapucu A, Ince C. Divergent effects of hypertonic fluid resuscitation on renal pathophysiological and structural parameters in rat model of lower body ischemia/reperfusion-induced sterile inflammation. Shock
14. Hoareau GL, Kashtan H, Walker LE, Beyer C, Wishy A, Grayson JK, Ross JD, Stewart IJ. A novel perfusion system for damage control of hyperkalemia in swine. Shock
15. Bloch A, Glas M, Kohler A, Baumann U, Jakob SM. Noninvasive assessment of intra-abdominal pressure using ultrasound-guided tonometry: a proof-of-concept study. Shock
16. Gorrasi J, Jakob SM, Tovar L, Balsiger B, Brandt S, Bruegger LE, Bracht H, Takala J. Perioperative fluid accumulation impairs intestinal contractility to a similar extent as peritonitis and endotoxemia. Shock
17. Huang H-C, Hsu S-J, Chang C-C, Tsai M-H, Lee F-Y, Hou M-C, Lee S-D. Beneficial effects of adrenal androgen supplement in bleeding cirrhotic rats. Shock