|
 
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| REVIEW ARTICLE |
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| Year : 2020 | Volume
: 2
| Issue : 3 | Page : 54-63 |
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Endoplasmic Reticulum Stress and Critical Care Medicine
Ying Shi, Tingting Wang, Xiangrong Zuo
Department of Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| Date of Submission | 02-Sep-2020 |
| Date of Acceptance | 24-Nov-2020 |
| Date of Web Publication | 31-Dec-2020 |
Correspondence Address:
Dr. Xiangrong Zuo
Department of Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 GuangZhou Road, Nanjing 210029, Jiangsu
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jtccm.jtccm_16_20
Many patients suffer from multiple organ dysfunction syndrome (MODS), which represents a dominant cause of death in the intensive care unit. Current theories about the mechanisms of MODS include inflammation, dysregulated immune response, reduced cellular oxygen utilization, cytopathic hypoxia, and apoptosis. Moreover, an increasing number of studies have shown that endoplasmic reticulum stress (ERS) is related to organ dysfunction. The endoplasmic reticulum is an organelle that is responsible for secretion and membrane protein synthesis and assembly as well as some other physiological activities. Under certain conditions, the homeostasis of ER can be lost, causing the accumulation of unfolded or misfolded protein, which is termed as ERS. During ERS, unfolded protein response (UPR) is activated. Once UPR fails to rebuilt cellular homeostasis, cell function will be impaired and apoptosis will be induced. To better understand the relationship between ERS and severe diseases, we summarize the current research in the context of ERS and UPR signaling associated with various organ dysfunction and severe diseases, including acute lung injury, hepatic injury, heart failure, hemorrhagic shock with multiple organ dysfunction, sepsis, and some other diseases. We also discuss ERS or UPR as a novel therapeutic target and their future directions.
Keywords: Endoplasmic reticulum stress, multiple organ dysfunction syndrome, sepsis, unfolded protein response
How to cite this article:
Shi Y, Wang T, Zuo X. Endoplasmic Reticulum Stress and Critical Care Medicine. J Transl Crit Care Med 2020;2:54-63 |
FNx01Ying Shi and Tingting Wang: contributed equally to this work
| Introduction | |  |
Critical care medicine is defined as a discipline that studies the characteristics and regularity of the body developing toward death caused by any acute injury or disease and treats critically ill patients according to these characteristics and regularity. These life-threatening severe diseases have always been a major issue in medical research or clinical medicine. Many patients in intensive care unit (ICU) suffer from multiple organ dysfunction syndrome (MODS), which is defined as the acute and potentially reversible dysfunction of 2 or more organ systems that is triggered by multiple different and clinically diverse factors.[1] MODS represents a dominant cause of death and its mortality rates remain between 44% and 76%.[1]
The pathophysiology of MODS is complex and multifactorial. Both infectious and noninfectious diseases can cause MODS. It is now generally believed that the imbalance between pro-inflammatory and anti-inflammatory cytokines plays a significant role in MODS, and the dysregulated immune response is central in MODS pathophysiology. Moreover, it is reported that reduced cellular oxygen utilization or cytopathic hypoxia, dysfunction of mitochondria and endothelium, as well as gut dysfunction can be possible mechanisms of MODS.[1] Furthermore, more and more studies have shown that the function of endoplasmic reticulum, especially endoplasmic reticulum stress (ERS), is closely related to the occurrence and development of diseases, including autoimmunity, infection, metabolic disorders, and neurodegenerative diseases as well as organ dysfunction. In this review, we summarized the current research on ERS associated with various organ dysfunction, in order to better understand the relationship between ERS and life-threatening illness and the potential use of therapies, so that we can do more in-depth research in future.
