Chronic Remodeling Research Articles

IGFBP5 affects cardiomyocyte survival and functional recovery in mice following myocardial ischemia

Insulin-like growth factor-binding protein 5 (IGFBP5) has been shown to be useful for the diagnosis and treatment of multiple tumors and cerebrovascular diseases. However, it is unknown whether IGFBP5 is involved in myocardial repair following myocardial infarction (MI). Here we show high expression of IGFBP5 in multiple models of ischemic and hypoxic injury. IGFBP5 affected the proliferation of neonatal rat cardiomyocytes (NRCMs) and the cardiomyocyte apoptosis induced by oxygen-glucose deprivation (OGD). Subsequently, heart-specific IGFBP5 knockdown inhibited myocardial apoptosis and increased cardiomyocyte proliferation in mice with MI. During the chronic remodeling stage, heart-specific regulation of IGFBP5 ameliorated pathological cardiac remodeling and dysfunction. Mechanistically, IGFBP5 regulated cardiomyocyte survival through the insulin-like growth factor 1 (IGF1) receptor (IGF1R)/protein kinase B (PKB/AKT) pathway. In summary, our results provide mechanistic insights into the effect of IGFBP5 on cardiomyocyte during cardiac repair. IGFBP5 may represent a therapeutic target for myocardial ischemic injury.

MMP8-mediated vascular remodeling in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease that impacts the cardiopulmonary system. Due to the currently limited understanding of vascular remodeling, a cure for PAH remains elusive. This study highlights the critical role of the STAT1 (signal transducer and activator of transcription 1)/MMP8 (matrix metallopeptidase 8)/DRP1 (dynamin-related protein 1) axis in vascular remodeling and the pathogenesis of pulmonary hypertension. Notably, MMP8 is significantly elevated in pulmonary arterial endothelial cells and its levels correlate with the severity of the disease. MMP8 binds to and activates DRP1, inducing mitochondrial fragmentation and promoting a malignant phenotype of endothelial cells under hypoxic conditions. Moreover, MMP8 is tightly regulated by STAT1. The knockout of MMP8 attenuates chronic pulmonary vascular remodeling, and drugs targeting MMP8 alleviate pulmonary hypertension and enhance cardiac function. This study offers fresh insights into hypoxia-induced vascular remodeling, laying a theoretical foundation for countering vascular remodeling by directly regulating the STAT1/MMP8/DRP1 axis.

Transient cerebral ischaemia alters mesenteric arteries in hypertensive rats: Limited reversal despite suberoylanilide hydroxamic acid cerebroprotection

Stroke induces brain injury, especially severe in hypertensive patients, and elevates mortality rates through non-neurological complications. However, the potential effects of a transient ischaemic episode on the peripheral vasculature of hypertensive individuals remain unclear. We investigated whether transient cerebral ischaemia (90 min)/reperfusion (1 or 8 days) induces alterations in mesenteric resistance artery (MRA) properties in adult male spontaneously hypertensive rats (SHR). In addition, we assessed whether the reported cerebroprotective effects of suberoylanilide hydroxamic acid (SAHA; 50 mg/kg; administered intraperitoneally at 1, 4, or 6 h after reperfusion onset) extend over several days and include beneficial effects on MRAs. Functional and structural properties of MRAs were examined at 1- and 8-days post-stroke. Nuclei distribution, collagen content, and oxidative stress were assessed. Ischaemic brain damage was evaluated longitudinally using magnetic resonance imaging. Following stroke, MRAs from SHR exhibited non-reversible impaired contractile responses to the thromboxane A2 receptor agonist U46619. Stroke increased the MRA cross-sectional area, wall thickness, and wall/lm ratio due to augmented collagen deposition. These changes were partially sustained 8 days later. SAHA did not improve U46619-induced contractions but mitigated stroke-induced oxidative stress and collagen deposition, preventing MRA remodelling at 24 h of reperfusion. Furthermore, SAHA induced sustained cerebroprotective effects over 8 days, including reduced brain infarct and oedema, and improved neurological scores. However, SAHA had minimal impact on chronic MRA contractile impairments and remodelling. These findings suggest that stroke causes MRA changes in hypertensive subjects. While SAHA treatment offers sustained protection against brain damage, it cannot fully restore MRA alterations.

