Sepsis‑induced cardiac dysfunction and pathogenetic mechanisms (Review)
- Authors:
- Published online on: October 17, 2023 https://doi.org/10.3892/mmr.2023.13114
- Article Number: 227
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Copyright: © Song et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Sepsis is a syndrome that occurs when microorganisms invade and cause systemic disease, which can be life-threatening (1,2). The third international consensus definition of septic shock and sepsis was published in 2016 and defined septic shock as organ dysfunction caused by systemic infection (3). The immune system is suppressed during sepsis, which leads to increased inflammatory response (4,5). The immune cells are triggered by bacteria, toxins and other factors that result in infection, releasing large quantities of inflammatory mediators (6,7). The release of inflammatory mediators without an appropriate anti-inflammatory response destroys the immune system, resulting in unrestrained inflammatory state and a decreased ability to neutralize pathogens (8–10).
Septic cardiomyopathy (SC), or septic shock, is a condition defined by cardiac dysfunction caused by sepsis. SC is clinically characterized by defective left ventricular systolic function and ventricular hypertrophy. According to statistics from the beginning of 2018, up to two-thirds of patients with septic shock experience SC, which has become one of the most common fatal diseases (11). Therefore, novel pathogenic mechanisms of SC must be researched. The present review aimed to summarize the pathophysiology of SC, focusing on mitochondrial dysfunction, metabolic alterations, signaling pathways and other mechanisms. These mechanisms of pathogenesis may be used to validate discovery of novel ways to treat sepsis contribute to decreased mortality in patients with SC.
Pathological findings and clinical symptoms
Before the onset of SC, pathogenic bacteria that infect the body and their endotoxins enter the bloodstream, stimulating the immune system and producing large amounts of inflammatory factors, leading to cytokine storm (12). Myocardial dysfunction may be caused by chronic inflammation with prolonged lasting effects. During sepsis, the inflammatory response contributes to an overproduction of catecholamines, which impairs myocardial function and myocardial contractility. Cardiac output is affected when tachycardia leads to reduced coronary perfusion and cardiac output (13). In addition, mitochondria in septic cardiomyocytes undergo structural changes, DNA damage, elevated permeability and activation of apoptotic pathways, which decrease metabolism, to accommodate inadequate ATP production caused by mitochondrial dysfunction (14). SC can be characterized by elevated cardiac enzymes, characteristic changes in the electrocardiogram, hemodynamic changes, decreased left ventricular ejection fraction and systolic dysfunction (15). Clinical treatment is mainly divided into two aspects: Treatment of sepsis characteristics using antibiotics, vasoactive drugs, dopamine, glucocorticoids and antibacterial peptides. Traditional Chinese Medicine (TCM) treats septic cardiomyopathy through anti-inflammatory and anti-viral effects, and inhibition of apoptosis. Currently, TCM injections used clinically include Xuebijing injection and Shenfu injection.
Mitochondrial dysfunction
ATP is a compound synthesized in mitochondria and the cytosol during glycolysis. Mitochondria are abundant in the heart and are responsible for a significant amount of ATP production (16). The primary products following substrate oxidation, nicotinamide adenine dinucleotide and flavin adenine dinucleotide, provide electrons for complexes I and II. Under physiological conditions, electrons move from complex I to complex II, then from complex III to complex IV by oxidative phosphorylation (OXPHOS) (17). Complexes I–IV are involved in transferring electrons from the tricarboxylic acid cycle to mitochondria (18). During this process, a proton can be transferred from the mitochondrial matrix to the inner mitochondrial membrane (IMM) and O2 is reduced to H2O in the mitochondria (19). Between the IMM space and the mitochondrial matrix, protons accumulate, causing a proton motive force (ΔΨ). ATP regeneration via F0F1-ATPase (ATP synthase) is activated by ΔΨ, which transfers the proton from the mitochondrial matrix to the IMM (20–22). Therefore, F0F1-ATPase activity is associated with respiratory chain activity and ATP formation.
In addition, increased superoxide (O2−) and nitric oxide (NO) production can cause direct oxidative or nitrosative damage and inhibition of OXPHOS complexes, leading to decreased O2 consumption and mitochondrial membrane potential. Finally, ΔΨ decreases due to increased uncoupling protein-mediated proton leak and Ca2+-induced mitochondrial permeability transition pore (mPTP) opening and direct oxidative damage of the IMM. The mechanism of mitochondrial dysfunction and adaptive response to mitochondrial dysfunction is shown in Fig. 1.
Mitochondrial dysfunction is a key component of sepsis (23). The most commonly used models of sepsis are lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) (24). In an LPS-induced rat model, the expression of the peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC1α) gene, as well as mitochondrial membrane potential, is significantly decreased (25). Mitochondrial respiratory chain complexes I and II function less efficiently in a CLP-induced rat model (26,27).
Reactive oxygen species (ROS) and nitric oxide (NO)
Under physiological conditions, mitochondria reduce monovalent O2 by generating O2− During substrate oxidation, a small amount of O2 is reduced by Mn superoxide dismutase to H2O2. However, a steady state concentration of ROS causes reversible or irreversible modifications to biomolecules, such as protein carbonylation or lipid peroxidation (28,29). In addition, mitochondrial enzymes function normally and mitochondrial DNA is particularly susceptible to damage caused by ROS, leading to incomplete reduction of oxygen and superoxide formation, which leads to ROS production (30). Decreased production of ROS prevents mitochondrial dysfunction in LPS-induced animal models (31,32). In LPS-induced rat models, increased ROS causes mitochondrial respiratory dysfunction, which leads to septic cardiac disease and performance (33,34). In addition, ROS production is decreased by increasing the activity of complex enzymes in mitochondria in CLP-induced mouse models (35,36).
Mitochondria also produce NO via the activity of mitochondrial NO synthase (mtNOS), which physiologically regulates mitochondrial respiration by inhibition of cytochrome C oxidase (37,38). Under physiological conditions, abundant O2− and NO react to form peroxynitrite (ONOO−), which acts as a strong oxidizing agent. The enhanced expression of mtNOS is induced in CLP-induced mouse models, which contributes to increased mitochondrial ONOO− levels (39,40). The critical causative factors responsible for mitochondrial dysfunction include inducible NOS (iNOS) synthase and mtNOS. It has been reported that mitochondrial dysfunction is not observed in the iNOS knockout mouse model (41). Pharmacological inhibition or genetic deletion of iNOS improves heart function in mouse models (41,42). Moreover, studies have found that the activities of complexes I and IV on the IMM are decreased by significantly boosting NO for a long time (43). Therefore, mitochondrial disorders attributed to NO may be primarily caused by abnormal iNOS expression. At present, most of the aforementioned studies have been conducted on iNOS-induced NO production, which may have some limitations, such as focus only on iNOS induced NO production, with a lack of mtNOS studies. However, NO is produced by multiple NOS isoforms (not only mitochondria) in different intracellular locations and cell types. In summary, one of the major causes of mitochondrial dysfunction involves ROS and NO, which may be key mechanisms of action in sepsis (Table I).
