Intense Inflammatory Response Research Articles

The role of pyroptosis in heart failure and related traditional chinese medicine treatments

Pyroptosis is a type of programmed cell death that is mediated by both typical and atypical pathways and ultimately leads to the lysis and rupture of cell membranes and the release of proinflammatory factors, triggering an intense inflammatory response. Heart failure (HF) is a serious and terminal stage of various heart diseases. Myocardial hypertrophy, myocardial fibrosis, ventricular remodeling, oxidative stress, the inflammatory response and cardiomyocyte ionic disorders caused by various cardiac diseases are all risk factors for and aggravate HF. Numerous studies have shown that pyroptosis can induce and exacerbate these reactions, causing progression to HF. Therefore, targeting pyroptosis is a promising strategy to treat HF. This paper summarizes the role of pyroptosis in the development of HF and the underlying mechanism involved. Recent research progress on the ability of traditional Chinese medicine (TCM) extracts and formulas to inhibit pyroptosis and treat HF was summarized, and some traditional Chinese medicine extracts and formulas can alleviate different types of HF, including heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with midrange ejection fraction (HFmrEF), by targeting pyroptosis. These findings may provide new ideas and evidence for the treatment or adjuvant treatment of HF by targeting pyroptosis.

Synergies of co-infecting pathogens, sea lice (Lepeophetheirus salmonis) and Moritella viscosa, are impacted by exposure order, and host response to initial infection

Sea lice infestations and winter ulcer disease caused by Moritella viscosa are two major challenges for the Atlantic salmon (Salmo salar) aquaculture industry. Despite their common tropisms for the skin/muscle we know very little about the interaction between these two significant pathogens. The objective of this study was to elucidate the transcriptomic response of Atlantic salmon to sea louse (Lepeophtheirus salmonis) and M. viscosa under single infection and different scenarios of co-infection (i.e. first, L. salmonis and then, M. viscosa and vice versa). After exposure, sampling was performed from the infestation site as well as the adjacent area on fish skin, followed by transcriptome analysis. RNA-seq analysis revealed that infection with either L. salmonis or M. viscosa induced a significant immune response from the skin and resulted in extensive transcriptomic changes. More differentially expressed genes (DEGs) were detected at M. viscosa lesion sites compared to L. salmonis attachment sites. In addition, the effect of the infection order was evaluated. Interestingly, we found that primary infection with lice was associated with a significantly higher number of DEGs during the co-infection process on fish skin compared to the fish first infected with M. viscosa (721 and 5336 DEGs from lice attachment and M. viscosa lesion sites, respectively, vs 291 and 3601 DEGs from lice attachment and M. viscosa lesion sites, respectively). We also found that lice infection caused localized effects on the skin of Atlantic salmon, while single infection with M. viscosa caused a moderate systemic impact and inhibited the tissue repair function of the skin, leading to severe ulceration. In addition, the C-type lectin receptor signaling pathway was drastically activated at the lice attachment sites during both lice alone- and co-infections, regardless of the order of infections, and similar results were observed in M. viscosa infection at both lesion and adjacent sites, indicating that this pathway played an essential role for immunity in Atlantic salmon. A more intense inflammatory and immune response was also observed at M. viscosa lesion sites. These results will promote our understanding of the immune interactions between L. salmonis and M. viscosa during the co-infection process and provide insights for the development of preventive and treatment strategies for these pathogens in salmon aquaculture.

Advances in the study of polydopamine nanotechnology in central nervous system disorders

Disorders of the central nervous system (CNS) constitute a significant global health concern at the moment. Most CNS disorders are characterized by severe neuronal damage with excessive production of reactive oxygen species, which induces high levels of oxidative stress and intense inflammatory responses in the affected tissues, thus aggravating disease pathology. Notably, the blood–brain barrier makes it difficult to deliver many drugs and biologics to the CNS, which creates great difficulties in the diagnosis and treatment of CNS disorders. Recent research on polydopamine nanotechnology has led to the discovery of many promising properties; it shows strong scavenging ability for reactive oxygen species, prevents activation of pro-inflammatory microglia, and its repair function can reduce brain damage and protect neurons. Moreover, polydopamine nanotechnology can improve the blood–brain barrier permeability of biologics and reduce their neurotoxicity. It is therefore a promising candidate in the treatment of CNS disorders associated with oxidative stress. In the present paper, we review the functionality of polydopamine nanotechnology as well as the potential and recent advances of polydopamine-based nanosystems in the diagnosis and treatment of various CNS disorders, including Alzheimer’s disease, Parkinson’s disease, stroke, spinal cord injury, and glioma. Finally, we predict how polydopamine nanoparticles may guide future therapeutic strategies to address CNS disorders such as epilepsy, which currently have no cure.