Correlation between antihypertensive drugs and cerebral hemodynamic parameters: insights from observational findings using transcranial Doppler.

Antihypertensives (AHD) can influence cerebral autoregulation (CA) and attenuate hypertrophic concentric remodelling of arterioles. The aim of this study was to examine the associations between AHD, CA and structural and functional properties of cerebral arteries. In this observational, cross-sectional study 115 volunteers were divided in group 1 (non-hypertensive) [n = 30]; group 2 (hypertensive with systolic blood pressure [SBP] < 140 and diastolic blood pressure [DBP] < 90 mmHg) [n = 54]; group 3 (hypertensive with SBP ≥ 140 or DBP ≥ 90 mmHg) [n = 31] and simultaneous measurements of systemic blood pressure (BP) and middle cerebral artery blood flow velocity (CBFV) were obtained from digital plethysmography and transcranial Doppler. Beat-to-beat, critical closing pressure (CrCP), resistance-area product (RAP) and autoregulation index (ARI) values were extracted by linear regression analysis of instantaneous BP and CBFV waveforms using computerised analysis. Pulsatility index (PI) was calculated and CO2 reactivity was assessed by the breath-holding test. Despite their higher RAP (1.7 [±0.7], p < 0.001) compared to groups 1 and 2, uncontrolled hypertensive using diuretics (p = 0.047) and α2-agonists (p = 0.009) had significantly lower PI. Impaired CO2 reactivity was common between the two hypertensive groups (p = 0.008), however ARI, CrCP and CBFV did not differ between them and non-hypertensive individuals and also did not correlate with any AHD used. Unlike the RAP, PI does not seem to reflect the real cerebrovascular resistence resulting from chronic arterial remodelling. Despite impaired CO2 reactivity, hypertensivehavearterial tonus and CA comparable to non-hypertensive. Experimental studies involving an untreated hypertensive control group are required to robustly make definitive conclusions about these questions.

Deep Crotonylproteomics Analysis of High-Altitude Exposure Hearts in Mice.

The potential molecular mechanisms of short-term adaptation and long-term structural deteriorations in the cardiac structure in response to high altitude remain not fully understood. This study aims to investigate changes in the crotonylproteome in the hearts of mice exposed to high altitude at different time points. The hearts were obtained from mice living at the lowland and 3, 10, and 30 days after arriving at a plateau. Crotonyllysolylated proteins were subsequently comprehensively evaluated. Among the identified 13,731 crotonyllysine sites, 11,140 were quantified. Furthermore, 1247 differentially expressed crotonyllysine sites on 764 proteins in 46 pathways were analyzed, and the results showed that the abundance of crotonylation increased with the increase of exposure time to altitude. Functional enrichment analysis showed that most of these significantly altered crotonylated proteins were enriched in the regulation of metabolism and myocardial function, indicating that these enriched biological processes may be involved in the acute adaptation and chronic remodeling of cardiac function and structural changes at a high altitude. Our study uncovers some crotonylation-affected processes and pathways in the heart's response to high-altitude exposure, giving novel insights into molecular processes of cardiac function and structure changes at high altitude (ProteomeXchange identifier: PXD044178).

A human stem cell-derived model reveals pathologic extracellular matrix remodeling in diabetic podocyte injury

Diabetic nephropathy results from chronic (or uncontrolled) hyperglycemia and is the leading cause of kidney failure. The kidney’s glomerular podocytes are highly susceptible to diabetic injury and subsequent non-reversible degeneration. We generated a human induced pluripotent stem (iPS) cell-derived model of diabetic podocytopathy to investigate disease pathogenesis and progression. The model recapitulated hallmarks of podocytopathy that precede proteinuria including retraction of foot processes and podocytopenia (detachment from the extracellular matrix (ECM)). Moreover, hyperglycemia-induced injury to podocytes exacerbated remodeling of the ECM. Specifically, mature podocytes aberrantly increased expression and excessively deposited collagen (IV)α1α1α2 that is normally abundant in the embryonic glomerulus. This collagen (IV) imbalance coincided with dysregulation of lineage-specific proteins, structural abnormalities of the ECM, and podocytopenia – a mechanism not shared with endothelium and is distinct from drug-induced injury. Intriguingly, repopulation of hyperglycemia-injured podocytes on decellularized ECM scaffolds isolated from healthy podocytes attenuated the loss of synaptopodin (a mechanosensitive protein associated with podocyte health). These results demonstrate that human iPS cell-derived podocytes can facilitate in vitro studies to uncover the mechanisms of chronic hyperglycemia and ECM remodeling and guide disease target identification.