Calcium transport
Mitochondrial membrane permeability occurs within the mitochondrial membrane via the Ca2+ transport channel mPTP (44), the primary components of which are ATP synthase dimers and mitochondrial phosphate transporters (45). The three key processes involved in calcium transport are as follows: Firstly, cyclophilin D activates the pores in response to changes in mitochondrial calcium levels (46). Secondly, mPTP activation facilitates release of calcium from the mitochondria into the cytosol, where it activates calcium-dependent pathways (47,48). Ca2+ overload triggers the mPTP to open and release cytochrome C into the cytoplasm and the cytoplasm is released (45). In addition, the Ca2+-dependent state of the mPTP is influenced by the calcium concentration within the cell (49). Generally, calcium transport causes mitochondrial swelling and dysfunction as a result of calcium transport. A study has shown mitochondrial vacuolation and damaged mitochondrial cristae in cardiomyocytes of septic rats with increased cytochrome C in the cytoplasm (50). At the same time, the amount of Ca2+ able to enter the cytoplasm is determined by the number of membrane L-type calcium channels and the amount of Ca2+ stored in the sarcoplasmic reticulum (51). Additionally, dantrolene prevents mitochondrial Ca2+ overload, which improves mitochondrial dysfunction, by inhibiting sarcoplasmic reticulum Ca2+ leaks (52). Taken together, these conditions may result in cytoplasmic calcium overload, leading to mitochondrial deterioration and contractile dysfunction due to mPTP opening.
Drugs for treating mitochondrial dysfunction
Triphenylphosphonium (TPP), covalent quinone (MitoQ) and vitamin E have been prescribed as medications for treating SC. A powerful antioxidant targeting mitochondria, MitoQ binds coenzyme Q10 via triphenylphosphine, used for improving mitochondrial function in SC (53). In a rat model of sepsis, treatment with vitamin E conjugated to TPP decreased ROS-related damage (54). Additionally, as an antioxidant, lipoic acid might improve mitochondrial performance and alleviate septic shock (55). To determine whether the treatment modality used to treat mitochondrial dysfunction could be a viable therapeutic option in the future, researchers need to use drugs to prevent or reverse specific mitochondrial functions.
Metabolic changes in SC
There is evidence that metabolic dysregulation occurs in SC, suggesting that targeting metabolic pathways may offer notable benefits in SC treatment (56). During sepsis, hypermetabolism is characterized by a catabolic state that depletes carbohydrate, lipid and protein stores (57). The primary metabolic processes during sepsis involve lipid, ketone, glucose and amino acid metabolism (Fig. 2). The physiological indices of lipid metabolism, such as fatty acid oxidation, are reduced during sepsis and the expression of both cardiac fatty acids and lipid metabolizing enzymes is reduced. When glucose is metabolized, glucose oxidation, insulin resistance and cardiac glucose uptake are decreased. Additionally, there is a reduction in the absorption of ketone bodies and amino acids during ketone and amino acid metabolism (58).
Lipid metabolism in SC
During sepsis, there is a significant demand for energy, which is met by lipid mobilization (59). To make up for energy loss, adipose tissue undergoes increased lipolysis to release fatty acid and glycerol into the bloodstream (60). Sepsis is characterized by notable deregulation of genes typically involved in lipid metabolism due to the inflammatory response, such as PPARα, PGC1α and PPARγ. At the same time, FA metabolism stops when carnitine palmitoyltransferase 1, acyl coenzyme a synthetase and carnitine palmitoyltransferase-1 expression is impaired. Studies have shown that LPS reduces PPARα and PGC1α expression in LPS-induced rats, thereby regulating the β-oxidation pathway (61,62). The inhibition of PPARγ activation protects mice from sepsis-related cardiac dysfunction (63). In addition, studies have found that defects in the enzymes carnitine palmitoyl transferase 1 and CD36 cause inefficient fatty acid transport, which contributes to fatty acid oxidation (64). Finally, studies have found that LPS reduces enzymes activity related to FA metabolism, such as acyl-CoA synthetase and carnitine palmitoyl transferase-1 (65,66). Imbalance of FA demand and supply between the cytoplasm and mitochondria may cause lipid accumulation in the cytoplasm (67). Moreover, patients with sepsis exhibit fat buildup in cardiac muscle, kidney and liver (68). Taken together, lipid metabolism and associated enzyme transport are notable energy providers in sepsis (Table II).
Ketone metabolism in SC
Sepsis may lead to a high metabolic state throughout the body, which increases ketone body production and lipid breakdown (69). During prolonged fasting, hypoglycemia occurs, resulting in promotion of ketogenesis in hepatocyte mitochondria. The ketogenic effect may serve a valuable role in biodefense as ketone bodies confer resistance to ROS (70). Ketone body metabolism may increase ATP production or contribute to systemic hypercatabolism associated with calorie restriction (71,72). Ketone metabolism is a method to maintain cardiac energy homeostasis. Studies have found that LPS injection in mice lacking fatty acid binding protein 4 (FABP4) and FABP5 inhibits hepatic and cardiac ketogenesis, as FABP4 serves an active role in FA transport (73,74). At the same time, gene expression associated with 3-oxoacid coenzyme was significantly reduced in both DoubleClick and wild-type mice (73,74).
The aforementioned studies suggest that ketone bodies may represent a pathogenic mechanism in sepsis (Table II).
Glucose metabolism in SC
During SC, glucose oxidation does not increase to compensate for the decrease in FAO caused by insulin resistance and glucose metabolism inhibition (75,76). In mice models of endotoxic shock, there is a rapid drop in myocardial glucose levels compared with hemorrhagic shock (77,78) Increased levels of pyruvate dehydrogenase kinase 2 (PDK2) and PDK4 protein inhibit glucose oxidation (79). Moreover, 2-deoxy-D-glucose (2-DG) also improves cardiac function and survival outcomes in a mouse model of sepsis (80). The aforementioned findings indicate that increased glycolytic metabolism contributes to cardiac dysfunction in sepsis and that modulating metabolism following sepsis would be an appropriate strategy (Table II).
Amino acid metabolism in SC
Amino acids play crucial roles in both the synthesis and breakdown of proteins, which is vital for maintaining cellular homeostasis. Sepsis activates proteolysis, which splits proteins into smaller polypeptides and amino acids, allowing them to rebuild energy-rich molecules (81–83). It is reported that amino acid uptake by the heart is 90% lower compared with other organs in CLP-induced mouse models (84,85). Moreover, studies have demonstrated that decreases in alanine and glutamate lead to changes in cardiac metabolism in rats (86,87). Collectively, amino acids may be required for the liver to maintain protein hydrolysis in sepsis (Table II).
Signaling pathway of SC
PPAR pathway
Nuclear receptor transcription factors regulate metabolic homeostasis, inflammatory response and cell death through nuclear receptors (76,77). Studies have found that PPARα is present in the liver, PPARβ is highly active in skeletal muscle and PPARγ is associated with the control of the inflammatory reaction, apoptosis and sepsis (88,89). PPARγ suppresses expression of pro-inflammatory genes, mainly by scavenging transcription factors and their cofactors, thus preventing binding to their cognate binding sites in the promoters of target genes (90,91). In addition, immune cells can produce large amounts of pro-inflammatory mediators in the early stages of sepsis, and PPARγ regulates sepsis by promoting apoptosis (92,93). In a mouse model of CLP-induced inflammation, inhibition of NF-κB p65 phosphorylation and activation via upregulation of PPARγ attenuates inflammation (94). Studies have found that total protein concentration, neutrophils and macrophages are reduced in LPS-induced mice (95,96) Decreased inflammatory factor release is attributed to the conversion of macrophages from type M1 to M2. Moreover, the M1 macrophage increases chemokine ligand production in a CLP-induced mouse model by increasing endothelial cell hyperpermeability and phosphorylation of p38 by inhibiting PPARγ (97). In conclusion, activation of PPARγ may contribute to reduction of pro-inflammatory properties during SC (Table III).
