Persistent Inflammatory Response Research Articles

IL-8 Links NF-κB and Wnt/β-Catenin Pathways in Persistent Inflammatory Response Induced by Chronic Helicobacter pylori Infection

IL-8 Links NF-κB and Wnt/β-Catenin Pathways in Persistent Inflammatory Response Induced by Chronic Helicobacter pylori Infection

The versatile roles of lumican in eye diseases: A review

Lumican is a keratan sulfate proteoglycan that belongs to the small leucine-rich proteoglycan family. Research has lifted the veil on the versatile roles of lumican in the pathogenesis of eye diseases. Lumican has pivotal roles in the maintenance of physiological tissue homogenesis and is often upregulated in pathological conditions, e.g., fibrosis, scar tissue formation in injured tissues, persistent inflammatory responses and immune anomaly, etc.Herein, we will review literature regarding the role of lumican in pathogenesis of inherited congenital and acquired eye diseases, e.g., cornea dystrophy, cataract, glaucoma and chorioretinal diseases, etc.

#6755 NOVEL ASPECT OF NATURAL FLAVONOL FISETIN VIA INHIBITING ACSL4-MEDIATED TUBULAR FERROPTOSIS AGAINST FIBROTIC KIDNEY DISEASE

Abstract Background and Aims Kidney fibrosis is the hallmark of chronic kidney disease (CKD) progression, whereas no effective anti-fibrotic therapies exist. We previously reported that natural flavonol fisetin alleviated septic acute kidney injury and protected against hyperuricemic nephropathy in mice. However, the versatile role and potential mechanism of fisetin against fibrotic kidney disease have not been well characterized. Recently, tubular ferroptosis contributes to the pathogenesis of CKD with a persistent inflammatory and profibrotic response. Method Here, we found that fisetin significantly improved tubular injury, inflammation, and tubulointerstitial fibrosis in adenine diet- and unilateral ureteral obstruction (UUO)-induced CKD mice. The renoprotective effects of fisetin were also confirmed to suppress inflammatory response and fibrogenesis in adenine- or TGF-β1-stimulated tubular epithelial cells. Results Mechanistically, fisetin inhibited ferroptosis in the kidneys of CKD mice as well as in injured tubular epithelial cells, as evidenced by a decrease of ACSL4, COX2, HMGB1, and an increase of GPX4. Meanwhile, fisetin effectively restored ultrastructural abnormalities of mitochondrial morphology and relieved the elevated iron, the downregulated GSH and GSH/GSSG, as well as the upregulated lipid peroxide MDA in the kidneys of CKD mice. Notably, abnormal expression of ferroptosis key marker ACSL4 was verified in renal tubules of CKD patients (IgAN, MN, FSGS, LN, and DN) and mice (adenine and UUO), which was also observed in injured tubular cells. Furthermore, ACSL4 knockdown inhibited tubular ferroptosis, while ACSL4 overexpression blocked anti-ferroptotic effect of fisetin and reversed the cytoprotective, anti-inflammation, and anti-fibrosis of fisetin in injured tubular cells. Conclusion In summary, we for the first time explored a novel aspect of fisetin via inhibiting ACSL4-mediated tubular ferroptosis against fibrotic kidney diseases.

A conductive multifunctional hydrogel dressing with the synergistic effect of ROS-scavenging and electroactivity for the treatment and sensing of chronic diabetic wounds