VCP Inhibition Augments NLRP3 Inflammasome Activation.

Lysosomal membrane permeabilization caused either via phagocytosis of particulates or the uptake of protein aggregates can trigger the activation of NLRP3 inflammasome- an intense inflammatory response that drives the release of the pro-inflammatory cytokine IL-1β by regulating the activity of CASPASE 1. The maintenance of lysosomal homeostasis and lysosomal membrane integrity is facilitated by the AAA+ ATPase, VCP/p97 (VCP). However, the relationship between VCP and NLRP3 inflammasome activity remains unexplored. Here, we demonstrate that the VCP inhibitors, DBeQ and ML240 elicit the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) when used as activation stimuli. Moreover, genetic inhibition of VCP or VCP chemical inhibition enhances lysosomal membrane damage and augments LLoME-associated NLRP3 inflammasome activation in BMDMs. Similarly, VCP inactivation also augments NLRP3 inflammasome activation mediated by aggregated alpha-synuclein fibrils and lysosomal damage. These data suggest that VCP is a participant in the complex regulation of NLRP3 inflammasome activation.

Pretreated MSCs with IronQ Transplantation Attenuate Microglia Neuroinflammation via the cGAS-STING Signaling Pathway.

Intracerebral hemorrhage (ICH), a devastating form of stroke, is characterized by elevated morbidity and mortality rates. Neuroinflammation is a common occurrence following ICH. Mesenchymal stem cells (MSCs) have exhibited potential in treating brain diseases due to their anti-inflammatory properties. However, the therapeutic efficacy of MSCs is limited by the intense inflammatory response at the transplantation site in ICH. Hence, enhancing the function of transplanted MSCs holds considerable promise as a therapeutic strategy for ICH. Notably, the iron-quercetin complex (IronQ), a metal-quercetin complex synthesized through coordination chemistry, has garnered significant attention for its biomedical applications. In our previous studies, we have observed that IronQ exerts stimulatory effects on cell growth, notably enhancing the survival and viability of peripheral blood mononuclear cells (PBMCs) and MSCs. This study aimed to evaluate the effects of pretreated MSCs with IronQ on neuroinflammation and elucidate its underlying mechanisms. The ICH mice were induced by injecting the collagenase I solution into the right brain caudate nucleus. After 24 hours, the ICH mice were randomly divided into four subgroups, the model group (Model), quercetin group (Quercetin), MSCs group (MSCs), and pretreated MSCs with IronQ group (MSCs+IronQ). Neurological deficits were re-evaluated on day 3, and brain samples were collected for further analysis. TUNEL staining was performed to assess cell DNA damage, and the protein expression levels of inflammatory factors and the cGAS-STING signaling pathway were investigated and analyzed. Pretreated MSCs with IronQ effectively mitigate neurological deficits and reduce neuronal inflammation by modulating the microglial polarization. Moreover, the pretreated MSCs with IronQ suppress the protein expression levels of the cGAS-STING signaling pathway. These findings suggest that pretreated MSCs with IronQ demonstrate a synergistic effect in alleviating neuroinflammation, thereby improving neurological function, which is achieved through the inhibition of the cGAS-STING signaling pathway.

Intramammary lipopolysaccharide challenge in early versus mid-lactation dairy cattle: immune, production, and metabolic responses.