NF-κB pathway
The predominant form of NF-κB is a heterodimer of p50 and p65 proteins (98). The protein is normally sequestered in the cytosol by a class of inhibitory proteins known as IκBs. These comprise seven members, including IκBα, IκBβ and IκΒγ (99). Under physiological conditions, NF-κB forms a complex with IκBα to undergo cytoplasmic sequestration. When stimulated by activating signals, NF-κB undergoes phosphorylation, ubiquitination and degradation, which leads to an activated NF-κB form that travels to the nucleus to induce gene transcription (100). NF-κB attenuates sepsis-induced systemic inflammation and myocardial injury by inhibiting NF-κB signaling (101). Additionally, studies have demonstrated that suppressing NF-κB activation decreases systemic hypotension, improves septic myocardial dysfunction and vascular abnormality, inhibits expression of numerous pro-inflammatory genes, decreases intravascular coagulation and neutrophil infiltration and prevents endothelial leakage (102,103).
When the NF-κB signaling pathway is engaged, phosphorylation of NF-κB pathway factors such as p65 and inhibitor κBα occurs (104,105). Moreover, studies have shown that decreasing TNF-α and IL-6 secretion, cytokines that promote inflammation in a LPS-induced rat model, stimulates the NF-κB signaling pathway (106,107). In summary, NF-κB suppresses inflammatory factors and proinflammatory genes that might be involved in sepsis symptoms (Table III).
Association between cell death and SC
Association between ferroptosis and SC
Ferroptosis pathways are iron-dependent, non-apoptotic and characterized by specific biochemical and morphological changes (108). The majority of iron in the body is bound to hemoglobin and myoglobin, with the rest primarily bound to ferritin and transferrin (109). In some cases, the cellular defense mechanism limits the cell iron export system, leading to an overload of cellular iron. Peroxylated lipids are produced as a result of the Fenton reaction, resulting in the damage of organelles (110). The bloodstream contains tetrapyrrole hemoglobin containing iron during SC. Under the action of heme oxygenase 1 (HO-1) enzyme, stable heme is degraded to biliverdin, carbon monoxide and iron in vivo (111,112). Additionally, HO-1 induces immunosuppression during sepsis, promotes helper T cell 1(Th1) to Th2 cytokine transfer and induces apoptosis in immune cells (113). The product of the HO-1 reaction is unstable iron, which promotes synthesis of ferritin and reduces the toxic effects of iron. The abnormal activation of HO-1 may result in the loss of the antioxidant action, increase levels of the labile iron pool (LIP) and eventually cause iron deficiency (114). In a mouse model of sepsis, the expression of HO-1 leads to altered iron metabolism protein levels and ferroptosis (115). Taken together, HO-1 causes ferroptosis by degrading heme and elevating LIP to release ferritin into the body.
Hepcidin, a liver-derived peptide hormone, maintains iron homeostasis in the body. Studies have shown that hepcidin ubiquitinates ferroportin (FPN) and reduces its activity, thus lowering iron concentrations (116,117) Patients with sepsis have significantly higher concentrations of hepcidin. Expression of hepcidin is induced by IL-6 and IL-1β when inflammation takes place (118). The serum iron levels are effectively regulated by hepcidin in a mouse model induced by LPS (119). Furthermore, studies have shown that high hepcidin expression decreases FPN activity, which decreases iron levels in plasma (120,121) Hence, hepcidin protein expression inhibits iron transport, causing an imbalance in iron homeostasis, which results in death from iron deficiency (Fig. 3).
Association between pyroptosis and SC
Under physiological conditions, pyroptosis is mediated by inflammasome-activated caspases and gasdermin D (GSDMD), final effectors of the GSDM protein family, leading to pore formation in the plasma membrane and leakage of inflammatory mediators (122,123). Under pathogenic conditions, LPS from Gram-negative bacteria directly activates caspase 4/5/11, in the inflammasome pathway, without the need for the inflammasome or caspase-1. GSDMD can be cleaved to produce N-GSDMD by activated caspase 4/5/11. N-GSDMD indirectly promotes NLRP3 inflammasome assembly via K+ efflux, which aggravates pyroptosis (124,125). Studies have found that doxorubicin upregulates NADPH oxidase 1 and NADPH oxidase 4 expression, thereby activating dynamin-related protein-1and promoting mitochondrial fission, leading to excessive accumulation of ROS in mitochondria and activation of the NLRP3 inflammasome and caspase-1dependent apoptosis (126,127) Certain studies have found that GSDMD knockout significantly decreases NLRP3 and caspase-1 expression, increases survival and improves cardiac dysfunction in mice (128,129). Moreover, LPS directly affects nuclear localization of sting and interferon regulatory factor-3-activated sting then activates NLRP3, leading to cardiac dysfunction as well as pyroptosis (130). Collectively, pyroptosis is induced in most forms of cardiomyopathy and blocking pyroptosis by direct or indirect approaches that target the pyroptotic machinery or upstream regulators may exert a protective effect.
Conclusion and future research prospects
Myocardial dysfunction caused by sepsis is one of the main reasons for the high mortality rate of sepsis and it is crucial to investigate the pathogenesis of sepsis-induced cardiac dysfunction and find treatment methods. The present study summarized the primary factors that contribute to the pathogenesis of SC, such as mitochondrial dysfunction, metabolic changes, cell death and signaling pathways. Mitochondrial dysfunction, primarily due to increased ROS and no steady-state concentrations inside mitochondria, increases various reversible and irreversible toxic modifications on biomolecules, such as protein carbonylation and lipid peroxidation (28,131). Meanwhile, excessive ROS and NO damage the mitochondrial respiratory chain structure and aggravate the biosynthesis of ROS (132,133). Metabolism in sepsis requires the adjustment of immune function via metabolism of fat, the metabolism of amino acids, metabolism of glucose and the absorption of a large amount of energy from cell's own metabolism (134,135). In addition, ferroptosis and pyroptosis contribute to pathogenesis of SC. Iron molecules contribute to the aggregation of ferritin at the cell membrane through the HO-1 reaction; however, activation of iron molecules by ferritin leads to an increase in iron output, leading to iron enrichment (136,137). By regulating the key molecule GSDMD, pyroptosis activates NLRP 3 inflammatory bodies and caspase 1-dependent apoptosis, leading to myocardial dysfunction in sepsis (138,139).
