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Molecular Mechanisms and Pathophysiology of Sepsis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 September 2025 | Viewed by 7744

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Dr. Vlad Pădureanu

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Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
Interests: genetic polymorphisms; inflammation; oxidative stress; sepsis; internal medicine; acute pancreatitis; diabetes mellitus; liver diseases; rheumatic disease
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Dear Colleagues,

Considering that antibiosis, eradication of the focus, and intensive care supply are the only treatment regimens for patients suffering from sepsis, it is obvious that new therapies are mandatory. Because the anamneses of sepsis patients are very heterogeneous, characterizing mechanistic details associated with sepsis initiation or progression will help to establish new therapeutic approaches. Therefore, manuscripts elucidating the molecular mechanisms in vitro or in vivo in preclinical models as well as patient studies providing insights into new therapeutic concepts to prevent or treat sepsis progression are welcome. Based on this research topic, this Special Issue aims to collate original research manuscripts and review articles in the field of the origin of sepsis and related therapies.

Submissions of review articles and original research papers that cover topics including, but not limited to, the following are welcome:

Cell culture studies characterizing and/or identifying new factors involved in sepsis development.
The role of immune cell subpopulations in sepsis progression.
Animal models providing mechanistic insights into the underlying principles leading to sepsis.
Therapeutic approaches to prevent or cure sepsis and future perspectives.
The definition of new sepsis biomarkers.
The characterization of putative subgroups of sepsis patients with a similar origin of sepsis.

Dr. Vlad Pădureanu
Guest Editor

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Keywords

animal models
therapeutic concepts
biomarkers
sepsis
immune suppression
epigenetics

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Published Papers (7 papers)

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Research

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13 pages, 2238 KiB

Open AccessArticle

Sex-Specific Differences in LPS-Induced Rapid Myocardial Dysfunction

by Brianna I. Harvey, Arris M. Yoniles, Andrea Monsivais, Jiayue Du, Lauren Zadorozny, Qing Yu and Meijing Wang

Int. J. Mol. Sci. 2025, 26(13), 5963; https://doi.org/10.3390/ijms26135963 - 21 Jun 2025

Viewed by 140

Abstract

Cardiac dysfunction is a severe complication of sepsis that significantly increases mortality in affected patients. Previous studies have shown better myocardial responses with preserved cardiac function in female animals compared to males following lipopolysaccharide (LPS)-induced sepsis. Our published findings have revealed that females exhibited less cardiac dysfunction than males when exposed to equivalent doses of tumor necrosis factor (TNF)α, which is markedly elevated in both heart tissue and serum following LPS. These raise the question of whether the observed sex differences in LPS-induced myocardial dysfunction are a direct effect of LPS or a secondary consequence mediated by inflammatory cytokines, like TNFα. In this study, we aimed to uncover sex differences in LPS-caused direct effects on cardiac function. To do so, isolated hearts from aged-matched adult male and female mice were subjected to LPS infusion using a Langendorff method. Left ventricular developed pressure (LVDP) was continuously recorded. The female estrous cycle was determined via vaginal smear. The oxidative phosphorylation (OXPHOS) pathway and estrogen receptors (ERs) were determined in heart tissue using Western blot. We found that males exhibited worse LV function than females following the infusion of LPS at 5.0 mg/kg body weight. However, no significant differences in cardiac function and expression of ERs were observed between female groups at different estrous stages. Interestingly, LV function returned to baseline after the initial depression of LVDP during the rapid response to LPS and then depressed again following the 50 min LPS infusion. Protein levels of OXPHOS were altered differently between male and female hearts after 50 min LPS infusion. Our data demonstrate that male hearts exhibit higher sensitivity to LPS-induced rapid cardiac dysfunction compared to females, although estrogen may have a minimal influence on LPS-induced rapid functional depression. Sex differences may exist in myocardial mitochondrial responses to direct LPS insult via the OXPHOS pathway. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Sepsis)