Sinomenine hydrochloride alleviates autoimmune myocarditis via suppressing Th1 cell induced-M1 macrophage pyroptosis

Abstract Background Myocarditis is typical of the complex inflammatory response in the heart with high morbidity and mortality, accompanied by tissue damage and cardiac fibrosis. Previous studies have demonstrated that CD4+ T cells are crucial to the cardiac autoimmunity of myocarditis, but the role of different CD4+ T cell subsets remains unclear. Recently, sinomenine hydrochloride, a natural compound from the traditional Chinese herb Sinomenium acutum, is reported to inhibit T cell proliferation in some systemic autoimmune diseases such as rheumatoid arthritis. Given that autoimmune myocarditis is an organ-specific autoimmune disease, the effect of sinomenine hydrochloride on autoimmune myocarditis demands further study. Purpose This study aims to elucidate the role of CD4+ T-helper 1 (Th1) cells in regulating inflammatory cell death in autoimmune myocarditis and investigate the pharmacological effect of sinomenine hydrochloride on CD4+ Th1 cells and autoimmune myocarditis. Methods Male Balb/c mice were immunized with myosin heavy chain-α peptides to establish the experimental autoimmune myocarditis (EAM) model, followed by the treatments with sinomenine hydrochloride by gavage. Tohoku Hospital Pediatrics-1 (THP-1) cell line and murine T cells were used for in vitro experiments. Results In the acute phase of EAM, we observed plenty of CD4+ T cells infiltrating the heart tissue. RNA sequencing revealed that among the genes encoding typical transcription factors of CD4+ T cell subset, only Tbx21 and Stat4, both representing Th1 cells, were upregulated, which consisted with immunofluorescence staining. Further studies indicated that Th1 cells not only mediated classical activated macrophage (M1 macrophage) polarization by secreting interferon-γ (IFN-γ) but also associated with pro-inflammatory macrophage pyroptosis in the EAM, with the cleavage of gasdermin D (GSDMD), caspase-1 and IL-1β. Subsequent in vitro experiments confirmed that IFN-γ could dramatically promote macrophage pyroptosis combined with ATP, leading to the release of IL-1β and IL-18(Figure 1). To find an effective method for Th1 cell suppression and myocarditis remission, we identified that sinomenine hydrochloride impeded Th1 cell activation, differentiation and proliferation in vitro. Furthermore, sinomenine hydrochloride inhibited Th1 cell infiltration and M1 macrophage pyroptosis in the EAM heart, In the chronic phase, cardiac remodeling and fibrosis were suppressed, and cardiac systolic function was significantly improved in the treatment group (Figure 2). Conclusion Our study demonstrates that Th1 cells-induced M1 macrophage pyroptosis is an essential pathogenic mechanism of EAM. Sinomenine hydrochloride can alleviate the severity and progression of EAM, which may become a novel therapeutic strategy for treating myocarditis.Figure 1Figure 2

Experimental Mouse Models and Human Lung Organoid Models for Studying Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality throughout the world, is a highly complicated disease that includes chronic airway inflammation, airway remodeling, emphysema, and mucus hypersecretion. For respiratory function, an intact lung structure is required for efficient air flow through conducting airways and gas exchange in alveoli. Structural changes in small airways and inflammation are major features of COPD. At present, mechanisms involved in the genesis and development of COPD are poorly understood. Currently, there are no effective treatments for COPD. To develop better treatment strategies, it is necessary to study mechanisms of COPD using proper experimental models that can recapitulate distinctive features of human COPD. Therefore, this review will discuss representative established mouse models to investigate inflammatory processes and basic mechanisms of COPD. In addition, human COPD-mimicking human lung organoid models are introduced to help researchers overcome limits of mouse COPD models.