Chronic diabetic wound with persistent inflammatory responses is still a serious threat to human health and life. Ideal wound dressings can be applied not only for covering the injury area, but also for regulating the inflammation to accelerate the wound healing and long-term monitoring of wound condition. However, there remains a challenge to design a multifunctional wound dressing for simultaneous treatment and monitoring of wound. Herein, an ionic conductive hydrogel with intrinsic reactive oxygen species (ROS)-scavenging properties and good electroactivity was developed for achieving the synergetic treatment and monitoring of diabetic wounds. In this study, we modified dextran methacrylate with phenylboronic acid (PBA) to prepare a ROS-scavenging material (DMP). Then the hydrogel was constructed by phenylboronic ester bonds induced dynamic crosslinking network, photo-crosslinked DMP and choline-based ionic liquid as the second network, and the crystallized polyvinyl alcohol as the third network, realizing good ROS-scavenging performance, high electroactivity, durable mechanical properties, and favorable biocompatibility. In vivo results showed that the hydrogel combined with electrical stimulation (ES) demonstrated good performance in promoting re-epithelization, angiogenesis and collagen deposition in chronic diabetic wound treatment by alleviating inflammation. Notably, with desirable mechanical properties and conductivity, the hydrogel could also precisely monitor movements of human body and possible tensile and compressive stresses of the wound site, providing timely alerts of excessive mechanical stress applied to the wound tissue. Thus, this “all-in-one” hydrogel exhibits great potential in constructing the next generation flexible bioelectronics for wound treatment and monitoring. Statement of significanceChronic diabetic wounds characterized by overexpressed reactive oxygen species (ROS) are still a serious threat to human health and life. However, there remains a challenge to design a multifunctional wound dressing for simultaneous wound treatment and monitoring. Herein, a flexible conductive hydrogel dressing with intrinsic ROS-scavenging properties and electroactivity was developed for the combined treatment and monitoring of the wound. The antioxidant hydrogel combined with electrical stimulation synergistically accelerated chronic diabetic wound healing by regulating oxidative stress, alleviating inflammation, promoting re-epithelization, angiogenesis and collagen deposition. Notably, with desirable mechanical properties and conductivity, the hydrogel also presented great potential in monitoring possible stresses of the wound site. The “all-in-one” bioelectronics integrating the treatment and monitoring functions present great application potential for accelerating chronic wound healing.

Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19.

The role of adaptive SARS-CoV-2 specific immunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although a growing population of convalescent COVID-19 patients with manifestation of PASC is observed. We analyzed the SARS-CoV-2-specific immune response, via pseudovirus neutralizing assay and multiparametric flow cytometry in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. Although frequencies of SARS-CoV-2-reactive CD4+ T cells were similar between the studied cohorts, a stronger SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant TEMRA phenotype but low functional TCR avidity was detected in PASC patients compared to controls. Of interest, high avidity SARS-CoV-2-reactive CD4+ and CD8+ T cells were comparable between the groups demonstrating sufficient cellular antiviral response in PASC. In line with the cellular immunity, neutralizing capacity in PASC patients was not inferior compared to controls. In conclusion, our data suggest that PASC may be driven by an inflammatory response triggered by an expanded population of low avidity SARS-CoV-2 reactive pro-inflammatory CD8+ T cells. These pro-inflammatory T cells with TEMRA phenotype are known to be activated by a low or even without TCR stimulation and lead to a tissue damage. Further studies including animal models are required for a better understanding of underlying immunopathogensis. Summary: A CD8+ driven persistent inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in PASC patients.

Implications of viral infections and oncogenesis in uterine cervical carcinoma etiology and pathogenesis.