According to previous treatment methods, the relevant methods for the treatment of sepsis were divided into two main categories, the first category was the basic treatment methods for the characteristics of sepsis. Antibiotics decrease the release of inflammatory factors and mediators by regulating pathogenic microorganisms and the immune system to improve shock relieve clinical symptoms and signs of sepsis (140,141). Dopamine, a vasoactive drug, maintains a steady state of cardiac function by regulating the mean arterial tone (142,143). Glucocorticoids are effective in decreasing the duration of vasopressor use and maintaining haemodynamic balance and improve the clinical symptoms of patients with sepsis within a short period of time (144,145). The second type of treatment is herbal injections, whose mechanism of action is to attenuate the release of inflammatory factors and increase body immunity. Xuebijing injection inhibits release of high mobility group protein B1 in the serum of patients and decreases release of inflammatory factor mediators, thus treating sepsis (146). Effective interventions to control the way sepsis develops are necessary to translate basic research into clinical practice. Knowledge of sepsis and heart failure may lead to better treatment of myocardial infarction in future.
To the best of our knowledge, the metabolism of cells has not been investigated in SC. Secondly, although metabolic changes during sepsis have been reported, there is a lack of information on specific mechanism of action studies. Lastly, it is unclear how ferroptosis and pyroptosis occur during SC. Therefore, researchers should investigate the pathogenesis of SC using new methods and tools, such as network pharmacology, proteomics, metabolomics and gut microbiota analysis.
The present study reviewed the pathogenesis of SC with the goal of providing new ideas for the prevention and treatment of SC. In conclusion, this review summarizes the mitochondrial dysfunction (including reactive oxygen species, nitric oxide and calcium ion transport), metabolic changes (including lipid metabolism, ketone body metabolism, glucose metabolism and amino acid metabolism) and cell death modes (including iron death and cellular pyroptosis) associated with septic cardiomyopathy during sepsis. SC was not caused by all pathogenic mechanisms, but only a few that were relatively important were discussed in the review.
Acknowledgements
Not applicable.
Funding
The present study was supported by the Natural Science Foundation of Jilin Province (grant no. YDZJ202201ZYTS199) and the National College Students Innovation and Entrepreneurship Project Training Program (grant no. 202210199020).
Availability of data and materials
Not applicable.
Authors' contributions
JS and XF conceived the subject of the review, performed the investigation, and wrote and edited the original draft. KZ, HB and LL wrote, reviewed, and edited the manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
Hammond N, Kumar A, Kaur P, Tirupakuzhi Vijayaraghavan BK, Ghosh A, Grattan S, Jha V, Mathai D and Venkatesh B; Sepsis in India Prevalence Study (SIPS) Investigator Network, : Estimates of sepsis prevalence and outcomes in adult patients in the ICU in India: A cross-sectional Study. Chest. 161:1543–1554. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Salomão R, Ferreira BL, Salomão MC, Santos SS, Azevedo LCP and Brunialti MKC: Sepsis: Evolving concepts and challenges. Braz J Med Biol Res. 52:e85952019. View Article : Google Scholar : PubMed/NCBI | |
|
Shankar-Hari M, Phillips G, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD and Singer M; Sepsis Definitions Task Force, : Developing a new definition and assessing new clinical criteria for septic shock: For the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 315:775–787. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM and Sibbald WJ: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM consensus conference committee. American college of chest physicians/society of critical care medicine. Chest. 101:1644–1655. 1992. View Article : Google Scholar : PubMed/NCBI | |
|
Makic MBF and Bridges E: CE: Managing sepsis and septic shock: Current guidelines and definitions. Am J Nurs. 118:34–39. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Delano MJ and Ward PA: The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol Rev. 274:330–353. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Antonucci E, Fiaccadori E, Donadello K, Taccone FS, Franchi F and Scolletta S: Myocardial depression in sepsis: From pathogenesis to clinical manifestations and treatment. J Crit Care. 29:500–511. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Rello J, Valenzuela-Sánchez F, Ruiz-Rodriguez M and Moyano S: Sepsis: A review of advances in management. Adv Ther. 34:2393–2411. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Skirecki T and Cavaillon JM: Inner sensors of endotoxin-implications for sepsis research and therapy. FEMS Microbiol Rev. 43:239–256. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Torres L, Pickkers P and van der Poll T: Sepsis-induced immunosuppression. Annu Rev Physiol. 84:157–181. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Ehrman RR, Sullivan AN, Favot MJ, Sherwin RL, Reynolds CA, Abidov A and Levy PD: Pathophysiology, echocardiographic evaluation, biomarker findings, and prognostic implications of septic cardiomyopathy: A review of the literature. Crit Care. 22:1122018. View Article : Google Scholar : PubMed/NCBI | |
|
Purcarea A and Sovaila S: Sepsis, a 2020 review for the internist. Rom J Intern Med. 58:129–137. 2020.PubMed/NCBI | |
|
Gotts JE and Matthay MA: Sepsis: Pathophysiology and clinical management. BMJ. 353:i15852016. View Article : Google Scholar : PubMed/NCBI | |
|
Huang M, Cai S and Su J: The pathogenesis of sepsis and potential therapeutic targets. Int J Mol Sci. 20:53762019. View Article : Google Scholar : PubMed/NCBI | |
|
Ackerman MH, Ahrens T, Kelly J and Pontillo A: Sepsis. Crit Care Nurs Clin North Am. 33:407–418. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang H, Feng YW and Yao YM: Potential therapy strategy: Targeting mitochondrial dysfunction in sepsis. Mil Med Res. 5:412018.PubMed/NCBI | |
|
Cheung R, Pizza G, Chabosseau P, Rolando D, Tomas A, Burgoyne T, Wu Z, Salowka A, Thapa A, Macklin A, et al: Glucose-dependent miR-125b is a negative regulator of β-cell function. Diabetes. 71:1525–1545. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Doke T and Susztak K: The multifaceted role of kidney tubule mitochondrial dysfunction in kidney disease development. Trends Cell Biol. 32:841–853. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Park K and Lee MS: Essential role of lysosomal Ca2+-mediated TFEB activation in mitophagy and functional adaptation of pancreatic β-cells to metabolic stress. Autophagy. 18:3043–3045. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Eldeeb MA, Thomas RA, Ragheb MA, Fallahi A and Fon EA: Mitochondrial quality control in health and in Parkinson's disease. Physiol Rev. 102:1721–1755. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Hocaoglu H and Sieber M: Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development. Semin Cell Dev Biol. 138:94–103. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Subramanian GN, Yeo AJ, Gatei MH, Coman DJ and Lavin MF: Metabolic stress and mitochondrial dysfunction in ataxia-telangiectasia. Antioxidants (Basel). 11:6532022. View Article : Google Scholar : PubMed/NCBI | |