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16 pages, 1403 KiB

Open AccessArticle

Profiling of miRNAs Contained in Circulating Extracellular Vesicles and Associated with Sepsis Development in Burn Patients: A Proof-of-Concept Study

by Martina Schiavello, Ornella Bosco, Barbara Vizio, Alberto Sciarrillo, Anna Pensa, Emanuele Pivetta, Fulvio Morello, Daniela Risso, Giuseppe Montrucchio, Filippo Mariano and Enrico Lupia

Int. J. Mol. Sci. 2025, 26(5), 1844; https://doi.org/10.3390/ijms26051844 - 21 Feb 2025

Viewed by 548

Abstract

Sepsis is the leading cause of mortality in patients with burn injuries and it may represent, in these patients, a real diagnostic challenge. Here we studied the profile of miRNAs contained in extracellular vesicles (EVs) (EV-miRNAs) isolated from plasma from burn patients complicated by sepsis at admission and 7 days later. We enrolled 28 burn patients, 18 with (Burn Septic Patients—BSPs) and 10 without (Burn non-Septic Patients—BnSPs) sepsis. Ten healthy subjects (HSs) were used as additional controls. After EV isolation by charge precipitation and miRNA extraction, we proceeded with a two-phase approach. Through a first screening phase, we identified 178 miRNAs differentially expressed in BSPs compared to HSs. Among these, by a validation phase based on qRT-PCR, we found that miR-483-5p, miR-193a-5p, and miR-188-3p were increased in the BSPs compared to the BnSPs and HSs. Upon ROC analysis, all three miRNAs showed a good accuracy in differentiating BSPs from BnSPs, especially miR-483-5p (AUC = 0.955, p-value = 0.001). Moreover, we found 173 miRNAs differentially expressed in BSPs after 7 days from enrollment compared to T0, among whose miR-1-3p, miR-34a-3p, and miR-193a-5p decreased in BSPs after 7 days, in parallel with a decrease in SOFA scores. Finally, the other two miRNAs, miR-34a-3p and miR-193a-5p, positively correlated with the SOFA score. In conclusion, we identified several miRNAs—namely miR-483-5p, miR-193a-5p, and miR-188-3p—with potential clinical utility as diagnostic biomarkers in a heterogeneous population of burn patients at high risk of developing sepsis. Moreover, we found some miRNAs (miR-1-3p, miR-34a-3p, and miR-193a-5p) that vary according to the course of sepsis and others (miR-34a-3p and miR-193a-5p) that are associated with its clinical severity. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Sepsis)

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20 pages, 1646 KiB

Open AccessArticle

Comparative Analysis of Hepatic Gene Expression Profiles in Murine and Porcine Sepsis Models

by Fëllanza Halimi, Tineke Vanderhaeghen, Steven Timmermans, Siska Croubels, Claude Libert and Jolien Vandewalle

Int. J. Mol. Sci. 2024, 25(20), 11079; https://doi.org/10.3390/ijms252011079 - 15 Oct 2024

Viewed by 1380

Abstract

Sepsis remains a huge unmet medical need for which no approved drugs, besides antibiotics, are on the market. Despite the clinical impact of sepsis, its molecular mechanism remains inadequately understood. Recent insights have shown that profound hepatic transcriptional reprogramming, leading to fatal metabolic abnormalities, might open a new avenue to treat sepsis. Translation of experimental results from rodents to larger animal models of higher relevance for human physiology, such as pigs, is critical and needs exploration. We performed a comparative analysis of the transcriptome profiles in murine and porcine livers using the following sepsis models: cecal ligation and puncture (CLP) in mice and fecal instillation (FI) in pigs, both of which induce polymicrobial septic peritonitis, and lipopolysaccharide (LPS)-induced endotoxemia in pigs, inducing sterile inflammation. Using bulk RNA sequencing, Metascape pathway analysis, and HOMER transcription factor motif analysis, we were able to identify key genes and pathways affected in septic livers. Conserved upregulated pathways in murine CLP and porcine LPS and FI generally comprise typical inflammatory pathways, except for ER stress, which was only found in the murine CLP model. Conserved pathways downregulated in sepsis comprise almost exclusively metabolic pathways such as monocarboxylic acid, steroid, biological oxidation, and small-molecule catabolism. Even though the upregulated inflammatory pathways were equally induced in the two porcine models, the porcine FI model more closely resembles the metabolic dysfunction observed in the CLP liver compared to the porcine LPS model. This comprehensive comparison focusing on the hepatic responses in mouse CLP versus LPS or FI in pigs shows that the two porcine sepsis models generally resemble quite well the mouse CLP model, with a typical inflammatory signature amongst the upregulated genes and metabolic dysfunction amongst the downregulated genes. The hepatic ER stress observed in the murine model could not be replicated in the porcine models. When studying metabolic dysfunction in the liver upon sepsis, the porcine FI model more closely resembles the mouse CLP model compared to the porcine LPS model. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Sepsis)