Study objectives were to compare the immune response, metabolism and production following intramammary lipopolysaccharide (IMM LPS) administration in early and mid-lactation cows. Early (E-LPS; n = 11; 20 ± 4 d in milk [DIM]) and mid- (M-LPS; n = 10; 155 ± 40 DIM) lactation cows were enrolled in an experiment consisting of 2 periods (P). During P1 (5 d) cows were fed ad libitum and baseline data were collected, including liver and muscle biopsies. At the beginning of P2 (3 d) cows received 10 mL sterile saline containing 10 µg of LPS from Escherichia coli O111:B4/mL into the left rear quarter of the mammary gland, and liver and muscle biopsies were collected at 12 h post-LPS. Tissues were analyzed for metabolic flexibility, which measures substrate switching capacity from pyruvic acid to palmitic acid oxidation. Data were analyzed with the MIXED procedure in SAS 9.4. Rectal temperature was assessed hourly for the first 12 h post-LPS and every 6 h thereafter for the remainder of P2. All cows developed a febrile response following LPS, but E-LPS had a more intense fever than M-LPS cows (0.7°C at 5 h after LPS). Blood samples were collected at 0, 3, 6, 9, 12, 24, 36, 48, and 72 h post-LPS for analysis of systemic inflammation and metabolism parameters. Total serum Ca decreased after LPS (26% at 6 h nadir) but did not differ by lactation stage (LS). Circulating neutrophils decreased, then increased post-LPS in both LS, but E-LPS had exaggerated neutrophilia (56% from 12 to 48 h) compared with M-LPS. Haptoglobin increased after LPS (15-fold) but did not differ by LS. Many circulating cytokines were increased post-LPS, and IL-6, IL-10, TNF-α, MCP-1, and IP-10 were further augmented in E-LPS compared with M-LPS cows. Relative to P1, all cows had reduced milk yield (26%) and dry matter intake (DMI; 14%) on d 1 that did not differ by lactation stage (LS). Somatic cell score increased rapidly in response to LPS regardless of LS and gradually decreased from 18 h onwards. Milk component yields decreased after LPS. However, E-LPS had increased fat (11%) and tended to have increased lactose (8%) yield compared with M-LPS cows throughout P2. Circulating glucose was not affected by LPS. Nonesterified fatty acids (NEFA) decreased in E-LPS (29%) but not M-LPS cows. β-hydroxybutyrate (BHB) slightly increased (14%) over time post-LPS regardless of LS. Insulin increased after LPS in all cows, but E-LPS had blunted hyperinsulinemia (52%) compared with M-LPS cows. Blood urea nitrogen (BUN) increased after LPS and the relative change in BUN was elevated in E-LPS cows compared with M-LPS cows (36 and 13%, respectively, from 9 to 24 h). During P1, metabolic flexibility was increased in liver and muscle in early lactating cows compared with mid-lactation cows, but 12 h post-LPS, metabolic flexibility was reduced and did not differ by LS. In conclusion, IMM LPS caused severe immune activation and E-LPS cows had a more intense inflammatory response compared with M-LPS cows, but the effects on milk synthesis was similar between LS. Some parameters of the E-LPS metabolic profile suggest continuation of metabolic adjustments associated with early lactation to support both a robust immune system and milk synthesis.

Nr4a1 enhances Wnt4 transcription to promote mesenchymal stem cell osteogenesis and alleviates inflammation-inhibited bone regeneration

Intense inflammatory response impairs bone marrow mesenchymal stem cell (BMSC)-mediated bone regeneration, with TGF-β1 being the most highly expressed cytokine. However, how to find effective and safe means to improve bone formation impaired by excessive TGF-β1 remains unclear. In this study, we found that the expression of orphan nuclear receptor Nr4a1, an endogenous repressor of TGF-β1, was suppressed directly by TGF-β1-induced Smad3 and indirectly by Hdac4, respectively. Importantly, Nr4a1 overexpression promoted BMSC osteogenesis and reversed TGF-β1-mediated osteogenic inhibition and pro-fibrotic effects. Transcriptomic and histologic analyses confirmed that upregulation of Nr4a1 increased the transcription of Wnt family member 4 (Wnt4) and activated Wnt pathway. Mechanistically, Nr4a1 bound to the promoter of Wnt4 and regulated its expression, thereby enhancing the osteogenic capacity of BMSCs. Moreover, treatment with Nr4a1 gene therapy or Nr4a1 agonist Csn-B could promote ectopic bone formation, defect repair, and fracture healing. Finally, we demonstrated the correlation of NR4A1 with osteogenesis and the activation of the WNT4/β-catenin pathway in human BMSCs and fracture samples. Taken together, these findings uncover the critical role of Nr4a1 in bone formation and alleviation of inflammation-induced bone regeneration disorders, and suggest that Nr4a1 has the potential to be a therapeutic target for accelerating bone healing.