|
Joffre J and Hellman J: Oxidative stress and endothelial dysfunction in sepsis and acute inflammation. Antioxid Redox Signal. 35:1291–1307. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Doi K, Leelahavanichkul A, Yuen PST and Star RA: Animal models of sepsis and sepsis-induced kidney injury. J Clin Invest. 119:2868–2878. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Salari S, Ghorbanpour A, Marefati N, Baluchnejadmojarad T and Roghani M: Therapeutic effect of lycopene in lipopolysaccharide nephrotoxicity through alleviation of mitochondrial dysfunction, inflammation, and oxidative stress. Mol Biol Rep. 49:8429–8438. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
de Souza Stork S, Hübner M, Biehl E, Danielski LG, Bonfante S, Joaquim L, Denicol T, Cidreira T, Pacheco A, Bagio E, et al: Diabetes exacerbates sepsis-induced neuroinflammation and brain mitochondrial dysfunction. Inflammation. 45:2352–2367. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Soriano FG, Nogueira AC, Caldini EG, Lins MH, Teixeira AC, Cappi SB, Lotufo PA, Bernik MM, Zsengellér Z, Chen M and Szabó C: Potential role of poly(adenosine 5′-diphosphate-ribose) polymerase activation in the pathogenesis of myocardial contractile dysfunction associated with human septic shock. Crit Care Med. 34:1073–1079. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Galley HF: Oxidative stress and mitochondrial dysfunction in sepsis. Br J Anaesth. 107:57–64. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Cimolai MC, Alvarez S, Bode C and Bugger H: Mitochondrial mechanisms in septic cardiomyopathy. Int J Mol Sci. 16:17763–17778. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Lee S, Xu H, Van Vleck A, Mawla AM, Li AM, Ye J, Huising MO and Annes JP: β-Cell succinate dehydrogenase deficiency triggers metabolic dysfunction and insulinopenic diabetes. Diabetes. 71:1439–1453. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Hu J, Cheng Y, Chen P, Huang Z and Yang L: Caffeine citrate protects against sepsis-associated encephalopathy and inhibits the UCP2/NLRP3 axis in astrocytes. J Interferon Cytokine Res. 42:267–278. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Huang Q, Ding Y, Fang C, Wang H and Kong L: The emerging role of ferroptosis in sepsis, opportunity or challenge? Infect Drug Resist. 16:5551–5562. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Ji L, He Q, Liu Y, Deng Y, Xie M, Luo K, Cai X, Zuo Y, Wu W, Li Q, et al: Ketone body β-hydroxybutyrate prevents myocardial oxidative stress in septic cardiomyopathy. Oxid Med Cell Longev. 2022:25138372022. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao H, Lin X, Chen Q, Wang X, Wu Y and Zhao X: Quercetin inhibits the NOX2/ROS-mediated NF-κB/TXNIP signaling pathway to ameliorate pyroptosis of cardiomyocytes to relieve sepsis-induced cardiomyopathy. Toxicol Appl Pharmacol. 477:1166722023. View Article : Google Scholar : PubMed/NCBI | |
|
Liu Z, Pan H, Zhang Y, Zheng Z, Xiao W, Hong X, Chen F, Peng X, Pei Y, Rong J, et al: Ginsenoside-Rg1 attenuates sepsis-induced cardiac dysfunction by modulating mitochondrial damage via the P2X7 receptor-mediated Akt/GSK-3β signaling pathway. J Biochem Mol Toxicol. 36:e228852022. View Article : Google Scholar : PubMed/NCBI | |
|
Wang J, Yang S, Jing G, Wang Q, Zeng C, Song X and Li X: Inhibition of ferroptosis protects sepsis-associated encephalopathy. Cytokine. 161:1560782023. View Article : Google Scholar : PubMed/NCBI | |
|
Vanasco V, Saez T, Magnani ND, Pereyra L, Marchini T, Corach A, Vaccaro MI, Corach D, Evelson P and Alvarez S: Cardiac mitochondrial biogenesis in endotoxemia is not accompanied by mitochondrial function recovery. Free Radic Biol Med. 77:1–9. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Burgoyne J, Rudyk O, Mayr M and Eaton P: Nitrosative protein oxidation is modulated during early endotoxemia. Nitric Oxide. 25:118–124. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Boveris A, Alvarez S and Navarro A: The role of mitochondrial nitric oxide synthase in inflammation and septic shock. Free Radic Biol Med. 33:1186–1193. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Escames G, López L, Ortiz F, López A, García JA, Ros E and Acuña-Castroviejo D: Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice. FEBS J. 274:2135–2147. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
van de Sandt AM, Windler R, Gödecke A, Ohlig J, Zander S, Reinartz M, Graf J, van Faassen EE, Rassaf T, Schrader J, et al: Endothelial NOS (NOS3) impairs myocardial function in developing sepsis. Basic Res Cardiol. 108:3302013. View Article : Google Scholar : PubMed/NCBI | |
|
McCall CE, Zhu X, Zabalawi M, Long D, Quinn MA, Yoza BK, Stacpoole PW and Vachharajani V: Sepsis, pyruvate, and mitochondria energy supply chain shortage. J Leukoc Biol. 112:1509–1514. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Joshi MS, Julian MW, Huff JE, Bauer JA, Xia Y and Crouser ED: Calcineurin regulates myocardial function during acute endotoxemia. Am J Respir Crit Care Med. 173:999–1007. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabó I, et al: Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA. 110:5887–5892. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Giorgio V, Guo L, Bassot C, Petronilli V and Bernardi P: Calcium and regulation of the mitochondrial permeability transition. Cell Calcium. 70:56–63. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Bernardi P: The mitochondrial permeability transition pore: A mystery solved? Front Physiol. 4:952013. View Article : Google Scholar : PubMed/NCBI | |
|
Rasola A and Bernardi P: Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis. Cell Calcium. 50:222–233. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Takeuchi A, Kim B and Matsuoka S: The destiny of Ca(2+) released by mitochondria. J Physiol Sci. 65:11–24. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Halestrap AP: Calcium, mitochondria and reperfusion injury: A pore way to die. Biochem Soc Trans. 34:232–237. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Bernardi P and Di Lisa F: The mitochondrial permeability transition pore: Molecular nature and role as a target in cardioprotection. J Mol Cell Cardiol. 78:100–106. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Ballard-Croft C, Maass DL, Sikes PJ and Horton JW: Sepsis and burn complicated by sepsis alter cardiac transporter expression. Burns. 33:72–80. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Hassoun SM, Marechal X, Montaigne D, Bouazza Y, Decoster B, Lancel S and Neviere R: Prevention of endotoxin-induced sarcoplasmic reticulum calcium leak improves mitochondrial and myocardial dysfunction. Crit Care Med. 36:2590–2596. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Supinski GS, Murphy MP and Callahan LA: MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol. 297:R1095–R1102. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Zang QS, Sadek H, Maass DL, Martinez B, Ma L, Kilgore JA, Williams NS, Frantz DE, Wigginton JG, Nwariaku FE, et al: Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model. Am J Physiol Heart Circ Physiol. 302:H1847–H1859. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Vanasco V, Cimolai MC, Evelson P and Alvarez S: The oxidative stress and the mitochondrial dysfunction caused by endotoxemia are prevented by alpha-lipoic acid. Free Radic Res. 42:815–823. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Vandewalle J and Libert C: Sepsis: A failing starvation response. Trends Endocrinol Metab. 33:292–304. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Lelubre C and Vincent JL: Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol. 14:417–427. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Collins K and Huen SC: Metabolism and nutrition in sepsis: In need of a paradigm shift. Nephron. Sep 13–2023.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI | |
