Trauma remains a leading cause of morbidity and mortality among all age groups in the United States (U.S.) (1). In 2016, 2.8 million people were hospitalized for severe injuries (1, 2). Furthermore, approximately 230,000 people die each year from such injuries, which results in costs of $671 billion dollars to the healthcare system annually in the U.S (3). The majority of these deaths occur within the first few hours following injury, half of which are secondary to hemorrhagic shock (4–7). Traumatic brain injury (TBI) is responsible for the majority of deaths thereafter (8). The combination of hemorrhagic shock and TBI is highly lethal with an early death rate of approximately 80% (9). Even when patients survive the early period, these injuries predispose them to severe immune dysregulation, often resulting in septic complications and late deaths.
Although resuscitative fluids replace intravascular volume and improve both systemic and cerebral circulation in the setting of trauma, they must be administered with caution. Fluid resuscitation does not have any innate pro-survival properties (10). When administered aggressively, crystalloid fluids can even lead to worsened clinical outcomes by increasing the blood loss, inflammation, and coagulopathy (11). At present, damage control resuscitation (DCR) is a major tenet of trauma care. DCR discourages crystalloid resuscitation in favor of early blood product administration, and promotes early hemostasis, correction of acidosis/coagulopathy, and limited resuscitation until control of hemorrhage (12–14). Due to logistical constraints, however, blood products are often not available in prehospital or far-forward settings. As such, development of life-sustaining adjunctive strategies for the prehospital setting has become a priority.
In recent years, many groups have demonstrated that pharmacologic agents can be used to prevent and even reverse trauma-induced cellular dysfunction (15–17). Among the drugs that have been investigated are agents such as histone deacetylase inhibitors (HDACis), which have demonstrated promise in both trauma and sepsis. As austere environments are often resource-limited and logistically constrained, HDACis offer a potential treatment strategy that is low volume, stable, cheap, and easy to administer. Studies demonstrate that these agents can improve survival, minimize neurologic injury, and attenuate organ dysfunction. In this narrative review, we highlight our and other's work of HDACi treatment in trauma and sepsis.
THE ROLE OF EPIGENETIC MODULATION
In recent years, it has been discovered that there is significant alteration of gene expression following hemorrhagic shock (18, 19). This impacts downstream protein expression, and impairs cells’ ability to employ pro-survival mechanisms to recover from injury. As such, epigenetic modulation has been suggested as a potential approach for the reversal of trauma-induced cellular dysfunction. Epigenetic modulation refers to mechanisms that alter gene expression through regulation of transcription (20). Modifications in histone and non-histone proteins reversibly alter the 3D chromatin structure, which changes the ability of transcription machinery to bind and transcribe genes (20).
Following hemorrhagic shock, the primary genomic alteration is hypoacetylation of lysine residues on histone proteins (16). Acetylation of histone proteins, mediated by histone acetyltransferases (HATs), promotes chromatin relaxation, allowing greater accessibility to transcription factors; likewise, hypoacetylation, mediated by histone deacetylases (HDACs), encourages condensation of chromatin structure, decreasing accessibility to transcription factors (21, 22). This global hypoacetylation in hemorrhagic shock represents an overall state of decreased transcriptional activity with downstream effects on the cell cycle, stress response, cell signaling, repair and healing, and proliferation (23–25). As such, preventing or reversing this change in transcription dynamics offers the potential to improve cell survival following hemorrhagic shock and other traumatic injuries.
HISTONE DEACETYLASES AND THEIR INHIBITORS
HDACs have been widely described and classified based on cellular and tissue distribution (Table 1). In humans, approximately 18 unique HDACs have been identified to date (26, 27). HDACS are subdivided into zinc-dependent classes (classes I, II, and IV) and NAD+ dependent classes (class III) (26–30). Beyond differential activity according to class, each individual HDAC is noted to have distinct physiologic functions and unique organ distribution. This suggests that each HDAC may play a very specific role in different disease processes (26, 27, 31, 32).