Delayed CCL23 response is associated with poor outcomes after cardiac arrest

Chemokines, a family of chemotactic cytokines, mediate leukocyte migration to and entrance into inflamed tissue, contributing to the intensity of local inflammation. We performed an analysis of chemokine and immune cell responses to cardiac arrest (CA). Forty-two patients resuscitated from cardiac arrest were analyzed, and twenty-two patients who underwent coronary artery bypass grafting (CABG) surgery were enrolled. Quantitative antibody array, chemokines, and endotoxin quantification were performed using the patients blood. Analysis of CCL23 production in neutrophils obtained from CA patients and injected into immunodeficient mice after CA and cardiopulmonary resuscitation (CPR) were done using flow cytometry. The levels of CCL2, CCL4, and CCL23 are increased in CA patients. Temporal dynamics were different for each chemokine, with early increases in CCL2 and CCL4, followed by a delayed elevation in CCL23 at forty-eight hours after CA. A high level of CCL23 was associated with an increased number of neutrophils, neuron-specific enolase (NSE), worse cerebral performance category (CPC) score, and higher mortality. To investigate the role of neutrophil activation locally in injured brain tissue, we used a mouse model of CA/CPR. CCL23 production was increased in human neutrophils that infiltrated mouse brains compared to those in the peripheral circulation. It is known that an early intense inflammatory response (within hours) is associated with poor outcomes after CA. Our data indicate that late activation of neutrophils in brain tissue may also promote ongoing injury via the production of CCL23 and impair recovery after cardiac arrest.

NR4A1 PROMOTES OSTEOGENIC DIFFERENTIATION OF MESENCHYMAL STEM CELLS AND IMPROVES INFLAMMATION-INHIBITED BONE REGENERATION

Stem cell therapy is an effective means to address the repair of large segmental bone defects. However, the intense inflammatory response triggered by the implants severely impairs stem cell differentiation and tissue regeneration. High-dose transforming growth factor β1 (TGF-β1), the most locally expressed cytokine in implants, inhibits osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and promotes tissue fibrosis, severely compromising the efficacy of stem cell therapy. Small molecule inhibitors of TGF-β1 can be used to ameliorate the osteogenic disorders caused by high concentrations of TGF-β1, but systemic inhibition of TGF-β1 function will cause strong adverse effects. How to find safe and reliable molecular targets to antagonize TGF-β1 remains to be elucidated. Orphan nuclear receptor Nr4a1, an endogenous inhibitory molecule of TGF-β1, suppresses tissue fibrosis, but its role in BMSC osteogenesis is unclear. We found that TGF-β1 inhibited Nr4a1 expression through HDAC4. Overexpression of Nr4a1 in BMSCs reversed osteogenic differentiation inhibited by high levels of TGF- β1. Mechanistically, RNA sequencing showed that Nr4a1 activated the ECM-receptor interaction and Hippo signaling pathway, which in turn promoted BMSC osteogenesis. In bone defect repair and fracture healing models, transplantation of Nr4a1-overexpressing BMSCs into C57BL/6J mice or treatment with the Nr4a1 agonist Csn-B significantly ameliorated inflammation-induced bone regeneration disorders. In summary, our findings confirm the endogenous inhibitory effect of Nr4a1 on TGF- β1 and uncover the effectiveness of Nr4a1 agonists as a therapeutic tool to improve bone regeneration, which provides a new solution strategy for the treatment of clinical bone defects and inflammatory skeletal diseases.

Polyphenolic oligomer-derived multienzyme activity for the treatment of ischemic Stroke through ROS scavenging and blood-brain barrier restoration.

Oxidative stress and blood-brain barrier (BBB) injury are two major stress disorders before and after ischemic stroke (IS) therapy. The intense inflammatory response also causes damage to nerve cells, affecting the repair of brain tissue. In this study, polyphenolic nanoparticles (PPNs) with strong free radical scavenging ability were designed to treat IS multimodally. To investigate the mechanism of polyphenolic polymerization, solid nanoparticles were synthesized using four kinds of polyphenol compounds as the basic unit under the control of temperature. The form of polymerization between monomers with different structures led to changes in the chemical properties of the corresponding nanoparticles as well as the antioxidant capacity at the cellular level. Particularly, PPNs can significantly improve cerebral infarction and penetrate and repair the BBB, and even downregulate levels of inflammatory cytokines. Molecular signaling pathway studies have shown that PPNs can provide comprehensive treatment of IS by promoting the expression of tight junction protein and enhancing the activity of antioxidant enzymes. Therefore, PPNs combined with the antioxidant, anti-inflammatory and BBB repair ability not only provide a perfect therapeutic pathway but also give ideas for the development of natural material carriers that have a wide application prospect.