| The Mechanisms of Endoplasmic Reticulum Stress Meditated Unfolded Protein Response Signal Pathways | | |
ER, a vital intracellular organelle for secretion and membrane protein synthesis and assembly, is responsible for protein translocation, protein folding, and protein posttranslational modification.[2] It is often encountered that the demand for protein folding will exceed the folding capacity of ER, resulting in the accumulation of unfolded or misfolded protein and causing ERS. Under the condition of ERS, in order to protect cells and rebuild homeostasis of ER, the intracellular signaling pathway called unfolded protein response (UPR) becomes active.[3] When the UPR fails to rebuilt cellular homeostasis or the stress is so severe, cell function will be impaired and apoptosis will be induced.[4]
There are mainly three types of ERS sensors, which are ER transmembrane protein playing an important role in UPR, including inositol-requiring protein 1 (IRE1), double-stranded RNA-dependent protein kinase (PKR)-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) in mammals. Binding immunoglobulin protein (Bip), also known as glucose-related protein 78 (GRP78), is combined with the ER domain of these ERS sensors in normal cells. They are activated in signal pathways, respectively, during ERS to reduce unfolded or misfolded protein. Furthermore, these sensors with their downstream signal factors jointly participate in the signaling cascades of inflammation, oxidative stress, and apoptosis.
Inositol requiring protein1-X-box binding protein1
IRE1 contains an ER domain that is involved in sensing unfolded or misfolded protein and a cytoplasmic domain which has protein kinase and endoribonuclease activities. During ERS, the bounded Bip dissociates from IRE1, which then is oligomerized and autophosphorylated.[5] IRE1 phosphorylation activates its endoribonuclease activity, which excises 26 base pairs from the X-box binding protein (XBP1) mRNA, and subsequent mRNA religation causes a translational reading frameshift generating a highly active transcription factor known as XBP1s.[6] XBP1s then is transferred into nucleus and activates UPR-related genes, including ER-associated degradation (ERAD) components.[7] Jeschke et al.[8] found that thermal injury leads to activation of the ERS response, Bip, and phosphorylation of IRE1, which mediates mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury.
In addition, IRE1 controls many other initiations of several downstream signaling pathways. Under certain condition, IRE1 degrades non-XBP1 mRNA substrates, a phenomenon known as regulated IRE1-dependent decay which lowers the expression of the derived protein.[9] Besides its cytoprotective function, IRE1 also activates Apoptotic Signaling Kinase 1 (ASK1) by binding to tumor necrosis factor (TNF) receptor associated factor 2 (TRAF2), leading to activation of downstream signals of stress kinase Jun N terminal kinase (JNK) that promotes apoptosis.[10] In Jeschke's study,[8] they also found upregulation of phosphorylated JNK in animals. Then, IRE1-dependent JNK stimulates the activation of transcription C/enhancer binding protein homologous protein (CHOP) and nuclear factor kappa B (NF-κB), which causes changes in gene expression that favor apoptosis and inflammatory response.[11]
Protein kinase RNA-like endoplasmic reticulum kinase
PERK senses unfolded or misfolded protein and has protein serine/tryptophan kinase activities. Like IRE1, in the situation of ERS, Bip releases from PERK and combines with unfolded protein, and PERK then is activated through oligomerization and phosphorylation. The activated PERK directly phosphorylates the translation initiation factor eIF2α, suppressing general protein translation.[12] This effect of translation inhibition alleviates ERS by reducing the production of unfolded or misfolded protein. The phosphorylation of PERK and eIF2α induces the translation of ATF4, which enhances the translation of the pro-apoptotic transcription CHOP under ERS.[13] Besides, ATF4 activates the transcription of target genes encoding growth arrest and DNA damage-inducible protein 34 (GADD34), which enhances dephosphorylation of eIF2α and resumes protein synthesis in the context of stress relief.[14] These studies[8],[15] suggest that burn injury leads to ERS, and the level of PERK phosphorylation is upregulated in animals. Wang et al.[16] demonstrated that paraquat (PQ) treatment upregulated the protein expression of ERS marker molecules Bip and CHOP in human lung epithelial A549 cell strain, suggesting that PQ-induced A549 cell apoptosis involved ERS, especially the PERK-eIF2α pathway.