HDAC inhibition has gained attention as a mechanism to temporarily alter transcription to create a favorable gene expression profile. HDACis have the potential to have rapid, reversible effects, and have also been recognized to exhibit effects specific to injured/diseased cells, while sparing normal cells, due to differential HDAC activity according to cell state (33–41). Some HDACis are non-selective (valproic acid [VPA]), acting on more than one HDAC class. Others target individual classes (isoform selective HDACis). Over the last decade, both non-selective and isoform-selective HDACis have demonstrated promise in preclinical models of trauma and sepsis.
NON-SELECTIVE HDACi TREATMENT IN HEMORRHAGIC SHOCK AND POLYTRAUMA
One of the first applications of HDACis in trauma models was in hemorrhagic shock. VPA, a non-selective HDACi, was evaluated as pretreatment in a rodent model of hemorrhagic shock (40% total blood volume) (24). Pretreatment with VPA in lethal hemorrhagic shock significantly improved survival time compared with normal saline (NS) alone. In follow-up studies assessing biological activity, VPA and other non-selective HDACis (suberoylanilide hydroxamic acid [SAHA], and trichostatin A) were found to induce histone acetylation in tissues in both a fluid- and organ-specific manner (25). These agents also stimulated changes in cellular metabolism, proliferation, growth, differentiation, and signaling. Overall, these “proof of concept” studies demonstrated that non-selective HDACIs can prolong survival, and this may be mediated, in part, through histone hyperacetylation.
Given the initial success with pretreatment, post-hemorrhage administration of non-selective HDACis was then evaluated. In a rodent model of lethal hemorrhagic shock without fluid resuscitation, post-hemorrhage administration of VPA and SAHA improved survival from 25% (no treatment) to 75% and 83%, respectively (42). VPA and SAHA also conferred cytoprotection to several major organs including the kidney (43), intestine (44), and lung (45, 46). Addition of VPA as a post-hemorrhage treatment to other management strategies, including therapeutic hypothermia (30 ± 2°C), revealed that combined treatment offers better cytoprotection than individual treatment in hemorrhagic shock (47). The success of non-selective HDACis in these studies demonstrates their potential as both a stand-alone and adjunctive treatment in hemorrhagic shock.
Despite the success of non-selective HDACis in models of hemorrhagic shock, little was known about their impact on complications of hemorrhagic shock. In a rodent model of isolated intestinal ischemia-reperfusion injury, which simulates organ dysfunction commonly encountered after hemorrhagic shock, VPA improved short-term survival and decreased acute lung injury (48). Further testing in a more translational swine model of 35% total blood volume hemorrhage followed by lethal ischemia-reperfusion injury provided evidence of physiologic benefit (49). VPA treatment significantly decreased acidosis, coagulopathy, and resuscitation requirements (crystalloids and epinephrine) following injuries (49). These effects, in part, were thought to be related to an increased expression of heat shock proteins (HSP), which helped mediate the stress responses in liver and lung tissues (49).
Even in complex animal models of hemorrhagic shock and polytrauma, the beneficial effects of VPA are evident. In a polytrauma model involving femur fracture, 60% hemorrhage, and a Grade V liver injury, swine were randomized to receive fresh whole blood, VPA (400 mg/kg), or no treatment (control) (50). Following injuries, VPA treatment was associated with a comparable improvement in short-term survival to fresh whole blood (50). At a reduced dose, VPA (300 mg/kg) still facilitated decreased resuscitation requirements and improved hemodynamics and physiology during resuscitation (51). Overall, the results of these studies suggest that treatment with HDACis can improve outcomes following a wide range of injuries.