Acute exacerbation of congestive heart failure following intranasal cocaine use

Background: Most presentations of decompensated congestive heart failure occur in patients diagnosed with pre-existing heart failure. Decompensation presents as progressive dyspnea, abdominal and peripheral congestions, as well as neurological symptoms. It typically occurs following physiological stressors such as infection, arrhythmia, or medical non-adherence. Chronic heart failure may result from cardiovascular comorbid conditions, such as coronary artery disease, valvular disease, and long-standing hypertension. Long term cocaine use also results in adverse cardiovascular health. Cocaine use can augment pre-existing risk factors for both chronic congestive heart failure and acute decompensations - namely, coronary artery disease, congestive heart failure, and peripheral vascular disease. It can also independently pose a cardiovascular risk by causing acute ischemia, vasoconstriction, tachycardia, systolic dysfunction, and cardiac remodeling. The Case: the case of a 49-year-old Caucasian male, who presented with worsening dyspnea on exertion and bilateral peripheral edema extending to his abdomen. His symptoms worsened over the preceding week and began after three consecutive days of intranasal cocaine use. He presented with a background history of congestive heart failure, coronary artery disease, peripheral vascular disease, a 30 pack-year smoking history, and weekly cocaine use for the past 12 years. Conclusion: Cocaine use can lead to decompensation of congestive heart failure in patients with extensive cardiac and vascular disease. Cocaine use can also acutely worsen systolic function and cause demand ischemia, on a background of chronic remodelling and atherosclerotic changes. Patient Consent Obtained: Yes

Immunomodulatory Hydrogel for Electrostatically Capturing Pro-inflammatory Factors and Chemically Scavenging Reactive Oxygen Species in Chronic Diabetic Wound Remodeling.

Diabetic wound exhibits the complex characteristics involving continuous oxidative stress and excessive expression of pro-inflammatory cytokines to cause a long-term inflammatory microenvironment. The repair healing of chronic diabetic wounding is tremendously hindered due to persistent inflammatory reaction. To address the aforementioned issues, here, a dual-functional hydrogel is designed, consisting of N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, N3-tetramethylpropane-1, 3-diaminium (TSPBA) modified polyvinyl alcohol (PVA) and methacrylamide carboxymethyl chitosan (CMCSMA) can not only electrostatically adsorb proinflammatory cytokines of IL1-β and TNF-α, but can also chemically scavenge the excessive reactive oxygen species (ROS) in situ. Both in vitro and in vivo evaluations verify that the negatively charged and ROS-responsive hydrogel (NCRH) can effectively modulate the chronic inflammatory microenvironment of diabetic wounds and significantly enhance wound remodeling. More importantly, the well-designed NCRH shows a superior skin recovery in comparison with the commercial competitor product of wound dressing. Consequently, the current work highlights the need for new strategies to expedite the healing process of diabetic wounds and offers a wound dressingmaterial with immunomodulation.

Rapid correction of chronic hyperglycemia and bone remodeling, warning against overdoing.

It is widely recognized that chronic hyperglycemia decreases bone quality, although little is known about the impact of the rapid correction of chronic hyperglycemia on the quality of bone remodeling. This spotlight article explores this correlation by focusing on the stages of bone remodeling linked to glucose levels.

30 Microbiota and Companion Animal Health

Abstract The intestinal microbiota has been shown to have an important role in health and disease of animals. It is a complex system that depends on interactions between the luminal environment and specific bacterial taxa and their function (e.g., production of short-chain fatty acids, conversion of bile acids). Dietary substrates are an important factor for microbial metabolism and supplements have the potential to help in maintaining intestinal health. Major changes in the microbiota and their loss of function (dysbiosis) are mainly associated with antibiotic treatment and in chronic intestinal disease likely due to chronic remodeling of the epithelium. Therefore, often these changes persist long-term. Chronic enteropathies (CE) occur very commonly in dogs and cats, and are frustrating to treat due to lack of specific markers. The pathophysiology is complex and includes changes in the immune system (e.g., inflammation), intestinal function, and the intestinal microbiome. The current classification based on treatment response (i.e., food- vs. steroid-responsive) is currently being questioned, as new research findings indicate that CE is a syndrome with many overlapping unspecific features, often with chronic irreversible changes in intestinal function and dysbiosis. The presentation will summarize novel research about the pathophysiology and novel concepts in multi-modal therapy to these conditions. This program will help better understand the role of the intestinal microbiota in health and disease (with focus on acute diarrhea and chronic intestinal inflammation). New diagnostic methods for evaluation of the intestinal microbiota will be covered. Finally, this lecture will review how to best manage the clinical signs of acute and chronic diarrhea. This includes new evidence of the negative impact of antibiotics on the microbiome and the critical role nutrition can play in managing these patients.