Uterine Cervical Carcinoma (UCC) is the most prevalent gynecological malignancy globally, with a rising incidence in recent years. Accumulating evidence indicates that specific viral infections, including human papillomavirus (HPV), Epstein-Barr virus (EBV), Hepatitis B and C viruses (HBV and HCV), and human herpesvirus (HHV), may contribute to UCC development and progression. Understanding the complex interplay between viral infections and UCC risk is crucial for developing novel preventative and therapeutic interventions. This comprehensive review investigates the association between viral infections and UCC risk by examining the roles of various viral pathogens in UCC etiology and pathogenesis, and possible molecular mechanisms. Additionally, we evaluate current diagnostic methods and potential therapeutic strategies targeting viral infections for UCC prevention or treatment. The prevention of UCC has been significantly advanced by the emergence of self-sampling for HPV testing as a crucial tool, allowing for early detection and intervention. However, an essential challenge in UCC prevention lies in understanding how HPV and other viral coinfections, including EBV, HBV, HCV, HHV, HIV, or their concurrent presence, may potentially contribute to UCC development. The molecular mechanisms implicated in the association between viral infections and cervical cancer development include: (1) interference of viral oncogenes with cellular regulatory proteins, resulting in uncontrolled cell proliferation and malignant transformation; (2) inactivation of tumor suppressor genes by viral proteins; (3) evasion of host immune responses by viruses; (4) induction of a persistent inflammatory response, contributing to a tumor-promoting microenvironment; (5) epigenetic modifications that lead to aberrant gene expression; (6) stimulation of angiogenesis by viruses; and (7) activation of telomerase by viral proteins, leading to cellular immortalization. Additionally, viral coinfections can also enhance oncogenic potential through synergistic interactions between viral oncoproteins, employ immune evasion strategies, contribute to chronic inflammation, modulate host cellular signaling pathways, and induce epigenetic alterations, ultimately leading to cervical carcinogenesis. Recognizing the implications of viral oncogenes in UCC etiology and pathogenesis is vital for addressing the escalating burden of UCC. Developing innovative preventative and therapeutic interventions requires a thorough understanding of the intricate relationship between viral infections and UCC risk.

756 Effects of Bioengineered Allogeneic Cellular Constructs on Macrophage Phenotype in the Context of Burns

Abstract Introduction The persistent inflammatory and stress responses generate in burn patients have a strong effect on the immune system. Macrophages that are activated in response to burn injuries polarize towards an immunosuppressive phenotype commonly known as M2b. Furthermore, due to sepsis, the chronic exposure to the pro-inflammatory environment also leads to an exhausted macrophage phenotype. Together these effects compromise macrophage behavior that influences the healing outcome. In clinical trials, bioengineered allogeneic cellular constructs (BACCs) have shown potential in promoting healing in patients with deep partial thickness burns. However, the mechanism(s) behind these successful effects are not totally understood yet. For this reason, the aim of this study is to investigate how the crosstalk with the BACC influence different burn-related macrophage phenotype. Methods Primary human macrophages (N=4 healthy donors) were co-cultured with the BACC or collagen controls. Macrophages were isolated over 6 days of co-culture and their RNA was extracted for gene expression analysis, and conditioned media was collected to analyze the secretion of proteins. To assess phenotype changes, we performed gene set analysis using single sample gene set enrichment. To investigate changes in the phenotype of macrophages relevant to burn wounds macrophages were polarized to the immune suppressive M2b phenotype or LPS-exhausted phenotypes before co-culturing them with the BACC. Undifferentiated macrophages (M0) were used as controls. Results Gene expression analysis revealed a shift in undifferentiated macrophage phenotype towards an M2 phenotype by day 3 and 6 in co-culture as demonstrated by an increase in the expression of multiple M2 genes, including MRC1 and CCL18. Secretory analysis revealed a decrease in the secretory of inflammatory proteins, like interleukin 6. Conclusions Collectively these results demonstrate that BACCs promote the transition of macrophage phenotype towards a pro-reparative M2 phenotype which may contribute to the construct’s pro-healing capabilities. Applicability of Research to Practice This study provides insight into the mechanism by which BACCs promote healing in the burn wound environment.

Extracellular Vesicles Released from Macrophages Infected with Mycoplasma pneumoniae Stimulate Proinflammatory Response via the TLR2-NF-κB/JNK Signaling Pathway.