Mechanisms of action
In addition to increasing HSP expression, numerous pro-survival pathways, including phosphorylated-Akt, GSK-3, and B-catenin pathways, are upregulated following VPA administration (50, 52, 53). These pathways promote transcription factor binding and gene transcription, improve protein stability, and regulate protein interactions (52, 53). Phosphorylated-JNK expression, which upregulates apoptotic proteins, has also been shown to be attenuated by VPA administration (54). As a whole, activation of these pathways translates into significant downstream effects. For example, VPA administration potentiates improvement in ischemia-induced endothelial injury, and reduces expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (55, 56). Additional pathways regulated by VPA in hemorrhagic shock and polytrauma have been investigated (17), although further work is required to gain a more comprehensive understanding as VPA has significant pleiotropic effects.
NON-SELECTIVE HDACi TREATMENT IN TRAUMATIC BRAIN INJURY
TBI remains a leading cause of preventable death following trauma. It is also considered the signature injury of current military conflicts, affecting over 30,000 military members in combat zones yearly (57, 58). Existing strategies for TBI are not only limited in efficacy, but are also somewhat contradictory to those employed in hemorrhagic shock. A central tenet of TBI care is to maintain arterial pressure to drive cerebral perfusion pressure, which is incongruous with the principles of DCR. Investigation of adjunctive therapies is therefore becoming an essential part of TBI research.
Use of HDACis alone or in combination with traditional resuscitative strategies for TBI has demonstrated promising results. In small animal models, VPA improves outcomes in rat models of TBI, conferring both neuroprotection and attenuation of early injury progression (59). The benefit of VPA in both hemorrhagic shock and TBI is maintained in more complex models of combined injuries in large animal models. Multiple studies demonstrate that VPA administration following combined hemorrhagic shock and TBI reduces brain lesion size, improves long-term neurologic outcomes, and promotes a faster rate of neurologic recovery (60). VPA has also been shown to be synergistic with 6% hetastarch (Hextend [Hex]) or fresh frozen plasma (FFP) (61, 62). In a swine model of 40% hemorrhage and cortical impact TBI, followed by a 2-h period of hemorrhagic shock, VPA (300 mg/kg) administration significantly decreased brain lesion size in the Hex + VPA group compared with those animals treated with Hex alone (62). Follow-up studies demonstrated that the addition of VPA to FFP in a similar model decreased brain swelling by 40% and lesion size by 25% compared with FFP alone (61).
Mechanisms of action
The mechanisms of the neuroprotection conferred by VPA in TBI have been investigated within recent years. VPA appears to improve cerebral metabolism as shown through decreased cerebral lactate and pyruvate levels (63); decrease excitotoxicity through reduction of extracelluar glutamate and glycerol accumulation (64–67); improve mitochondrial membrane function and pyruvate dehydrogenase (PDH) retention (63); and decrease perivascular albumin extravasation and preserve blood–brain barrier (BBB) integrity (68). The neuroprotective effects of VPA have also been demonstrated through significant alterations in gene expression profiles following VPA treatment. Nine hours following hemorrhagic shock and TBI, peri-injured brain was assessed using RNA sequencing (69). VPA was found to upregulate gene pathways involved in neurogenesis and neural development, while inhibiting pathways involved in apoptosis and neuroinflammation (69).
Proteomic and transcriptomic assessment of peripheral blood mononuclear cells (PBMCs) has been performed in 30-day survival studies of swine subjected to TBI, hemorrhagic shock, and polytrauma to identify gene expression changes after VPA treatment (70). Molecular changes in neurologic disorders are reflected in PBMCs, which can provide a window into brain pathology. VPA was found to upregulate pathways involved in cell proliferation and differentiation, and inhibit the pathways involved in apoptosis and inflammation (70). These protective effects were shown to occur within minutes following VPA administration (71), and were sustained for 24 h (70). VPA's effects on pathways regulating inflammation translate into changes in associated biomarkers (72). In animals given NS alone, serum glial fibrillary acid protein (GFAP) and neurofilament light chain (NF-L) levels increase immediately following injuries and peak at 24 h. However, VPA administration significantly attenuated these levels (72), which also correlated with decreased brain lesion size and edema and earlier time to normalization of neurocognitive function following TBI (73).