|
Wolowczuk I, Verwaerde C, Viltart O, Delanoye A, Delacre M, Pot B and Grangette C: Feeding our immune system: Impact on metabolism. Clin Dev Immunol. 2008:6398032008. View Article : Google Scholar : PubMed/NCBI | |
|
Rittig N, Bach E, Thomsen HH, Pedersen SB, Nielsen TS, Jørgensen JO, Jessen N and Møller N: Regulation of lipolysis and adipose tissue signaling during acute endotoxin-induced inflammation: A human randomized crossover trial. PLoS One. 11:e01621672016. View Article : Google Scholar : PubMed/NCBI | |
|
Drosatos K, Drosatos-Tampakaki Z, Khan R, Homma S, Schulze PC, Zannis VI and Goldberg IJ: Inhibition of c-Jun-N-terminal kinase increases cardiac peroxisome proliferator-activated receptor alpha expression and fatty acid oxidation and prevents lipopolysaccharide-induced heart dysfunction. J Biol Chem. 286:36331–36339. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Wang W, Xu RL, He P and Chen R: MAR1 suppresses inflammatory response in LPS-induced RAW 264.7 macrophages and human primary peripheral blood mononuclear cells via the SIRT1/PGC-1α/PPAR-γ pathway. J Inflamm (Lond). 18:82021. View Article : Google Scholar : PubMed/NCBI | |
|
Drosatos K, Khan RS, Trent CM, Jiang H, Son NH, Blaner WS, Homma S, Schulze PC and Goldberg IJ: Peroxisome proliferator-activated receptor-γ activation prevents sepsis-related cardiac dysfunction and mortality in mice. Circ Heart Fail. 6:550–562. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, Noon GP, Frazier OH and Taegtmeyer H: Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 18:1692–1700. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Memon RA, Fuller J, Moser AH, Smith PJ, Feingold KR and Grunfeld C: In vivo regulation of acyl-CoA synthetase mRNA and activity by endotoxin and cytokines. Am J Physiol. 275:E64–E72. 1998.PubMed/NCBI | |
|
Feingold K, Kim M, Shigenaga J, Moser A and Grunfeld C: Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. Am J Physiol Endocrinol Metab. 286:E201–E207. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Rossi MA, Celes MRN, Prado CM and Saggioro FP: Myocardial structural changes in long-term human severe sepsis/septic shock may be responsible for cardiac dysfunction. Shock. 27:10–18. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Koskinas J, Gomatos IP, Tiniakos DG, Memos N, Boutsikou M, Garatzioti A, Archimandritis A and Betrosian A: Liver histology in ICU patients dying from sepsis: A clinico-pathological study. World J Gastroenterol. 14:1389–1393. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, et al: Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 339:211–214. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, Koves T, Gardell SJ, Krüger M, Hoppel CL, et al: The failing heart relies on ketone bodies as a fuel. Circulation. 133:698–705. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Wang A, Huen SC, Luan HH, Yu S, Zhang C, Gallezot JD, Booth CJ and Medzhitov R: Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell. 166:1512–1525.e12. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Umbarawan Y, Syamsunarno MRAA, Obinata H, Yamaguchi A, Sunaga H, Matsui H, Hishiki T, Matsuura T, Koitabashi N, Obokata M, et al: Robust suppression of cardiac energy catabolism with marked accumulation of energy substrates during lipopolysaccharide-induced cardiac dysfunction in mice. Metabolism. 77:47–57. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Soni S, Martens MD, Takahara S, Silver HL, Maayah ZH, Ussher JR, Ferdaoussi M and Dyck JRB: Exogenous ketone ester administration attenuates systemic inflammation and reduces organ damage in a lipopolysaccharide model of sepsis. Biochim Biophys Acta Mol Basis Dis. 1868:1665072022. View Article : Google Scholar : PubMed/NCBI | |
|
Dhainaut JF, Huyghebaert MF, Monsallier JF, Lefevre G, Dall'Ava-Santucci J, Brunet F, Villemant D, Carli A and Raichvarg D: Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation. 75:533–541. 1987. View Article : Google Scholar : PubMed/NCBI | |
|
Chew MS, Shekar K, Brand BA, Norin C and Barnett AG: Depletion of myocardial glucose is observed during endotoxemic but not hemorrhagic shock in a porcine model. Crit Care. 17:R1642013. View Article : Google Scholar : PubMed/NCBI | |
|
Liu T, Wen Z, Shao L, Cui Y, Tang X, Miao H, Shi J, Jiang L, Feng S, Zhao Y, et al: ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis. Clin Immunol. 254:1096982023. View Article : Google Scholar : PubMed/NCBI | |
|
Standage SW, Bennion BG, Knowles TO, Ledee DR, Portman MA, McGuire JK, Liles WC and Olson AK: PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis. Am J Physiol Heart Circ Physiol. 312:H239–H249. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zheng Z, Ma H, Zhang X, Tu F, Wang X, Ha T, Fan M, Liu L, Xu J, Yu K, et al: Enhanced glycolytic metabolism contributes to cardiac dysfunction in polymicrobial sepsis. J Infect Dis. 215:1396–1406. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Lang CH, Frost RA, Jefferson LS, Kimball SR and Vary TC: Endotoxin-induced decrease in muscle protein synthesis is associated with changes in eIF2B, eIF4E, and IGF-I. Am J Physiol Endocrinol Metab. 278:E1133–E1143. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Lang CH, Frost RA, Nairn AC, MacLean DA and Vary TC: TNF-alpha impairs heart and skeletal muscle protein synthesis by altering translation initiation. Am J Physiol Endocrinol Metab. 282:E336–E347. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Plank LD and Hill GL: Sequential metabolic changes following induction of systemic inflammatory response in patients with severe sepsis or major blunt trauma. World J Surg. 24:630–638. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Warner BW, Hummel RP III, Hasselgren PO, James JH and Fischer JE: Inhibited amino acid uptake in skeletal muscle during starvation. JPEN J Parenter Enteral Nutr. 13:344–348. 1989. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Q, Bao X, Cui M, Wang C, Ji J, Jing J, Zhou X, Chen K and Tang L: Identification and validation of key biomarkers based on RNA methylation genes in sepsis. Front Immunol. 14:12318982023. View Article : Google Scholar : PubMed/NCBI | |
|
Hotchkiss RS, Song SK, Neil JJ, Chen RD, Manchester JK, Karl IE, Lowry OH and Ackerman JJ: Sepsis does not impair tricarboxylic acid cycle in the heart. Am J Physiol. 260:C50–C57. 1991. View Article : Google Scholar : PubMed/NCBI | |