Mycoplasma pneumoniae (M. pneumoniae, Mp) is an intracellular pathogen that causes pneumonia, tracheobronchitis, pharyngitis, and asthma in humans and can infect and survive in the host cells leading to excessive immune responses. Extracellular vesicles (EVs) from host cells carry components of pathogens to recipient cells and play a role in intercellular communication during infection. However, there is limited knowledge on whether EVs derived from M. pneumoniae-infected macrophages play as intercellular messengers and functional mechanisms. In this study, we establish a cell model of M. pneumoniae-infected macrophages that continuously secrete EVs to further asses their role as intercellular messengers and their functional mechanisms. Based on this model, we determined a method for isolating the pure EVs from M. pneumoniae-infected macrophages, which employs a sequence of operations, including differential centrifugation, filtering, and ultracentrifugation. We identified EVs and their purity using multiple methods, including electron microscopy, nanoparticle tracking analysis, Western blot, bacteria culture, and nucleic acid detection. EVs from M. pneumoniae-infected macrophages are pure, with a 30-200 nm diameter. These EVs can be taken up by uninfected macrophages and induce the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 through the nuclear factor (NF)-κB, and mitogen-activated protein kinases (MAPK) signals pathway. Moreover, the expression of inflammatory cytokines induced by EVs relies on TLR2-NF-κB/JNK signal pathways. These findings will help us better understand a persistent inflammatory response and cell-to-cell immune modulation in the context of M. pneumoniae infection.

Antibacterial Conductive Collagen-Based Hydrogels for Accelerated Full-Thickness Wound Healing

Antibacterial conductive hydrogels have been extensively utilized in tissue repair and regeneration on account of their unique electrochemical performances and advantages of anti-pathogenic bacterial infection. Here, multi-functional collagen-based hydrogels (CHLY) with adhesivity, conductivity, and antibacterial and antioxidant activities were developed by introducing cysteine-modified ε-poly(l-lysine) (ε-PL-SH) and in situ-polymerized polypyrrole (PPy) nanoparticles to induce full-thickness wound healing. CHLY hydrogels have a low swelling ratio, good compressive strength, and viscoelasticity due to chemical crosslinking, chelation, physical interaction, and nano-reinforcements in the matrix network of hydrogels. CHLY hydrogels possess excellent tissue adhesion ability, low cytotoxicity, enhanced cell migration ability, and good blood coagulation performance without causing hemolysis. Interestingly, the chemical conjugation of ε-PL-SH in the hydrogel matrix gives hydrogels an inherently robust and broad-spectrum antibacterial activity, while the introduction of PPy endows hydrogels with superior free radical scavenging capacity and good electroactivity. Significantly, CHLY hydrogels have advantages in alleviating persistent inflammatory response as well as promoting angiogenesis, epidermis regeneration, and orderly collagen deposition at the wound sites through their multi-functional synergies, thus effectively accelerating full-thickness wound healing and improving wound healing quality. Overall, our developed multi-functional collagen-based hydrogel dressing demonstrates promising application prospects in the field of tissue engineering to induce skin regeneration.

Persistent alveolar inflammatory response in critically ill patients with COVID-19 is associated with mortality

IntroductionPatients with COVID-19-related acute respiratory distress syndrome (ARDS) show limited systemic hyperinflammation, but immunomodulatory treatments are effective. Little is known about the inflammatory response in the lungs and if this...

Characterization of antigen-specific CD8+ memory T cell subsets in peripheral blood of patients with multiple sclerosis.