Activating transcription factor 6
The ER luminal domain of ATF6 is responsible for sensing unfolded or misfolded protein and its cytoplasmic part has a DNA-binding domain containing the basic-leucine zipper motif and a transcriptional activation domain. During ERS, Bip dissociates from ATF6, and ATF6 is translocated from ER to Golgi apparatus by vesicular transport.[17] In the Golgi apparatus, ATF6 is subsequently cleaved by site 1 and site 2 proteases (S1P, S2P), yielding the active transcription factor ATF6f (a fragment of ATF6).[18] ATF6f then migrates to the nucleus and enhances molecular chaperones and several genes associated with ERAD and protein folding, such as GRP78, GRP94, and calreticulin.[2],[19] Furthermore, ATF6f can also activate target gene encoding CHOP in nucleus and then regulates cell programmed death during prolonged ERS.[20] In Wang et al.'s study,[16] they also found that the level of cleaved ATF6 is significantly upregulated in PQ-treated A549 cell.
| Endoplasmic Reticulum Stress and Apoptosis | | |
If the various UPR-induced mechanisms fail to alleviate ERS, UPR sensors divert their signals to cell death possibly through different overlapping signal mechanisms, including (1) the transcriptional activation of CHOP meditating by IRE1, PERK, and ATF6,[21] which plays an important role in ERS-induced apoptosis, whose apoptosis-relevant target includes GADD34, Bim, death receptor5 (DR5), and ER oxidoreductase-1, which hyperoxidizes the ER and promotes cell death;[20] (2) the activation of JNK pathway meditating by IRE1, and it is followed by the activation of TRAF2 and ASK1;[10] and (3) the activation of ER-related caspase-12, which is remarkably specific to insults that cause ERS and is not activated by other death stimuli according to Toshiyuki Nakagawa et al.'s research.[22] They found that caspase-12-null mice and cells are partially resistant to apoptosis induced by ERS, but not by other apoptotic stimuli. Moreover, ER is the major storage of intracellular Ca2+, and intracellular Ca2+ homeostatic mechanism is a key signal pathway connecting apoptosis to ER-mitochondrial interaction.
| Endoplasmic Reticulum Stress and Inflammation | | |
Both ERS and inflammation are defensive responses triggered by stressful stimuli, but can become destructive when sustained. ERS interacts with inflammation through numerous mechanisms and in various disease states, including autoimmunity and infection, metabolic disorders, asthma, and neurodegenerative diseases. In addition, pro-inflammatory stimuli such as reactive oxygen species (ROS), Toll-like receptors (TLRs) and their ligands, and some cytokines (interleukin [IL-17] and TNF-α) can also activate UPR to further exacerbate inflammation. On the one hand, IRE1 can be phosphorylated by the signals of TLRs to induce XBP1 mRNA splicing and stimulates yielding proinflammation cytokines in macrophages.[23] On the other hand, TLR signaling can also inhibit ATF6 and CHOP in macrophages.[24] Several studies[25],[26],[27] indicate that ERS induces inflammation responses by activating UPR factors such as XBP1, ATF6, and cAMP response element-binding protein H (CREBH), while these UPR factors upregulate proinflammation factors including IL-1 β, TNF-α, and IFN-γ.[18] It is reported that the aminoterminal fragment of CREBH upregulated acute phase proteins such as serum amyloid P-component and C-reactive protein, contributing to the acute phase of inflammatory response.[27]
| Endoplasmic Reticulum Stress and Oxidative Stress | | |
Oxidative stress, an imbalance between the production of ROS and the ability of the body to repair the resulting damage, is interconnected with ERS. Unfolded or misfolded protein can induce production of ROS; likewise, oxidative stress disturbs ER redox state, and then it disrupts normal disulfide bond formation and proper protein folding.[28] Li et al.[29] demonstrated that ERS stimulates oxidative stress in macrophages, which is dependent on CHOP, proapoptotic calcium signaling, and nicotinamide adenine dinucleotide phosphate reduced oxidase, suggesting that NADPH oxidase links ERS, oxidative stress, and PKR activation to induce apoptosis.