NON-SELECTIVE HDACi TREATMENT IN SEPSIS
Non-selective HDACis have also been investigated for use in sepsis. The inflammatory response induced by sepsis is considered to be similar to that induced by hemorrhagic shock (74). Furthermore, the development of sepsis is a potential sequela of the immune dysregulation following injury. Trauma often acts as an initial insult and primes the body for a “second hit,” potentiating susceptibility to infection (75, 76). As such, evaluating the effects of non-selective HDACis in sepsis remains crucial to their evaluation for use in trauma.
SAHA, a non-selective HDACi, was tested in a lethal mouse model of lipopolysaccharide (LPS)-induced sepsis (77). Pretreatment with SAHA improved survival to 87.5% in lethal sepsis (77). SAHA also markedly reduced the severity of acute lung injury at 48 h following LPS. Follow-up studies have shown that post-LPS administration of SAHA maintains this survival advantage, even in the absence of fluid resuscitation (78). SAHA has also been shown to provide hepatoprotection in LPS-mediated shock (79, 80).
LPS-induced endotoxic shock, however, does not fully replicate the complexities of a polymicrobial infection. Therefore, testing of both SAHA and VPA in models of cecal ligation and puncture (CLP), which more accurately represent polymicrobial sepsis, has been done. In a murine model of CLP-induced sepsis, treatment with SAHA produced a significant long-term survival benefit (81). VPA administration showed efficacy in combined hemorrhagic shock + CLP, significantly improving survival and decreasing the severity of secondary acute lung injury (82).
Use of non-selective HDACis has raised concerns about unintended effects; therefore, targeting specific HDACs to provide selective therapeutic effects has become an area of interest. Early studies suggest that VPA and SAHA likely inhibit class I and class II HDACs; however, the specific class responsible for their clinical benefit still needs to be better defined (52). These HDAC classes therefore represented potential for targeted HDAC inhibition.
In recent years, isoform-selective HDACis have been evaluated in trauma and sepsis models. In a rodent model of hemorrhagic shock evaluating different classes of HDACis, class IIa (MC1568, 5 mg/kg) and IIb (ACY1083, 30 mg/kg) HDACis demonstrated the most promising results (52). MC1568 and ACY1083 significantly improved 24-h survival compared to untreated controls, while class III inhibition (EX527, 50 mg/kg) improved survival, but did not meet statistical significance. Class I HDACi, MS275 (50 mg/kg), however, showed no improvement in survival. Overall, this suggested that the benefit observed with non-selective HDAC inhibition may be mediated largely through class II HDAC inhibition.
Additional studies have been conducted using class II HDACis including, Tubastatin A (TubA), a selective HDAC6 inhibitor (Class IIb). TubA has been tested in models of hemorrhagic shock and CLP, and it significantly improves survival compared to no treatment (83, 84). Furthermore, administration of TubA has been shown to protect intestinal tight junction integrity in hemorrhagic shock (85). TubA has also been shown to restore immune function by following CLP (86, 87). Initial results with novel HDAC6 inhibitors, including ACY-1083, are promising (88); however, further work needs to be done to isolate the specific isoforms within each class. Additional studies evaluating class II HDACis are currently underway.
The therapeutic effects of class III HDACis appear specific to pathology. Class III HDACs, the sirtuins (SIRTs), have been thoroughly investigated in models of sepsis. EX-527, a class III-specific agent that acts on SIRT1, has been shown to significantly reduce mortality in a lethal model of CLP-induced sepsis (89). AGK2, a SIRT2-selective inhibitor, has also been shown to reduce mortality in a similar model of lethal sepsis (90). In a model of hemorrhagic shock, EX-527, however, failed to provide any statistically significant improvement in survival (52). As such, it appears that class III HDACs may play a greater role in sepsis than in hemorrhagic shock, although more work needs to be done to elucidate the effects of this class.