Increasing evidence indicates the importance of CD8+ T cells in autoimmune attack against CNS myelin and axon in multiple sclerosis (MS). Previous research has also discovered that myelin-reactive T cells have memory phenotype functions in MS patients. However, limited evidence is available regarding the role of CD8+ memory T cell subsets in MS. This study aimed to explore potential antigen-specific memory T cell-related biomarkers and their association with disease activity. The myelin oligodendrocyte glycoprotein (MOG)-specific CD8+ memory T cell subsets and their related cytokines (perforin, granzyme B, interferon (IFN)-γ) and negative co-stimulatory molecules (programmed cell death protein 1 (PD-1), T- cell Ig and mucin domain 3 (Tim-3)) were analyzed by flow cytometry and real-time PCR in peripheral blood of patients with relapsing-remitting MS. We found that MS patients had elevated frequency of MOG-specific CD8+ T cells, MOG-specific central memory T cells (TCM), MOG-specific CD8+ effector memory T cells (TEM), and MOG-specific CD8+ terminally differentiated cells (TEMRA); elevated granzyme B expression on MOG-specific CD8+ TCM; and, on MOG-specific CD8+ TEM, elevated granzyme B and reduced PD-1 expression. The Expanded Disability Status Scale score (EDSS) in MS patients was correlated with the frequency of MOG-specific CD8+ TCM, granzyme B expression in CD8+ TCM, and granzyme B and perforin expression on CD8+ TEM, but with reduced PD-1 expression on CD8+ TEM. The dysregulation of antigen-specific CD8+ memory T cell subsets, along with the abnormal expression of their related cytokines and negative co-stimulatory molecules, may reflect an excessive or persistent inflammatory response induced during early stages of the illness. Our findings strongly suggest positive regulatory roles for memory T cell populations in MS pathogenesis, probably via molecular mimicry to trigger or promote abnormal peripheral immune responses. Furthermore, downregulated PD-1 expression may stimulate a positive feedback effect, promoting MS-related inflammatory responses via the interaction of PD-1 ligands. Therefore, these parameters are potential serological biomarkers for predicting disease development in MS.

Abstract 706: The Development Of New Therapies Targeting Pneumonia-accelerated Atherosclerosis

Background/Objectives: Pneumonia is inflammation of the lungs caused by an infection. Recent studies show an association between pneumonia and an increased risk of a heart attack. This is likely caused by the persistent inflammatory burden in the lungs and arterial vasculature even 30-45 days after clearance of the infection. Therefore, as inflammation is a strong contributor to the progression of atherosclerosis, there is a need to address the persistent inflammatory burden in this patient population. A normal course of inflammation begins with an initial pro-inflammatory phase and ends with a resolution phase, which is marked by tissue return to homeostasis. During pneumonia, resolution pathways are impaired. Returning resolution processes to normal functioning may prove to be an effective strategy to attenuate prolonged pneumonia-associated inflammation. Resolution pathways are mediated by fatty acid derivatives termed specialized pro-resolving lipid mediators (SPMs), the metabolites of poly-unsaturated fatty acids such as eicosapentaenoic acid (EPA). To improve the therapeutic impact, EPA can be encapsulated in nanoparticle carriers to increase bioavailability and therapeutic delivery. We hypothesize that delivery of EPA nanoparticles into the lungs will control the persistent inflammatory response following pneumonia and reduce atherosclerotic burden. Results: Bone-marrow derived macrophages (mouse) stimulated with gram-positive toxins and EPA-nanoparticles demonstrated reduced expression of pro-inflammatory markers measured using ELISA. We have also developed a mouse model of atherosclerosis combined with S. pneumoniae lung infection. Without EPA administration, S.pneumoniae infection followed by 8 weeks on a high fat diet resulted in a trend towards increased plaque size and lesion lipid content. We are currently evaluating if our EPA-nanoparticles promote resolution processes in the S.pneumoniae mouse model. Clinical Impact: We believe that promotion of resolution pathways via increasing SPM production will prove to be an effective strategy to address inflammation during pneumonia while reducing the risk of suppressive effects on the immune system often caused by currently prescribed anti-inflammatories.

Rheumatological symptoms after COVID-19 pneumonia presenting as long COVID: What we need to know?