| Endoplasmic Reticulum Stress and Ischemia/Reperfusion Injury | | |
Ischemia/reperfusion (I/R) injury can lead to hypoxia, acidosis, accumulation of free radicals, and energy depletion of cells, which causes ERS and affects the synthesis and folding of numerous proteins. I/R injury is a common pathophysiological change during trauma, shock, and other critically ill. Grootjans et al.[30] described that in jejunum samples from humans and rats, I/R activated the UPR and resulted in Paneth cell apoptosis. They also showed increased Bip staining, specifically in Paneth cells upon reperfusion of ischemic jejunum. Tajiri et al.[31] expressed that mRNAs for CHOP and Bip are markedly induced at 12 h after brain ischemia in wild-type mice. Moreover, they found that ischemia-associated apoptotic loss of neurons was decreased in CHOP-null mince, suggesting that ischemia-induced cell death is meditated by ERS pathway involving CHOP.
| Endoplasmic Reticulum Stress and Multiple Organ Dysfunction Syndrome | | |
Endoplasmic reticulum stress and acute lung injury/acute respiratory distress syndrome
Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory failure that can result from a variety of causes. It is one of the common fatal causes of respiratory failure in critically ill patients.[32] According to statistics, the incidence of ARDS in critically ill patients worldwide is about 10% and the mortality rate is 30%–40%.[32] The pathogenesis of ARDS is complex. Systemic or local injury factors can activate ERS and UPR, thereby mediating oxidative stress, inflammation, apoptosis, and other injury mechanisms, and ultimately leading to structural damage and functional deterioration of lung tissue.[33],[34]
Under pathological conditions, ERS induces an inflammatory response, which further activates ERS. This positive feedback ultimately destroys protein homeostasis in lung tissue, exacerbates inflammatory stress in lung tissue, and results in the deterioration of metabolism of various immune cells in lung tissue.[27],[35] Lipopolysaccharide (LPS), a primary component of endotoxin of Gram-negative bacteria cell walls, is involved in a variety of inflammatory disorders. In Kim et al.'s research,[36] acute lung injury (ALI) mouse model was established by intratracheal instillation with LPS. The expression of GRP78, CHOP, and other stress-related markers of ERS in LPS-treated mice was significantly increased. In addition, 4-phenylbutyrate (4-PBA), as an ERS specific inhibitor, reduced the increase of LPS- induced various ERS markers in the lung. Besides, inhibition of ERS ameliorates LPS-induced lung inflammation through modulation of NF-κB/IκB and HIF-1α signaling pathway. Their research results suggest that ERS is an important factor in inducing and maintaining inflammatory lung injury in ARDS.
According to further research, activated ERS can induce the apoptosis of lung tissue cells, which may play an important role in the pathophysiology of ARDS. Studies have demonstrated that the PERK signaling pathway induces apoptosis in alveolar epithelial cells and pulmonary microvascular endothelial cells, leading to structural damage and functional deterioration in lung tissue.[37] Similarly, increased expression of IRE1 signaling pathway proteins and apoptosis markers were detected in the lung tissues of cecal ligation and puncture-induced ALI rats, accompanied by increased apoptosis rate of pulmonary microvascular endothelial cells.[38]
When the balance between production and degradation of ROS in the body is disturbed, uncontrolled oxidative stress can be induced, thereby disrupting protein homeostasis and activating ERS. One research[39] in 2018 showed that inhalation of sea water can activate ERS in lung parenchymal cells. In addition, seawater inhalation induces the production of ROS, which interacts with ERS to jointly cause alveolar cell injury, suggesting that ERS is one of the pathogeneses of lung injury.
Induction of ERS in the pulmonary endothelium is central to the pulmonary vascular dysfunction in diet-induced obese mice. Some studies[40] have shown that the fatty acids in the serum of the obese model could induce ERS in the endodermal cells of the lung, thus causing the function damage of the lung endothelial cells and enhancing the susceptibility of ARDS. Furthermore, therapies that reduce ERS might prevent ARDS in the obese.
From what has been discussed above, when external injury factors persist, ERS signaling pathways will be correlated with inflammatory response, oxidative stress, apoptosis, and other injury mechanisms, jointly aggravating inflammatory lung injury.
Endoplasmic reticulum stress and hemorrhagic shock with multiple organ dysfunction
Hemorrhagic shock is a common acute and critical disease in clinical practice. It is characterized by acute circulatory disorder and severe hypoxia in tissues, with severe consequences of tissue cell injury and dysfunction. It is one of the causes of death in trauma patients. Posttraumatic hemorrhage is characterized by increased oxidative stress, hypoxia, and proinflammatory cytokines, which can initiate ERS.[41] Several studies[42],[43] have found that ERS triggers the deleterious cascade that leads to organ dysfunction after trauma and bleeding.