Isoform-specific HDAC inhibition for TBI is complex and currently being investigated. Isoform-selective HDACis must not only have desirable tissue-specific effects but should also have the ability to cross the blood–brain barrier. The impact of HDACis on neuronal viability appears to be more isoform-specific, with studies showing opposing effects of different isoforms even within the same class (ex. class II HDACs) (91). Since specific HDAC isoforms are thought to have distinct roles in brain development and function, targeting these differential roles may be promising for the treatment of TBI.
At present, studies assessing the effects of isoform-specific HDACis in models of TBI are limited. SIRT1 has been suggested as a potential target for TBI based on studies in neonatal brain injury (92), while class I inhibitors have been evaluated for their neuroprotective potential (93) and in traumatic spinal cord injury (94). We have recently demonstrated that ACY-1083 decreases brain lesion size and edema following injuries in a model of combined hemorrhagic shock and TBI (88). However, further investigation of these specific agents in TBI is needed.
Among HDACis, VPA has the most experimental data to support human use. It was originally approved by the FDA for clinical use in epilepsy in 1978. However, VPA doses that have been used in preclinical swine studies of trauma are much higher (3–5×) than doses conventionally used in humans for epilepsy. To address this, a phase I, dose-escalation trial of VPA to evaluate the maximum safe dose in healthy human subjects, was recently conducted (95). In this study, no dose-limiting toxicities or significant adverse events were observed in healthy human subjects until the dose of 150 mg/kg. At this dose, toxicities and events were relatively minor, and included nausea and headache. However, all of these resolved within 24 h without intervention. Furthermore, no significant drug-related abnormalities were seen in terms of clinical laboratories, ECG studies, organ injury, or cognitive functions. The study concluded that the maximum tolerated human dose is 140 mg/kg, which is factor-equivalent to the 150 mg/kg dose observed to have clinical benefit in swine models (95). Despite these findings, the pharmacokinetic profile of VPA in trauma patients may be different than the healthy subjects. A dose-escalation trial evaluating the safety in patients presenting with hemorrhagic shock (Clinical Trials Identifier NCT02872428; https://clinicaltrials.gov/ct2/show/NCT02872428) is currently underway. This will be correlated with dose-optimization studies in large animal models, which is currently underway.
In addition to optimal dosing, confirmation of VPA's mechanisms of action in humans is required. PBMCs of healthy humans from the dose-escalation trial were analyzed for proteomic changes following VPA administration (96). Gene pathways most significantly affected included those related to apoptosis, cell death, cell proliferation, amyloidosis, fatty acid metabolism, steroid metabolism, and cell movement (96). Interestingly, no significant changes in the acetylation status of histone and non-histone proteins were observed in these healthy individuals (96). However, a recent human study evaluating HDAC expression in leukocytes in blunt trauma patients with hemorrhagic shock highlights the role of protein acetylation (97). Expression of HDAC1, HDAC3, and HDAC11 was higher in patients with complicated outcomes, including death or no recovery by 28 days following injures, and HDAC3 and SIRT5 expression was correlated with multi-organ failure. These findings highlight the role of HDACs in traumatic injuries. With further studies, targeted HDAC inhibition may help to improve clinical outcomes for trauma patients.
Over the last few decades, tremendous improvements in trauma care have been made; however, there is still room for additional refinements, especially in austere/prehospital settings (98). HDACis represent a potential strategy in patients subjected to trauma and sepsis. They have been shown to improve survival and minimize neurologic injury, coagulopathy, inflammation, and oxidative stress in models of hemorrhagic shock, TBI, polytrauma, and sepsis. As definitive strategies, including blood products and hemorrhage control, remain difficult to implement in the prehospital setting, HDACi administration may provide a bridge to definitive resuscitation. Of numerous HDACis, VPA appears to be the most promising in preclinical studies and is currently in clinical evaluation. Further work, including dose optimization and further assessment in clinical trials, is required for human translation. Overall, HDACis may represent a high-impact strategy for use in far-forward and austere settings in the near future.
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