Transcriptome network analysis of inflammation and fibrosis in keloids

BackgroundKeloid (KL) is a common benign skin tumor. KL is typically characterized by significant fibrosis and an intensive inflammatory response. Therefore, a comprehensive understanding of the interactions between cellular inflammation and fibrotic cells is essential to elucidate the mechanisms driving the progression of KL and to develop therapeutics. ObjectiveInvestigate the transcriptome landscape of inflammation and fibrosis in keloid scars. MethodsIn this paper, we performed transcriptome sequencing and microRNA (miRNA) sequencing on unselected live cells from six human keloid tissues and normal skin tissues to elucidate a comprehensive transcriptome landscape. In addition, we used single-cell RNA sequencing (scRNA-seq) analysis to analyze intercellular communication networks and enrich fibroblast populations in two additional keloid and normal skin samples to study fibroblast diversity. ResultsBy RNA sequencing and a miRNA-mRNA-PPI network analysis, we identified miR-615–5p and miR-122b-3p as possible miRNAs associated with keloids, as they differed most significantly in keloids. Similarly, COL3A1, COL1A2, THBS2, TNC, IGTA, THBS4, TGFB3 as genes with significant differences in keloid may be associated with keloid development. Using single-cell RNA sequencing data from 24,086 cells collected from normal or keloid, we report reconstructed intercellular signaling network analysis and aggregation to modules associated with specific cell subpopulations at the cellular level for keloid alterations. ConclusionsOur multitranscriptomic dataset delineates inflammatory and fibro heterogeneity of human keloids, underlining the importance of intercellular crosstalk between inflammatory cells and fibro cells and revealing potential therapeutic targets.

Crosstalk of ferroptosis and oxidative stress in infectious diseases.

Ferroptosis is a type of programmed cell death that pathogens can leverage to enhance their replication, transmission, and pathogenicity. Hosts typically combat pathogenic infections by utilizing oxidative stress as a defense mechanism. Nonetheless, some pathogens can trigger considerable oxidative stress while infecting, inducing an intense inflammatory response in the host's immune system and activating cell death. The process of ferroptosis is closely linked to oxidative stress, with their interaction exerting a substantial impact on the outcome of infectious diseases. This article presents an overview of the interrelated mechanisms of both Ferroptosis and oxidative stress in infectious diseases, identifying potential targets for treating such diseases in the context of their interaction.

Analysis of clinical characteristics and risk factors between elderly patients with severe and nonsevere Omicron variant infection

BACKGROUND Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to millions of confirmed cases and deaths worldwide. Elderly patients are at high risk of developing and dying from COVID-19 due to advanced age, decreased immune function, intense inflammatory response, and comorbidities. Shanghai has experienced a wave of infection with Omicron, a new variant of SARS-CoV-2, since March 2022. There is a pressing need to identify clinical features and risk factors for disease progression among elderly patients with Omicron infection to provide solid evidence for clinical policy-makers, public health officials, researchers, and the general public. AIM To investigate clinical characteristic differences and risk factors between elderly patients with severe and nonsevere Omicron SARS-CoV-2 variant infection. METHODS A total of 328 elderly patients with COVID-19 admitted to the Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from April 2022 to June 2022 were enrolled and divided into a severe group (82 patients) and a nonsevere group (246 patients) according to the diagnosis and treatment protocol of COVID-19 (version 7). The clinical data and laboratory results of both groups were collected and compared. A chi-square test, t test, Mann-Whitney U test, hierarchical log-rank test, univariate and multivariate logistic regression, and hierarchical analyses were used to determine significant differences. RESULTS The severe group was older (84 vs 74 years, P < 0.001), included more males (57.3% vs 43.9%, P = 0.037), had a lower vaccination rate (P < 0.001), and had a higher proportion of comorbidities, including chronic respiratory disease (P = 0.001), cerebral infarction (P < 0.001), chronic kidney disease (P = 0.002), and neurodegenerative disease (P < 0.001), than the nonsevere group. In addition, severe disease patients had a higher inflammatory index (P < 0.001), greater need for symptomatic treatment (P < 0.001), longer hospital stay (P = 0.011), extended viral shedding time (P = 0.014), and higher mortality than nonsevere disease patients (P < 0.001). No difference was observed in the application of Paxlovid in the severe and nonsevere groups (P = 0.817). Oxygen saturation, cerebral infarction, and D-dimer were predictive factors for developing severe disease in patients with COVID-19, with D-dimer having an excellent role (area under the curve: 90.1%, 95%CI: 86.1-94.0%). In addition, D-dimer was a risk factor for developing severe COVID-19 according to multivariate stratified analysis. CONCLUSION The clinical course of severe COVID-19 is complex, with a higher need for symptomatic treatment. D-dimer is a suitable biomarker for identifying patients at risk for developing severe COVID-19.