Kozlov et al.[44] found that trauma and hemorrhagic shock in rats significantly affects mitochondrial function, ERS markers, and free iron levels, suggesting that ERS plays an important and harmful role in the proliferation of cell death components. Yu et al.[45] demonstrated that prolonged stress induced ATF6α-dependent ERS and ER-related apoptosis in the medial prefrontal cortex neurons of the rat, which indicated the participation of ERS in posttrauma-induced apoptosis.
Numerous studies[41],[42],[43] demonstrated that hemorrhagic shock increases the mRNA expressions of ERS marker CHOP, spliced XBP1, and GRP78 in liver cells.The expression of GRP78/Bip, ATE6, PERK, IRE1, CHOP, protein disulfide isomerase and the content of caspase-12 in liver tissues increased, which improved the apoptosis rate and reduced the proliferation index of liver cells.
Besides, IR increases the expression of Paneth cell GADD34, XBP1s, and CHOP in jejunum samples from humans and rats, suggesting that the UPR is enhanced, and the expression level of these ERS marker molecules is positively correlated with the apoptosis rate.[30] Sodhi et al.[46] found that trauma/hemorrhagic shock induces ERS in the intestinal epithelium in a TLR4-dependent manner, causing enterocyte apoptosis and the release of high mobility, group box-1 protein (HMGB1). Their research also demonstrates that activation of TLR4 in the intestinal epithelium is required for the induction of secondary lung injury after trauma. Remote lung injury after trauma requires HMGB1 release from the intestinal epithelium. The novel TLR4 inhibitor C34 inhibits TLR4 and protects against lung injury after trauma in mice. In summary, excessive ERS plays a role in the pathogenesis of intestinal injury caused by hemorrhagic shock and acute blood loss causes ERS in intestinal epithelial cells by activating the TLR4/HMGBI signaling pathway.
In addition, the injury of nervous system in hemorrhagic shock is also related to ERS. According to the research of Hu et al.,[47] after 72 h of hemorrhagic shock, the rats presented learning and memory dysfunction. The expressions of GRP78, CHOP, IRE1, and Caspase-12 proteins in the hippocampus increased, and the number of neuronal cell necrosis and apoptosis increased. They also found that sevoflurane postconditioning not only improved the learning and memory ability of rats with hemorrhagic shock, but also inhibited the protein expression of ERS marker molecules and neuronal apoptosis. Similarly, Begum et al.[48] investigated that sustained ERS may play a role in chronic neuronal damage after traumatic brain injury, suggesting that inhibition of ERS reduces the abnormal protein accumulation and neurological deficits.
These studies suggest that ERS is involved in the process of multiorgan structural damage and dysfunction caused by hemorrhagic shock. Its role in the pathogenesis of multiple organ injury caused by hemorrhagic shock cannot be ignored.
Endoplasmic reticulum stress and hepatic injury
Liver failure is a kind of serious liver disease caused by multiple causes with high fatality rate. The pathogenesis of liver failure is very complex, which is closely related to immune injury and inflammation of the host.
At present, most scholars believe that TLR4 in the liver recognizes and combines with LPS to cause inflammatory cascade amplification effect, and excessive inflammatory immune response leads to large amounts of hepatocytes apoptosis and necrosis, and finally leads to liver failure.[49],[50] Since inflammation and apoptosis are important pathogenesis of liver failure, ERS plays an indispensable role in the pathogenesis of liver failure.
ERS plays a key role in the development of liver inflammation and injury. ERS is associated with several inflammatory pathways in liver failure, which are mainly involved in two inflammatory pathways, JNK and NF-κB.