|
Sun S, Wang D, Dong D, Xu L, Xie M, Wang Y, Ni T, Jiang W, Zhu X, Ning N, et al: Altered intestinal microbiome and metabolome correspond to the clinical outcome of sepsis. Crit Care. 27:1272023. View Article : Google Scholar : PubMed/NCBI | |
|
Chang WH and Lai AG: The pan-cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia. Ann N Y Acad Sci. 1448:65–82. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Anghel SI and Wahli W: Fat poetry: A kingdom for PPAR gamma. Cell Res. 17:486–511. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Christodoulides C and Vidal-Puig A: PPARs and adipocyte function. Mol Cell Endocrinol. 318:61–68. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Villarroel-Vicente C, Gutiérrez-Palomo S, Ferri J, Cortes D and Cabedo N: Natural products and analogs as preventive agents for metabolic syndrome via peroxisome proliferator-activated receptors: An overview. Eur J Med Chem. 221:1135352021. View Article : Google Scholar : PubMed/NCBI | |
|
von Knethen A, Soller M and Brüne B: Peroxisome proliferator-activated receptor gamma (PPAR gamma) and sepsis. Arch Immunol Ther Exp (Warsz). 55:19–25. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Li Z, Jia Y, Feng Y, Cui R, Wang Z, Qu K, Liu C and Zhang J: Methane-rich saline protects against sepsis-induced liver damage by regulating the PPAR-γ/NF-κB signaling pathway. Shock. 52:e163–e172. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Gong W, Zhu H, Lu L, Hou Y and Dou H: A benzenediamine analog FC-99 drives M2 macrophage polarization and alleviates lipopolysaccharide-(LPS-) induced liver injury. Mediators Inflamm. 2019:78230692019. View Article : Google Scholar : PubMed/NCBI | |
|
Wen Q, Miao J, Lau N, Zhang C, Ye P, Du S, Mei L, Weng H, Xu Q, Liu X, et al: Rhein attenuates lipopolysaccharide-primed inflammation through NF-κB inhibition in RAW264.7 cells: targeting the PPAR-γ signal pathway. Can J Physiol Pharmacol. 98:357–365. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Xia H, Ge Y, Wang F, Ming Y, Wu Z, Wang J, Sun S, Huang S, Chen M, Xiao W and Yao S: Protectin DX ameliorates inflammation in sepsis-induced acute lung injury through mediating PPARγ/NF-κB pathway. Immunol Res. 68:280–288. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Chen Q, Shao X, He Y, Lu E, Zhu L and Tang W: Norisoboldine attenuates sepsis-induced acute lung injury by modulating macrophage polarization via PKM2/HIF-1α/PGC-1α pathway. Biol Pharm Bull. 44:1536–1547. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Zhu XX, Wang X, Jiao SY, Liu Y, Shi L, Xu Q, Wang JJ, Chen YE, Zhang Q, Song YT, et al: Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function. Acta Pharmacol Sin. Jun 16–2023.(Epub ahead of print). | |
|
Chen W, Wang Y, Zhou Y, Xu Y, Bo X and Wu J: M1 macrophages increase endothelial permeability and enhance p38 phosphorylation via PPAR-γ/CXCL13-CXCR5 in sepsis. Int Arch Allergy Immunol. 183:997–1006. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Mitchell S, Vargas J and Hoffmann A: Signaling via the NFκB system. Wiley Interdiscip Rev Syst Biol Med. 8:227–241. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Somensi N, Rabelo TK, Guimarães AG, Quintans-Junior LJ, de Souza Araújo AA, Moreira JCF and Gelain DP: Carvacrol suppresses LPS-induced pro-inflammatory activation in RAW 264.7 macrophages through ERK1/2 and NF-kB pathway. Int Immunopharmacol. 75:1057432019. View Article : Google Scholar : PubMed/NCBI | |
|
Liu B, Wu Y, Wang Y, Cheng Y, Yao L, Liu Y, Qian H, Yang H and Shen F: NF-κB p65 Knock-down inhibits TF, PAI-1 and promotes activated protein C production in lipopolysaccharide-stimulated alveolar epithelial cells type II. Exp Lung Res. 44:241–251. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Wu Z, Chen J, Zhao W, Zhuo CH and Chen Q: Inhibition of miR-181a attenuates sepsis-induced inflammation and apoptosis by activating Nrf2 and inhibiting NF-κB pathways via targeting SIRT1. Kaohsiung J Med Sci. 37:200–207. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Liu SF and Malik AB: NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol. 290:L622–L645. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Zang B and Wang L: Synthesis and protective effect of pyrazole conjugated imidazo[1,2-a]pyrazine derivatives against acute lung injury in sepsis rats via attenuation of NF-κB, oxidative stress, and apoptosis. Acta Pharm. 73:341–362. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Cao L and Yang K: Paeoniflorin attenuated TREM-1-mediated inflammation in THP-1 cells. J Healthc Eng. 2022:70516432022. View Article : Google Scholar : PubMed/NCBI | |
|
Wang X, Xu T, Jin J, Ting Gao MM, Wan B, Gong M, Bai L, Lv T and Song Y: Topotecan reduces sepsis-induced acute lung injury and decreases the inflammatory response via the inhibition of the NF-κB signaling pathway. Pulm Circ. 12:e120702022. View Article : Google Scholar : PubMed/NCBI | |
|
Franco JH, Chen X and Pan ZK: Novel treatments targeting the dysregulated cell signaling pathway during sepsis. J Cell Signal. 2:228–234. 2021.PubMed/NCBI | |
|
Ruan W, Ji X, Qin Y, Zhang X, Wan X, Zhu C, Lv C, Hu C, Zhou J, Lu L and Guo X: Harmine alleviated sepsis-induced cardiac dysfunction by modulating macrophage polarization via the STAT/MAPK/NF-κB pathway. Front Cell Dev Biol. 9:7922572022. View Article : Google Scholar : PubMed/NCBI | |
|
Dang X, Huan X, Du X, Chen X, Bi M, Yan C, Jiao Q and Jiang H: Correlation of ferroptosis and other types of cell death in neurodegenerative diseases. Neurosci Bull. 38:938–952. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Kim J and Wessling-Resnick M: The role of iron metabolism in lung inflammation and injury. J Allergy Ther. 3 (Suppl 4):S0042012. | |
|
de Lima VM, Batista BB and da Silva Neto JF: The regulatory protein ChuP connects heme and siderophore-mediated iron acquisition systems required for chromobacterium violaceum virulence. Front Cell Infect Microbiol. 12:8735362022. View Article : Google Scholar : PubMed/NCBI | |
|
Englert FA, Seidel RA, Galler K, Gouveia Z, Soares MP, Neugebauer U, Clemens MG, Sponholz C, Heinemann SH, Pohnert G, et al: Labile heme impairs hepatic microcirculation and promotes hepatic injury. Arch Biochem Biophys. 672:1080752019. View Article : Google Scholar : PubMed/NCBI | |
|
Stefanson AL and Bakovic M: Falcarinol Is a potent inducer of heme oxygenase-1 and was more effective than sulforaphane in attenuating intestinal inflammation at diet-achievable doses. Oxid Med Cell Longev. 2018:31535272018. View Article : Google Scholar : PubMed/NCBI | |
|
Yoon SJ, Kim SJ and Lee SM: Overexpression of HO-1 contributes to sepsis-induced immunosuppression by modulating the Th1/Th2 balance and regulatory T-cell function. J Infect Dis. 215:1608–1618. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Puentes-Pardo JD, Moreno-SanJuan S, Carazo Á and León J: Heme oxygenase-1 in gastrointestinal tract health and disease. Antioxidants (Basel). 9:12142020. View Article : Google Scholar : PubMed/NCBI | |
|
Fernández-Mendívil C, Luengo E, Trigo-Alonso P, García-Magro N, Negredo P and López MG: Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism. Redox Biol. 38:1017892021. View Article : Google Scholar : PubMed/NCBI | |