The Function of RhoA/ROCK Pathway and MYOCD in Airway Remodeling in Asthma

Plain Language SummaryAsthma is a common chronic respiratory disease characterized by chronic airway inflammation and abnormal airway remodeling. The regulation process of RhoA/ROCK signaling pathway and downstream MRTF-A gene is well studied and exhibits significant associations with cell contraction and cell proliferation, which correlates tightly with airway remodeling. While most studies focusing on the MRTF-A to clarify the mechanism of cell growth, we paid close attention to MYOCD gene, which shares homology with MRTF-A but expressed specifically in smooth muscle cells. Through the series cell experiments, molecular assays, and literature review, we firstly illustrated the potential function of MYOCD underlying the regulation of RhoA/ROCK activated cell proliferation and subsequent airway remodeling in airway smooth muscle cells. This novel sight provides therapeutic targets for asthma.

Association of I/D polymorphism of ACE gene with different course of chronic heart failure and myocardial remodeling in patients with coronary heart disease after coronary artery bypass grafting

Association of I/D polymorphism of ACE gene with different course of chronic heart failure and myocardial remodeling in patients with coronary heart disease after coronary artery bypass grafting

Alpha-ketoglutarate is required for chronic hypoxia-induced cardiac remodeling.

Chronic hypoxia (CH) is commonly associated with various cardiovascular diseases, with cardiac hypertrophy being the most frequently observed alteration. Metabolic remodeling is another consequence seen in the hypoxic heart. However, the mechanistic linkage between metabolic remodeling and cardiac hypertrophy in the hypoxic heart remains unclear. In this study, wild-type C57BL/6J mice were subjected to CH for 4 wk. Echocardiography and morphological analysis were used to assess the cardiac effects. We found that 4 wk of CH led to significant cardiac hypertrophy in the mice, whereas cardiac function remained unchanged compared with normoxic mice. In addition, CH induced an elevation in cardiac alpha-ketoglutarate (α-KG) content. Promoting α-KG degradation in the CH hearts prevented CH-induced cardiac hypertrophy but led to noticeable cardiac dysfunction. Mechanistically, α-KG promoted the transcription of hypertrophy-related genes by regulating histone methylation. Silencing lysine-specific demethylase 5 (KDM5), a histone demethylation enzyme, blunted α-KG-induced transcription of hypertrophy-related genes. These data suggest that α-KG is required for CH-induced cardiac remodeling, thus establishing a connection between metabolic changes and cardiac remodeling in hypoxic hearts.NEW & NOTEWORTHY We reported that alpha-ketoglutarate (α-KG) is indispensable for chronic hypoxia (CH)-induced cardiac remodeling, which builds the bridge between metabolic intermediates and cardiac remodeling.

Ablation of Akt2 rescues chronic caloric restriction-provoked myocardial remodeling and dysfunction through a CDK1-mediated regulation of mitophagy