IRE1 links ERS with ERK phosphorylation and ATF4 activation, upregulating inflammatory cytokines by activating JNK, which is involved in the regulation of inflammation in liver failure.[51] Furthermore, IRE1, PERK, and ATF6 all activate the NF-κB signaling pathway. When the cells are stressed, NF-κB activation regulates inflammatory cytokines and participates in various biological processes including inflammatory response and apoptosis.[52] Other research found that 4-PBA could significantly inhibit hepatotoxicity on acetaminophen-induced and CCl4-induced liver injury in mice.[53],[54]
ERS-induced UPR promotes inflammatory responses by IRE1, ATF6, and PERK, which mediate pathways associated with inflammatory signals to alert neighboring cells and prevent further tissue damage. However, as the disease progresses, uncontrolled severe ERS and inflammatory response synergistically promote the production of a large number of proinflammatory factors.[52] Two-way function and synergistic inflammatory response of ERS play a complex and critical role in the pathogenesis and progression of disease. The ability of ERS to induce inflammatory response is thought to play an important role in the pathogenesis of disease, and regulating ERS to control inflammatory process may be a potential therapeutic target for inhibiting disease progression.[55]
Apoptosis plays an important role in the pathogenesis of liver failure. Currently known apoptosis pathways include DR pathway, mitochondrial pathway, Granzyme B signaling pathway-mediated apoptosis, and ERS apoptosis pathway.
In mice with acute liver injury caused by ethanol, activation of hepatic microsomal pigment P450 promotes UPR and ERS, which is manifested as upregulation of GRP78, GRP94, CHOP, and other genes,[56] promoting the occurrence of ERS, inducing cell apoptosis and affecting lipid metabolism. Intervention of ursodeoxycholic acid in patients with nonalcoholic fatty liver disease can reduce the level of pro-apoptotic factor miR-34a in serum, reduce the expression levels of ERS reactive protein CHOP and GRP78, change the threshold of apoptosis, inhibit ERS-mediated hepatocyte apoptosis, and improve liver function.[57]
The pathophysiological effects of ERS and UPR demonstrate that ERS is associated with the development of various liver diseases, suggesting that the development of drugs targeting UPR signal transduction may provide new ideas for severe diseases such as liver failure.
Endoplasmic reticulum stress and heart failure
Heart failure is a condition in which the systolic and/or diastolic functions of the heart are impaired, resulting in an inability of the cardiac output to meet the metabolic needs of the body's tissues. This condition is characterized by congestion of the systemic and/or pulmonary circulation and insufficient blood perfusion to the organs and tissues.
According to some studies,[58],[59],[60] ERS promotes apoptosis through signaling pathways such as PERK/CHOP, IRE1/ASK, and caspase-12.These pathways can be affected by the activated renin–angiotensin–aldosterone system, sympathetic adrenaline system, and the concentration of B-type brain natriuretic peptide in circulation, which could lead to cell apoptosis and even heart failure. Meanwhile, myocardial remodeling fibrosis can also occur due to the release of fibrogenic factors and the induction of inflammatory response caused by CHOP pathway.
When ERS is excess and/or prolonged, the initiation of the apoptotic processes, which could cause myocardial hypertrophy and heart failure, is promoted by transcriptional induction of CHOP or by the activation of JNK and/or caspase-12-dependent pathways.[61],[62] Therefore, inhibiting the expression of the proteins above can treat heart failure by reducing cell apoptosis. In addition, it has been found that ERS occurs in failing hearts and this can be reversed by beta-adrenergic receptor blockade. Alleviation of ERS may be an important mechanism underlying the therapeutic effect of beta-adrenergic receptor blockers on heart failure.[60]
Besides, ERS is closely related to atherosclerosis, ischemic cardiomyopathy, hypertension, heart failure, and other cardiovascular diseases. It is widely involved in the occurrence and development of various cardiovascular diseases. Therefore, to explore the protective mechanism of ERS rationally, block the activation of ERS apoptosis pathway, and resist the key link of stress injury will become an important direction for the research and treatment of various mechanisms of cardiovascular diseases.
| Endoplasmic Reticulum Stress in Sepsis | | |
Sepsis and septic shock are often-deadly complications of infection, which can lead to tissue hypoperfusion and multiple organ failure.[63] ERS response was found to be involved in sepsis progression in different sepsis models.