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18 pages, 3487 KiB

Open AccessArticle

C5a Induces Inflammatory Signaling and Apoptosis in PC12 Cells through C5aR-Dependent Signaling: A Potential Mechanism for Adrenal Damage in Sepsis

by Lucas Mrozewski, Sujeenthar Tharmalingam, Paul Michael, Aseem Kumar and T. C. Tai

Int. J. Mol. Sci. 2024, 25(19), 10673; https://doi.org/10.3390/ijms251910673 - 3 Oct 2024

Cited by 1 | Viewed by 1439

Abstract

The complement system is critically involved in the pathogenesis of sepsis. In particular, complement anaphylatoxin C5a is generated in excess during sepsis, leading to cellular dysfunction. Recent studies have shown that excessive C5a impairs adrenomedullary catecholamine production release and induces apoptosis in adrenomedullary cells. Currently, the mechanisms by which C5a impacts adrenal cell function are poorly understood. The PC12 cell model was used to examine the cellular effects following treatment with recombinant rat C5a. The levels of caspase activation and cell death, protein kinase signaling pathway activation, and changes in inflammatory protein expression were examined following treatment with C5a. There was an increase in apoptosis of PC12 cells following treatment with high-dose C5a. Ten inflammatory proteins, primarily involved in apoptosis, cell survival, and cell proliferation, were upregulated following treatment with high-dose C5a. Five inflammatory proteins, involved primarily in chemotaxis and anti-inflammatory functions, were downregulated. The ERK/MAPK, p38/MAPK, JNK/MAPK, and AKT protein kinase signaling pathways were upregulated in a C5aR-dependent manner. These results demonstrate an apoptotic effect and cellular signaling effect of high-dose C5a. Taken together, the overall data suggest that high levels of C5a may play a role in C5aR-dependent apoptosis of adrenal medullary cells in sepsis. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Sepsis)

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Review

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21 pages, 1065 KiB

Open AccessReview

Biomarkers as Beacons: Illuminating Sepsis-Associated Hepato-Renal Injury

by Maria-Antoanela Pasare, Cristian Sorin Prepeliuc, Maria Gabriela Grigoriu, Ionela-Larisa Miftode and Egidia Gabriela Miftode

Int. J. Mol. Sci. 2025, 26(10), 4825; https://doi.org/10.3390/ijms26104825 - 18 May 2025

Viewed by 709

Abstract

Sepsis, defined as a dysregulated host response to infection, is one of the leading causes of mortality worldwide. It unleashes in the organism a cascade of molecules, cytokines, and proteins which leads to an inflammatory storm. If this response to infection is uncontrolled, any organ is susceptible to damage. Acute kidney injury (AKI) is one of the most frequent organ dysfunctions in septic patients, and while it can be reversible, its presence leads to a higher burden of morbidity and mortality. While serum creatinine is essential in evaluating kidney function, the pathophysiology of AKI is not completely elucidated, and a plethora of novel biomarkers have been studied in the hope of an early diagnosis and fast treatment. While the liver is not as affected by sepsis, it plays an important role as a guardian by providing acute-phase proteins, activating neutrophils, and controlling iron balance. Acute liver failure (ALF) could impair the organism’s capacity to contain and eliminate pathogens. Some molecules have been associated with either AKI or ALF, although biomarkers specific for organ dysfunction are difficult to validate. The aim of this review is to understand the role of several molecules in the pathophysiology of sepsis and their clinical ability for diagnosing or predicting sepsis-induced hepato-renal dysfunction. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Sepsis)