COVID-19 pandemic is in verge of over and evolved over last three years in different waves across the globe with various genetic mutants or strains. As of now, many COVID-19 recovered patients are lingering with residual symptoms of illness irrespective of disease severity called as long COVID. Nonspecific or vague and organic or topographical organ specific symptoms are very well described in literature in COVID-19 survived cases. Rheumatological symptoms are most documented in published data as sequel after COVID-19 illness. Clinical presentations of rheumatological symptoms are joint or musculoskeletal pain, chronic fatigue with minimal exertion and weakness or impaired quality of life. Pathophysiology involving in rheumatological manifestations would be persistent or dysregulated inflammatory response, immune activation or thrombogenic pathway abnormality after acute COVID-19 illness. Diagnosis is little difficult and needs prompt workup to rule out underlying rheumatological illness. Inflammatory markers and autoantibody analysis has documented role in work up and confirming the diagnosis in majority of cases. Management of these cases is still evolving and showed response to lifestyle modification, physiotherapy, and short course of steroids and multivitamins in various published studies.

Protective effects of Theracurmin treatment during experimental infection of the Colombian strain of Trypanosoma cruzi at the testicular site.

Chagas' disease is a tropical neglected illness caused by Trypanosoma cruzi and remains one of the most significant causes of morbidity and mortality in South and Central Americas. The disease is caused by a moderate to intense and persistent inflammatory response characterized by local upregulated expression and production of inflammatory mediators that favors the activation and recruitment of distinct cells of the immune system into different tissues to eliminate the parasites. Theracurmin is a curcumin's derived formulation of nanoparticles. Its anti-inflammatory properties make this bioactive compound a mitigating factor in pathological cases after an overwhelming inflammatory response. Our research focused on the testicular investigation in 28 mice infected by 103 trypomastigote forms of Colombian strain of T. cruzi and preventively treated with Theracurmin. The mice were treated with 30 mg/Kg of Theracurmin during the period of 30 days. At the 30th day post infection animals were euthanized, and its testicles were collected to morphological and immunological assays. The animals infected and treated with Theracurmin presented a reduction in the testicular levels of IL-15 and IL-6. The volume density (%) of the tunica propria was also higher in all infected animals, but Theracurmin decreased this parameter in the treated animals. In the intertubular area, the percentage of some intertubular components was decreased in the infected animals such as the percentage and volume of Leydig cells, connective tissue, and macrophages. Furthermore, our data pointed to the daily use of Theracurmin in the diet as a protective element of the testicular function.

Downregulated VISTA enhances Th17 differentiation and aggravates inflammation in patients with acute-on-chronic liver failure.

Persistent inflammatory response and immune activation are the core mechanisms underlying acute-on-chronic liver failure (ACLF). Previous studies have shown that deficiency of V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) exacerbates the progression of inflammatory diseases. We aimed to clarify the role of VISTA in the pathogenesis of ACLF. Blood and liver samples were collected from healthy subjects, stable cirrhosis, and ACLF patients to characterize VISTA expression and function. An ACLF mouse model was used to ascertain potential benefits of anti-VISTA monoclonal antibody (mAb) treatment. VISTA expression was significantly reduced in the naïve and central memory CD4+ T cells from patients with ACLF. The expression of VISTA on CD4+ T cells was associated with disease severity and prognosis. VISTA downregulation contributed to the activation and proliferation of CD4+ T cells and enhanced the differentiation of T helper 17 cells (Th17) and secretion of inflammatory cytokines through the activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. Moreover, agonistic anti-VISTA mAb treatment inhibited the activation and cytokine production of CD4+ T cells and reduced mortality and liver inflammation of the ACLF mice. The decreased expression of VISTA may facilitate development of Th17 cells and promote the progression of inflammation in ACLF patients. These findings are helpful for elucidating the pathogenesis of ACLF and for the identification of new drug targets.