Hiramatsu et al.[64] found that intraperitoneal injection of LPS caused the upregulation of GRP78 expression in spleen, lung, liver, heart, and other organs of mice, which suggested that endotoxemia induced systemic ERS. Schildberg et al.[65] reported that LPS stimulates apoptosis of human umbilical vein endothelial cells. They found that ER disintegration was noticed as early as 6 h of incubation with LPS, thus preceding and outweighing the functional loss of cell viability. As a sensitive marker of ERS, notable activation of PERK occurs after the addition of LPS. Moreover, the degradation of caspase 12 is accompanied by cleavage of caspase 9 and, eventually, the activation of caspase 3. This suggests that the activation of ERS-related apoptotic signals is the key event to trigger endothelial cell apoptosis.
In the research of Kozlov et al.,[66] LPS can lead to functional ER failure tentatively via a mitochondrion-dependent pathway in livers of rats, whereas histological examination did not reveal significant damage to liver in form of necroses. The spliced mRNA variant of XBP1 and also the mRNA of GRP78 were upregulated, but the translocation of apoptosis inducing factor to the nucleus was not accompanied, suggesting that the cells entered a preapoptotic state, but apoptosis was not executed. This suggests that after the stress response of ER, the cells may survive, but the function of ER may fail. Apoptosis and basic cell dysfunction are the cytological basis of multiple organ failure induced by sepsis. Therefore, ERS response may be an important target in the treatment of sepsis.
CHOP is a major inducer of apoptosis in response to ERS, and there was evidence suggesting an inflammatory role of CHOP as a mediator of the inflammatory response in sepsis. Ferlito et al.[67] reported that septic mice exhibited increased expression of CHOP and H2S treatment increased survival in a model of experimental sepsis by inhibiting the CHOP expression, suggesting the participation of ERS in sepsis. They found that CHOP may act as an amplifier of the inflammatory response in the pathogenesis of sepsis, and H2S inhibits CHOP expression at least partially through a mechanism involving Nrf2 activation.[67] Moreover, ERS pathway, including CHOP, is activated in the lungs of LPS-treated mice, and the lung damage induced by LPS treatment is attenuated in CHOP knockout mice.[68] These results further demonstrate that the CHOP-mediated ERS plays a key role in the pathogenesis of septic injury in mice. Moreover, Kim et al.[36] have reported that using a specific ERS inhibitor 4-PBA reduced the increase of LPS-induced various ERS markers and attenuated lung inflammation in mice. These results increase our knowledge of the pathogenetic mechanisms of sepsis, and therapeutic regimens targeting ERS responses may improve outcomes in patients with sepsis.
Sepsis complicated with multiple organ dysfunction is one of the main causes of death in critically ill patients. Its pathophysiological mechanism is relatively complex, and there is still a lack of targeted prevention and treatment measures. With the in-depth study of ERS, the role of ERS and its mediated apoptosis in the development of sepsis need to be further confirmed. To explore the specific mechanism of ERS in sepsis and try to intervene every link of the ERS pathway will hopefully bring a new way for the treatment of sepsis.
| Endoplasmic Reticulum Stress and other Diseases | | |
ERS has been found to be associated with many other diseases, in addition to the above-mentioned diseases. For example, ERS is evident in various renal diseases, including primary glomerulonephritides, glomerulopathies associated with genetic mutations, diabetic nephropathy, acute kidney injury (AKI), chronic kidney disease, and renal fibrosis.[69] AKI, a common disease in critically ill patients, is often concerned by ICU physicians. In a retrospective study,[70] Fan et al. showed the induction of multiple ERS markers in the renal biopsies of AKI patients. And, as a key mediator of ERS, Reticulon 1A, the induction of which correlated positively with the severity of AKI.
Moreover, ERS is also associated with brain injury caused by cerebral hemorrhage. Apoptosis plays a major role in the development of cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH).[71] According to the research of He et al., CHOP orchestrates apoptosis in a variety of cell types in response to ERS, implicated in the brain injury after SAH. In addition, their study strongly suggests that ERS, a main CHOP inducer, plays a major role in the development of CVS. Moreover, CHOP siRNA treatment can effectively combat apoptotic mechanisms of CVS set in motion by subarachnoid bleeding.