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10 pages, 1243 KiB

Open AccessReview

The Role of Scavenger Receptor BI in Sepsis

by Dan Hao, Jian-Yao Xue, Qian Wang, Ling Guo and Xiang-An Li

Int. J. Mol. Sci. 2024, 25(24), 13441; https://doi.org/10.3390/ijms252413441 - 15 Dec 2024

Cited by 1 | Viewed by 1104

Abstract

Sepsis is a life-threatening condition resulting from a dysregulated host response to infection. Currently, there is no effective therapy for sepsis due to an incomplete understanding of its pathogenesis. Scavenger receptor BI (SR-BI) is a high-density lipoprotein (HDL) receptor that plays a key role in HDL metabolism by modulating the selective uptake of cholesteryl ester from HDL. Recent studies, including those from our laboratory, indicate that SR-BI protects against sepsis through multiple mechanisms: (1) preventing nitric oxide-induced cytotoxicity; (2) promoting hepatic lipopolysaccharide (LPS) clearance and regulating cholesterol metabolism in the liver; (3) inhibiting LPS-induced inflammatory signaling in macrophages; and (4) mediating the uptake of cholesterol from HDL for inducible glucocorticoid (iGC) synthesis in the adrenal gland, which controls systemic inflammatory response. In this article, we review the roles of SR-BI in sepsis. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Sepsis)

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27 pages, 3319 KiB

Open AccessReview

Neonatal Fungemia by Non-Candida Rare Opportunistic Yeasts: A Systematic Review of Literature

by Alexandra Mpakosi, Vasileios Cholevas, Joseph Meletiadis, Martha Theodoraki and Rozeta Sokou

Int. J. Mol. Sci. 2024, 25(17), 9266; https://doi.org/10.3390/ijms25179266 - 27 Aug 2024

Cited by 1 | Viewed by 1586

Abstract

Fungal colonization poses a significant risk for neonates, leading to invasive infections such as fungemia. While Candida species are the most commonly identified pathogens, other rare yeasts are increasingly reported, complicating diagnosis and treatment due to limited data on antifungal pharmacokinetics. These emerging yeasts, often opportunistic, underscore the critical need for early diagnosis and targeted therapy in neonates. This systematic review aims to comprehensively analyze all published cases of neonatal fungemia caused by rare opportunistic yeasts, examining geographical distribution, species involved, risk factors, treatment approaches, and outcomes. Searching two databases (PubMed and SCOPUS), 89 relevant studies with a total of 342 cases were identified in the 42-year period; 62% of the cases occurred in Asia. Pichia anomala (31%), Kodamaea ohmeri (16%) and Malassezia furfur (15%) dominated. Low birth weight, the use of central catheters, prematurity, and the use of antibiotics were the main risk factors (98%, 76%, 66%, and 65%, respectively). 22% of the cases had a fatal outcome (80% in Asia). The highest mortality rates were reported in Trichosporon beigelii and Trichosporon asahii cases, followed by Dirkmeia churashimamensis cases (80%, 71%, and 42% respectively). Low birth weight, the use of central catheters, the use of antibiotics, and prematurity were the main risk factors in fatal cases (84%, 74%, 70%, and 67%, respectively). 38% of the neonates received fluconazole for treatment but 46% of them, died. Moreover, the rare yeasts of this review showed high MICs to fluconazole and this should be taken into account when planning prophylactic or therapeutic strategies with this drug. In conclusion, neonatal fungemia by rare yeasts is a life-threatening and difficult-to-treat infection, often underestimated and misdiagnosed. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Sepsis)

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