Dual-drug loaded polysaccharide-based self-healing hydrogels with multifunctionality for promoting diabetic wound healing

Diabetic chronic wound healing still faces huge clinical challenge. The arrangement and coordination of healing processes are disordered in diabetic wound caused by the persistent inflammatory response, microbial infection, impaired angiogenesis, resulting in the delayed and even non-healing wounds. Here, the dual-drug loaded nanocomposite polysaccharide-based self-healing hydrogels (OCM@P) with multifunctionality were developed to promote diabetic wound healing. Curcumin (Cur) loaded mesoporous polydopamine nanoparticles (MPDA@Cur NPs) and metformin (Met) were introduced into the polymer matrix formed by the dynamic imine bonds and electrostatic interactions between carboxymethyl chitosan and oxidized hyaluronic acid to fabricate OCM@P hydrogels. OCM@P hydrogels show homogeneous and interconnected porous microstructure, which possess good tissue adhesiveness, enhanced compression strength, great anti-fatigue behavior, excellent self-recovery capacity, low cytotoxicity, rapid hemostatic ability and robust broad-spectrum antibacterial activity. Interestingly, OCM@P hydrogels exhibit rapid release of Met and long-term sustained release of Cur, thereby to effectively scavenge extracellular and intracellular free radicals. Significantly, OCM@P hydrogels remarkably promote re-epithelization, granulation tissue formation, collagen deposition and arrangement, angiogenesis as well as wound contraction in diabetic wound healing. Overall, the multifunctional synergy of OCM@P hydrogels greatly contributes to accelerating diabetic wound healing, which demonstrate promising application as scaffolds in regenerative medicine.

Pneumonia-Induced Inflammation, Resolution and Cardiovascular Disease: Causes, Consequences and Clinical Opportunities

Pneumonia is inflammation in the lungs, which is usually caused by an infection. The symptoms of pneumonia can vary from mild to life-threatening, where severe illness is often observed in vulnerable populations like children, older adults, and those with preexisting health conditions. Vaccines have greatly reduced the burden of some of the most common causes of pneumonia, and the use of antimicrobials has greatly improved the survival to this infection. However, pneumonia survivors do not return to their preinfection health trajectories but instead experience an accelerated health decline with an increased risk of cardiovascular disease. The mechanisms of this association are not well understood, but a persistent dysregulated inflammatory response post-pneumonia appears to play a central role. It is proposed that the inflammatory response during pneumonia is left unregulated and exacerbates atherosclerotic vascular disease, which ultimately leads to adverse cardiac events such as myocardial infarction. For this reason, there is a need to better understand the inflammatory cross talk between the lungs and the heart during and after pneumonia to develop therapeutics that focus on preventing pneumonia-associated cardiovascular events. This review will provide an overview of the known mechanisms of inflammation triggered during pneumonia and their relevance to the increased cardiovascular risk that follows this infection. We will also discuss opportunities for new clinical approaches leveraging strategies to promote inflammatory resolution pathways as a novel therapeutic target to reduce the risk of cardiac events post-pneumonia.

Chronic poor healing wounds of post cesarean scar diverticulum: Altered angiogenesis and immunobiology

Cesarean section (CS) scar diverticula (CSD) is an important cause impede further fecundity, with rather complicated pathophysiologic mechanisms and unclear etiopathogenesis. In this study, we detect the influences of CSD on the pregnancy outcomes in in-vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI) embryo transfer (ET) cycles, and further explore the mechanisms involved based on histopathology and immunology differences in endometrium between CSD and vaginal birth (VB) women. The CS group had significantly lower CLBR compared to NCS group. Histopathological analysis showed that the higher prevalent of CE is accompanied by excessive fibroblast proliferation at the lower segment of uterus and significantly exaggerated vascular proliferation in situ. Intrauterine inflammatory cytokines including IL-1α, IL-1β, IL-6, IL-8, TNF-α and SDF-1α were also increased in CSD group. The present data suggests impaired fecundity in CSD women undergoing IVF/ICSI treatment. Although the causal relationship is ambiguous, the potential mechanisms may involve persistent inflammatory response in the uterine cavity, active vascular proliferation accompanied with increased fibrosis which are responsible for poor chronic wound healing of CSD.