|
Qiao B, Sugianto P, Fung E, Del-Castillo-Rueda A, Moran-Jimenez MJ, Ganz T and Nemeth E: Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab. 15:918–924. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Cross JH, Jarjou O, Mohammed NI, Gomez SR, Touray BJB, Kessler NJ, Prentice AM and Cerami C: Iron homeostasis in full-term, normal birthweight Gambian neonates over the first week of life. Sci Rep. 13:103492023. View Article : Google Scholar : PubMed/NCBI | |
|
Drakesmith H and Prentice AM: Hepcidin and the iron-infection axis. Science. 338:768–772. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Scindia Y, Wlazlo E, Leeds J, Loi V, Ledesma J, Cechova S, Ghias E and Swaminathan S: Protective role of hepcidin in polymicrobial sepsis and acute kidney injury. Front Pharmacol. 10:6152019. View Article : Google Scholar : PubMed/NCBI | |
|
Deng Q, Yang S, Sun L, Dong K, Li Y, Wu S and Huang R: Salmonella effector SpvB aggravates dysregulation of systemic iron metabolism via modulating the hepcidin-ferroportin axis. Gut Microbes. 13:1–18. 2021. View Article : Google Scholar | |
|
Czempik PF and Wiórek A: Iron deficiency in sepsis patients based on reticulocyte hemoglobin and hepcidin concentration: A prospective cohort study. Arch Med Sci. 19:805–809. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Martinon F, Burns K and Tschopp J: The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 10:417–426. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F and Shao F: Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 526:660–665. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Feng Y, Li M, Yangzhong X, Zhang X, Zu A, Hou Y, Li L and Sun S: Pyroptosis in inflammation-related respiratory disease. J Physiol Biochem. 78:721–737. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Man SM, Karki R and Kanneganti TD: Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev. 277:61–75. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zeng C, Duan F, Hu J, Luo B, Huang B, Lou X, Sun X, Li H, Zhang X, Yin S and Tan H: NLRP3 inflammasome-mediated pyroptosis contributes to the pathogenesis of non-ischemic dilated cardiomyopathy. Redox Biol. 34:1015232020. View Article : Google Scholar : PubMed/NCBI | |
|
Wu S, Liao J, Hu G, Yan L, Su X, Ye J, Zhang C, Tian T, Wang H and Wang Y: Corilagin alleviates LPS-induced sepsis through inhibiting pyroptosis via targeting TIR domain of MyD88 and binding CARD of ASC in macrophages. Biochem Pharmacol. 1158062023.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI | |
|
Dai S, Ye B, Zhong L, Chen Y, Hong G, Zhao G, Su L and Lu Z: GSDMD mediates LPS-induced septic myocardial dysfunction by regulating ROS-dependent NLRP3 inflammasome activation. Front Cell Dev Biol. 9:7794322021. View Article : Google Scholar : PubMed/NCBI | |
|
Meng L, Gu T, Wang J, Zhang H and Nan C: Knockdown of PHLDA1 alleviates sepsis-induced acute lung injury by downregulating NLRP3 inflammasome activation. Allergol Immunopathol (Madr). 51:41–47. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Li W, Shen X, Feng S, Liu Y, Zhao H, Zhou G, Sang M, Sun X, Jiao R and Liu F: BRD4 inhibition by JQ1 protects against LPS-induced cardiac dysfunction by inhibiting activation of NLRP3 inflammasomes. Mol Biol Rep. 49:8197–8207. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao M, Zheng Z, Zhang P, Xu Y, Zhang J, Peng S, Liu J, Pan W, Yin Z, Xu S, et al: IL-30 protects against sepsis-induced myocardial dysfunction by inhibiting pro-inflammatory macrophage polarization and pyroptosis. iScience. 26:1075442023. View Article : Google Scholar : PubMed/NCBI | |
|
Nong Y, Wei X and Yu D: Inflammatory mechanisms and intervention strategies for sepsis-induced myocardial dysfunction. Immun Inflamm Dis. 11:e8602023. View Article : Google Scholar : PubMed/NCBI | |
|
Lima MR and Silva D: Septic cardiomyopathy: A narrative review. Rev Port Cardiol. 42:471–481. 2023.(In English, Portuguese). View Article : Google Scholar : PubMed/NCBI | |
|
Nadamuni M, Venable AH and Huen SC: When a calorie isn't just a calorie: A revised look at nutrition in critically ill patients with sepsis and acute kidney injury. Curr Opin Nephrol Hypertens. 31:358–366. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Costa NA, Pereira AG, Sugizaki CSA, Vieira NM, Garcia LR, de Paiva SAR, Zornoff LAM, Azevedo PS, Polegato BF and Minicucci MF: Insights into thiamine supplementation in patients with septic shock. Front Med (Lausanne). 8:8051992022. View Article : Google Scholar : PubMed/NCBI | |
|
Huo L, Liu C, Yuan Y, Liu X and Cao Q: Pharmacological inhibition of ferroptosis as a therapeutic target for sepsis-associated organ damage. Eur J Med Chem. 257:1154382023. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou P, Zhang S, Wang M and Zhou J: The induction mechanism of ferroptosis, necroptosis, and pyroptosis in inflammatory bowel disease, colorectal cancer, and intestinal injury. Biomolecules. 13:8202023. View Article : Google Scholar : PubMed/NCBI | |
|
Wu J, Lan Y, Wu J and Zhu K: Sepsis-induced acute lung injury is alleviated by small molecules from dietary plants via pyroptosis modulation. J Agric Food Chem. 71:12153–12166. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Perveen I, Bukhari B, Najeeb M, Nazir S, Faridi TA, Farooq M, Ahmad QU, Abusalah MAHA, ALjaraedah TY, Alraei WY, et al: Hydrogen therapy and its future prospects for ameliorating COVID-19: Clinical applications, efficacy, and modality. Biomedicines. 11:18922023. View Article : Google Scholar : PubMed/NCBI | |
|
Expert Panel on Urological Imaging, . Smith AD, Nikolaidis P, Khatri G, Chong ST, De Leon AD, Ganeshan D, Gore JL, Gupta RT, Kwun R, et al: ACR appropriateness criteria® acute pyelonephritis: 2022 Update. J Am Coll Radiol. 19((11S)): S224–S239. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Diaconescu B, Uranues S, Fingerhut A, Vartic M, Zago M, Kurihara H, Latifi R, Popa D, Leppäniemi A, Tilsed J, et al: The bucharest ESTES consensus statement on peritonitis. Eur J Trauma Emerg Surg. 46:1005–1023. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, et al: Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 47:1181–1247. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, et al: Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of critical care medicine (SCCM) and European society of intensive care medicine (ESICM) 2017. Intensive Care Med. 43:1751–1763. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, et al: Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American college of critical care medicine. Crit Care Med. 36:1937–1949. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Zhong G, Han Y, Zhu Q, Xu M, Chang X, Chen M, Men L, Zhang Q and Wang L: The effects of Xuebijing injection combined with ulinastatin as adjunctive therapy on sepsis: An overview of systematic review and meta-analysis. Medicine (Baltimore). 101:e311962022. View Article : Google Scholar : PubMed/NCBI | |
|
Xiaoxia Q, Cheng C, Minjian W, Huilin C, Zhen L, Yuedong Y and Xingyu Z: Effect of integrative medicines on 28-day mortality from sepsis: A systematic review and network meta-analysis. Eur Rev Med Pharmacol Sci. 26:664–677. 2022.PubMed/NCBI |