Effects of colchicine treatment after myocardial infarction on top of standard therapy: evidence from a preclinical study

Abstract Background An intense inflammatory and fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling, increasing the risk for ventricular arrhythmias and heart failure. Colchicine is an anti-inflammatory drug that has been reported to improve the outcome of patients with MI; its effects on LV remodeling have not been specifically investigated. We aimed to characterize the effects of the anti-inflammatory drug colchicine in an animal model of reperfused MI. Methods In 4-month-old pigs, MI was induced by occluding the LAD artery through an angioplasty balloon for 90 minutes. Pigs surviving MI induction were randomized in a 1:1 fashion to 2 arms: - control group (n=13): MI induction and reperfusion, standard treatment (the same therapies as in the rat study), - colchicine group (n=13): MI induction and reperfusion, standard treatment plus colchicine. The pigs underwent a first CMR scan 72 hours after MI induction, and another CMR at day 30. The pigs were then sacrificed the day after the second CMR. The primary efficacy endpoint was LGE mass (as a percentage of LV mass). Results The infarcted area at 72 hours (expressed as absolute mass or as a percentage of the LV mass) and the changes over 1 month did not differ significantly between pigs on colchicine plus standard therapy vs. those on standard therapy alone. When assessing the extent of fibrosis on the explanted hearts (as a percentage of the tissue sample areas) there was a trend toward a lower extent of myocardial fibrosis in pigs on colchicine plus standard therapy (p=0.091). The percent differences in LV volumes, ejection fraction and mass across the two CMR scans did not reach statistical difference. Conclusions The results from a pig model of reperfused MI suggest that colchicine has no additional effects to standard MI therapy on MI size and LV remodeling.

Diabetes mellitus and response to IL-1 blockade with Anakinra after ST-elevation myocardial infarction: a pooled analysis of the VCU-ART studies

Abstract Background ST segment elevation myocardial infarction (STEMI) elicits an intense inflammatory response which is thought to contribute to subsequent maladaptive myocardial healing and remodeling, ultimately leading to heart failure (HF). The interleukin-1 (IL-1) blocker anakinra administered during the first 14 days after STEMI patients has been shown to effectively dampen the inflammatory response and reduce the incidence of HF events in pilot randomized controlled trials. Diabetes mellitus is a condition of enhanced systemic inflammation. Purpose To assess the role of diabetes mellitus as a modulating factor in respect to the efficacy of anakinra treatment during the first 14 days after STEMI. Methods We conducted a pooled analysis of three previous proof of principle trials on anakinra in STEMI. Diabetes mellitus was defined based on clinical history, use of glucose-lowering medications, or elevated hemoglobin A1c >6.5% at time of enrollment and further characterized as type I or type II based on the available clinical assessment. The area-under-the-curve for C reactive protein (AUC-CRP) at 14 days was used as a measure of the systemic inflammatory response during STEMI. The clinical endpoint was composite of death, hospitalizations for HF and urgent HF visits. Results The study population included 139 patients, of whom 39 (28%) had a diagnosis of diabetes mellitus at time of enrolment, all with type II. Median age was 56 [49-63] and 56 [49-63] years in patients with and without diabetes, respectively (p=0.652). There were 29 (21%) female and 52 (37%) Black-African American patients among those with diabetes compared to 29 (21%) female and 52 (37%) Black-African American patients in those without diabetes (p=0.69 and p=0.16, respectively). Treatment with anakinra (N=84) significantly dampened acute inflammation associated with STEMI in patients with diabetes (AUC-CRP 223 [117-399] vs 76 [42-148] mg•day/L, p<0.001) and in those without diabetes (AUC-CRP 223 [117-399] vs 76 [42-148] mg•day/L, p<0.001 – Figure 1). No statistically significant interaction between diabetes status and treatment with anakinra on outcomes was detected (pint=0.92): treatment with anakinra was associated with a hazard ratio [HR] 0.28 [0.09-0.84](p=0.02) in non-diabetic patients and HR 0.26 [0.11-1.32](p=0.10) in diabetic patients – Figure 2. Conclusion In this pooled analysis of the VCU-ART trials, the presence of type II diabetes mellitus showed no interaction with the efficacy of the treatment with anakinra early after STEMI in reducing the systemic inflammatory response or preventing new onset heart failure, hospitalization for HF or death.Figure 1.Figure 2