Abstract P515: HIV/HCV Co-Infection and the Risk of Cardiovascular Disease: A Meta-Analysis of 91,153 Patients

Introduction: Antiretroviral therapy has improved the life expectancy of people living with human immunodeficiency virus (HIV). However, these patients are more susceptible to developing cardiovascular diseases (CVD) and subsequent mortalities. Many studies examining the association between HIV and hepatitis C virus (HCV) co-infection and the risk of CVD, compared to HIV mono-infection, have inconsistent results. We conducted a meta-analysis to quantify this association. We hypothesized that CVD risk will be synergistically increased by the persistent inflammatory responses of dual viral infections. Method: We searched Pubmed, EMBASE, CINAHL, Google Scholar, Cochrane, and Web of Science from inception to July 2022 to identify studies on HIV/HCV co-infection and CVD, defined as coronary artery disease, congestive heart failure, and stroke. We used either a random or fixed effect model considering the heterogeneity. Adjusted hazard ratios (aHR) and crude Odds ratio (COR) for CVD and mortality were used. Results: Among the 453 articles reviewed, 11 observational studies met the inclusion criteria, with a total of 91,153 participants. Of these, 9633 (10.5%) were HIV/HCV coinfected, 81,520 (89.5%) were HIV monoinfected. Pooled hazard ratio for the association between HIV/HCV co-infection and CVD was significant (aHR = 1.45, 95% CI: 1.24, 1.65, I2 = 38%, P=0.12) compared to HIV mono-infection. Furthermore, the odds of mortality due to HIV/HCV co-infection in patients with CVD is significantly higher compared to HIV mono-infection (COR = 4.07, 95% CI: 3.19, 5.18, I2 = 0%, P=0.56). Conclusion: We found a positive association between HIV/HCV coinfection and increased CVD risk and associated mortality compared to those with HIV mono-infection. However, more research is needed for further assessment of this association, determining potential underlying mechanisms and evaluating whether treatment for HIV and HCV infections can reduce CVD morbidities and mortalities.

Bio-Guided Isolation of Compounds from Fraxinus excelsior Leaves with Anti-Inflammatory Activity.

Inflammation is the first physiological defence mechanism against external and internal stimuli. The prolonged or inappropriate response of the immune system may lead to the persistent inflammatory response that can potentially become a basis for chronic diseases e.g., asthma, type II diabetes or cancer. An important role in the alleviation of inflammatory processes, as an adjunct to traditional pharmacological therapy, is attributed to phytotherapy, especially to raw materials with a long tradition of use, e.g., ash leaves. Despite their long-term use in phytotherapy, the specific mechanisms of action have not been confirmed in a sufficient number of biological or clinical studies. The aim of the study is a detailed phytochemical analysis of infusion and its fractions, isolation of pure compounds from the leaves of Fraxinus excelsior and evaluation of their effect on the secretion of anti-inflammatory cytokines (TNF-α, IL-6) and IL-10 receptor expression in an in vitro model of monocyte/macrophage cells isolated from peripheral blood. Methods: Phytochemical analysis was carried out by the UHPLC-DAD-ESI-MS/MS method. Monocytes/macrophages were isolated from human peripheral blood using density gradient centrifugation on Pancoll. After 24 h incubation with tested fractions/subfractions and pure compounds, cells or their supernatants were studied, respectively, on IL-10 receptor expression by flow cytometry and IL-6, TNF-α, IL-1β secretion by the ELISA test. Results were presented with respect to Lipopolysaccharide (LPS) control and positive control with dexamethasone. Results: The infusion, 20% and 50% methanolic fractions and their subfractions, as well as their dominating compounds, e.g., ligstroside, formoside and oleoacteoside isolated from the leaves, show the ability to increase the IL-10 receptor expression on the surface of monocyte/macrophage cells, stimulated by LPS, and to decrease the secretion of pro-inflammatory cytokines, e.g., TNF-α, IL-6.