Besides, many studies have shown that ERS also plays an indispensable role in the development and progression of Acute pancreatitis (AP).[72] Pancreatic cells are more prone to external stimuli in the case of ER disorder.[73] The ER structure can change significantly during the pathogenesis of pancreatitis. Moreover, the ERS-induced morphological changes in the ER have been confirmed by Hartley et al.[74]
Patients in ICU are often involved in MODS. Unfortunately, at present, there is still a lack of targeted prevention and efficient treatment measures with regard to MODS. As we can see from the discussion above, ERS is associated with various organ dysfunctions. The research on the relationship between ERS and human diseases, especially critical diseases, not only improves the research on the pathogenesis of diseases, but also provides new ideas and methods for the exploration of disease surveillance and targeted therapy.
| Therapeutic Target | | |
ERS is associated with the pathogenesis of many diseases; therefore, UPR pathway may be an important therapeutic target for regulating ERS and ER-related diseases. A research[75] showed that the Mdivi-1 (a derivative of quinazolinone)-induced decrease of mitochondrial fragmentation reduced ROS production and prevented ERS in sepsis, and Mdivi-1 ameliorated apoptosis in CD4+ T cells by reestablishing mitochondrial fusion-fission balance and preventing the induction of ERS in experimental sepsis. Rosen et al.[76] have discovered that Sigma-1 receptor (S1R) restricts the endonuclease activity of the ERS sensor IRE1 and cytokine expression, which may have substantial clinical implications, as they have further found that fluvoxamine, an antidepressant therapeutic with high affinity for S1R, protects mice from lethal septic shock and dampens the inflammatory response in human blood leukocytes, placing S1R as a possible therapeutic target to treat bacterial-derived inflammatory pathology. Chen et al.[77] indicate that heme oxygenase-1 protects sepsis-induced ALI and alleviates intrapulmonary cell apoptosis through suppression of the PERK/eIF2α/ATF4/CHOP pro-apoptosis pathway in ERS. Hou et al.,[78] whose study shows exogenous adiponectin at a dose of 120 mg/kg attenuated endothelial cell apoptosis in the septic rats, confirmed that the administration of adiponectin may alleviate endothelial cell apoptosis by suppressing the ERS IRE1α pathway. Hong et al.[79] demonstrated that 4-PBA diminishes the expression of ERS markers (Bip, CHOP, PREK, ATF6, and IRE1) in vital organ of AP rats, and it protects pancreas, lung, liver, and kidney from injury in AP rats by regulating ERS and mitigating inflammatory response to restrain cell death. Furthermore, ER-resident GRP94 has been identified as a strong modulator of the immune system that could be used in anticancer immunotherapy.[80]
Moderate ERS can protect cells, but too strong or too long ERS leads to apoptosis. Exploring the protective mechanisms of ERS and blocking the activation of apoptosis pathways of ERS cells to resist stress injury will be a significant direction for the research and treatment of various organ dysfunction, providing new ideas for the treatment of critical care medicine.
| Perspectives and Future Directions | | |
Despite increasing understanding of the pathophysiology of critically illness and associated MODS in critical care medicine, no effective clinical treatments or preventive strategies have been developed yet. The discovery of some common key pathogenic mechanisms or pathways of many of these diseases is also a new strategy and direction of precision medicine and targeted therapy. The bidirectional role of ERS and its synergistic inflammatory response plays a complex and critical role in the occurrence and development of diseases. In-depth research will be conducted on the mechanism and self-regulation mechanism of ERS, to explore new targets for disease treatment and take some effective prevention and treatment measures. How to effectively mobilize appropriate ERS to resist stress injury, block apoptotic pathways, clarify the molecular mechanism of disease and drug therapy to achieve targeted therapy, and even promote the gradual transition from experimental research to clinical application in disease prevention and treatment, as well as from the perspective of precision medicine, will be the direction and goal of our continuous efforts.
Acknowledgments
This study was supported by Jiangsu Provincial Medical Youth Talent (QNRC 2016557), the third level of 333 High Level Talent Training Project in Jiangsu Province, “Six One Project” Research Project of High-level Medical Talents of Jiangsu Province (LGY2019067).
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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