Abstract 17996: One-Year Outcomes of Patients With ST-Segment Elevation Myocardial Infarction According to Eosinophil Blood Count

Background: ST-segment elevation myocardial infarction (STEMI) elicits an intense inflammatory response but the relation between eosinophil blood count and outcomes in this setting is not clear. Hypothesis: A difference in eosinophil blood count in patients with STEMI is associated with a different incidence of death or hospitalization for heart failure (HF). Methods: In this retrospective study using the US cohort of 49 healthcare organizations in the TriNetX database, we included 41,945 patients with STEMI (identified by ICD-10-CM code) between January 1, 2012, and June 2, 2022. Patients were divided into two groups according to the median of eosinophil blood count measured 2-3 days after the acute event in our previous study (0.2x103/μL). The Kaplan-Meier method was used to compare the risks of the composite outcome of death or HF hospitalization within the two cohorts. Results: We included 15,725 and 26,220 patients with median eosinophil blood count equal/above and below 0.2x103/μL, respectively. At 1-year follow-up, the risk of death or HF hospitalization was lower in patients with eosinophil blood count above/equal to the median, 0.2x103/μL (13.6% vs 18.9%; Hazard Ratio 0.68, 95% CI [0.64-0.71]; p<0.001). The incidence of the composite outcome at 1 year was 15.3% and 21.5% for patients with median eosinophil blood count equal/above and below 0.2x103/μL, respectively (p<0.001 for the log-rank test). Figure 1. Secondary analysis suggested that this result was driven mainly by lower mortality in the cohort with higher eosinophil count (10.1% vs 14.9%; HR 0.63, 95% CI [0.59-0.67]; p<0.001). Conclusions: In our large 'real world' analysis, a higher eosinophil blood count within the normal range during the acute phase post-STEMI is associated with a better outcome of death or hospitalization for heart failure.

Abstract 170: Late CCL23 Response is Associated With Poor Outcomes After Cardiac Arrest

Introduction: Chemokines mediate the entrance and migration of leukocytes to inflamed tissue areas, contributing to the intensity of local inflammation. We found a high level of circulating chemokines, CCL2, CCL4, and CCL23, in patients resuscitated after cardiac arrest (CA). Hypothesis: The level of circulating chemokines is associated with systemic immune cell response, neurologic injury, and outcome after cardiac arrest. Goal: To characterize temporal chemokine and immune cell responses to cardiac arrest. Methods: A total of 42 patients after CA and 22 control subjects who underwent coronary artery bypass grafting (CABG) were enrolled. ELISA was used to determine chemokines in plasma at 6 hr, 24 hr, 48 hr, and 72 hr after CA and in CABG patients pre-operatively. Flow cytometry was used to determine subpopulations of immune cells. We measured changes in chemokines over time and the association of chemokine levels with outcome, markers of inflammation, and brain injury. A mouse model of CA was employed to assess the activation of human neutrophils locally in brain tissue. Results: Temporal dynamics were different for each chemokine, with early increases in CCL2 and CCL4, followed by a late elevation in CCL23 at 48 hours after resuscitation. A higher level of CCL23 was associated with a worse cerebral performance category score (r s =0.3, p=0.042) and higher mortality (r s =0.3, p=0.039). Positive correlations were found between CCL23 and an increased number of neutrophils, cellular mediators of inflammation, and levels of neuron-specific enolase. To study the potential role of neutrophil activation locally in injured brain tissue, we injected human post-CA neutrophils into the bloodstream of successfully resuscitated mice and measured the CCL23 in human neutrophils in mouse blood and brain 24 hours after resuscitation. An increased level of CCL23 production was found in mouse brain neutrophils compared to those in the peripheral circulation. Conclusion: It is well known that an early intense inflammatory response is associated with poor outcomes after CA. Our new data indicate that late activation of neutrophils in brain tissue may represent an additional mechanism contributing to ongoing brain tissue injury via the production of CCL23 after cardiac arrest.

Remote Outcomes with Poly-ε-Caprolactone Aortic Grafts in Rats.

Poly-ε-caprolactone ((1,7)-polyoxepan-2-one; PCL) is a biodegradable polymer widely used in various fields of bioengineering, but its behavior in long-term studies appears to depend on many conditions, such as application specificity, chemical structure, in vivo test systems, and even environmental conditions in which the construction is exploited in. In this study, we offer an observation of the remote outcomes of PCL tubular grafts for abdominal aorta replacement in an in vivo experiment on a rat model. Adult Wistar rats were implanted with PCL vascular matrices and observed for 180 days. The results of ultrasound diagnostics and X-ray tomography (CBCT) show that the grafts maintained patency for the entire follow-up period without thrombosis, leakage, or interruptions, but different types of tissue reactions were found at this time point. By the day of examination, all the implants revealed a confluent endothelial monolayer covering layers of hyperplastic neointima formed on the luminal surface of the grafts. Foreign body reactions were found in several explants including those without signs of stenosis. Most of the scaffolds showed a pronounced infiltration with fibroblastic cells. All the samples revealed subintimal calcium phosphate deposits. A correlation between chondroid metaplasia in profound cells of neointima and the process of mineralization was supported by immunohistochemical (IHC) staining for S100 proteins and EDS mapping. Microscopy showed that the scaffolds with an intensive inflammatory response or formed fibrotic capsules retain their fibrillar structure even on day 180 after implantation, but matrices infiltrated with viable cells partially save the original fibrillary network. This research highlights the advantages of PCL vascular scaffolds, such as graft permeability, revitalization, and good surgical outcomes. The disadvantages are low biodegradation rates and exceptionally high risks of mineralization and intimal hyperplasia.

Effects of Dietary Supplementation with a Ferulic Acid-Rich Bioactive Component of Wheat Bran in a Murine Model of Graft-Versus-Host Disease.

Graft-versus-host disease (GvHD) is a common and severe complication following allogeneic hematopoietic stem cell transplantation (HSCT). Its prevention and treatment is a major challenge. Ferulic acid (FA) has anti-inflammatory and antioxidant properties that could be attractive in this setting. Our aim was to evaluate a bioactive ingredient derived from wheat bran (WB), selected for its high concentration of FA, in a murine model of GvHD. The ingredient was obtained via a bioprocess involving hydrolysis and spray-drying. GvHD was induced via HSCT between MHC-mismatched mouse strains. FA treatment was administered orally. Survival and disease scores (weight loss, hunching, activity, fur texture, and skin integrity, each scored between 0 and 2 depending on disease severity) were recorded daily, histological evaluation was performed at the end of the experiment, and serum inflammatory cytokines were analyzed on days 9 and 28. Treatment with FA did not protect GvHD mice from death, nor did it diminish GvHD scores. However, histological analysis showed that ulcers with large areas of inflammatory cells, vessels, and keratin were less common in skin samples from FA-treated mice. Areas of intense inflammatory response were also seen in fewer small intestine samples from treated mice. In addition, a slight decrease in INF-γ and TNF-α expression was observed in the serum of treated mice on day 28. The results showed some local effect of the ingredient intervention, but that the dose used may not be sufficient to control or reduce the inflammatory response at the systemic level in mice with GvHD. Higher dosages of FA may have an impact when evaluating the immunomodulatory capabilities of the hydrolyzed WB ingredient. Thus, further experiments and the use of technological strategies that enrich the ingredients in soluble ferulic acid to improve its efficacy in this setting are warranted.

Colchicine added to standard therapy further reduces fibrosis in pigs with myocardial infarction.

The anti-inflammatory drug colchicine improves the outcome of patients with myocardial infarction (MI). As an intense inflammatory and fibrotic response after MI may lead to scar expansion and left ventricular (LV) remodeling, the clinical benefit of colchicine could be related to a positive effect on the infarct scar and LV remodeling. Pigs underwent left anterior descending artery occlusion through an angioplasty balloon for 90 min and were then randomized into two groups: standard therapy [ACE inhibitor, beta blocker, mineralocorticoid receptor antagonist (MRA), aspirin] plus colchicine (n = 14) or standard therapy alone (n = 13). The pigs were treated for 30 days and underwent two cardiac magnetic resonance (CMR) scans at 72 h and 30 days. The pigs were then sacrificed the day after the second CMR. The primary efficacy end point was the extent of fibrosis in the infarct zone (calculated on eight samples from this zone and averaged). In the hearts explanted after 31 days, pigs in the colchicine group had less fibrosis in the infarct zone than the other animals [41.6% (20.4-51.0) vs. 57.4% (42.9-66.5); P = 0.022]. There was a trend toward a higher myocardial salvage index (MSI; an index of the efficacy of revascularization) in pigs on colchicine (P = 0.054). Conversely, changes in LV volumes, ejection fraction and mass did not differ between groups. Colchicine therapy for 1 month after reperfused MI further reduces myocardial fibrosis when added to standard therapy, while it does not have additional effects on LV remodeling.