Chronic caloric restriction triggers unfavorable alterations in cardiac function albeit responsible scenarios remain unclear. This work evaluated the possible involvement of Akt2 in caloric restriction-evoked cardiac geometric and functional changes and responsible processes focusing on autophagy and mitophagy. Akt2 knockout and WT mice were subjected to caloric restriction for 30 weeks prior to assessment of myocardial homeostasis. Caloric restriction compromised echocardiographic parameters (decreased LV wall thickness, LVEDD, stroke volume, cardiac output, ejection fraction, fractional shortening, and LV mass), cardiomyocyte contractile and intracellular Ca2+ capacity, myocardial atrophy, interstitial fibrosis and mitochondrial injury associated with elevated blood glucocorticoids, autophagy (LC3B, p62, Atg7, Beclin-1), and mitophagy (Pink1, Parkin, TOM20), dampened cardiac ATP levels, mitochondrial protein PGC1α and UCP2, anti-apoptotic protein Bcl2, intracellular Ca2+ governing components Na+-Ca2+ exchanger, phosphorylation of SERCA2a, mTOR (Ser2481) and ULK1 (Ser757), and upregulated Bax, phospholamban, phosphorylation of Akt2, AMPK, and ULK1 (Ser555), the responses except autophagy markers (Beclin-1, Atg7), phosphorylation of AMPK, mTOR and ULK1 were negated by Akt2 ablation. Levels of CDK1 and DRP1 phosphorylation were overtly upregulated with caloric restriction, the response was reversed by Akt2 knockout. Caloric restriction-evoked changes in cardiac remodeling and cardiomyocyte function were alleviated by glucocorticoid receptor antagonism, Parkin ablation and Mdivi-1. In vitro experiment indicated that serum deprivation or glucocorticoids evoked GFP-LC3B accumulation and cardiomyocyte dysfunction, which was negated by inhibition of Akt2, CDK1 or DRP1, whereas mitophagy induction reversed Akt2 ablation-evoked cardioprotection. These observations favor a protective role of Akt2 ablation in sustained caloric restriction-evoked cardiac pathological changes via correction of glucocorticoid-induced mitophagy defect in a CDK1-DRP1-dependent manner.

Sex-specific cardiac remodeling in aged rats after adolescent chronic stress: associations with endocrine and metabolic factors

BackgroundCardiovascular disease is a leading cause of death worldwide. Rates of cardiovascular disease vary both across the lifespan and between sexes. While multiple factors, including adverse life experiences, impact the development and progression of cardiovascular disease, the potential interactions of biological sex and stress history on the aged heart are unknown. To this end, we examined sex- and stress-specific impacts on left ventricular hypertrophy (VH) after aging. We hypothesized that early-life chronic stress exposure impacts behavioral and physiologic responses that predict cardiac remodeling in a sex-specific manner.MethodsHistological analysis was conducted on hearts of male and female rats previously exposed to chronic variable stress during the late adolescent period (postnatal days 43–62). These animals were challenged with a forced swim test and a glucose tolerance test before aging to 15 months and again being challenged. Predictive analyses were then used to isolate factors that relate to cardiac remodeling among these groups.ResultsEarly-life chronic stress impacted cardiac remodeling in a sex-specific manner. Among rats with a history of chronic stress, females had increased concentric VH. However, there were few associations within the female groups among individual behavioral and physiologic parameters and cardiac remodeling. While males as a group did not have VH after chronic stress, they exhibited multiple individual associations with cardiac susceptibility. Passive coping in young males and active coping in aged males related to VH in a stress history-dependent manner. Moreover, baseline corticosterone positively correlated with VH in unstressed males, while chronically-stressed males had positive correlations between VH and visceral adiposity.ConclusionsThese results indicate that females as a group are uniquely susceptible to the effects of early-life stress on cardiac remodeling later in life. Conversely, males have more individual differences in vulnerability, where susceptibility to cardiac remodeling relates to endocrine, metabolic, and behavioral measures depending on stress history. These results ultimately support a framework for assessing cardiovascular risk based on biological sex and prior adverse experiences.

Edwardsiella tarda induces airways inflammation and production of autoantibodies against lung tissues through regulation of the IL-33-ST2 axis.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic respiratory disease characterised by irreversible airways obstruction associated with chronic airways inflammation and remodelling, while the pathogenesis and the mechanistic differences between patients remain to be fully elucidated. We previously reported that alarmin cytokine IL-33 may contribute to the production of autoantibodies against respiratory epithelial cells. Here we expand the hypothesis that pulmonary autoimmune responses induced by airway microbiota also contribute to the progression of COPD. We focused on Edwardsiella tarda which we detected uniquely in the induced sputum of patients with acute exacerbations of COPD. Pernasal challenge of the airways of WT mice with supernatants of cultured E. tarda induced marked, elevated expression of IL-33 in the lung tissues. Immunisation of animals with supernatants of cultured E. tarda resulted in significantly elevated airways inflammation, the formation of tertiary lymphatic structures and significantly elevated proportions of T follicular helper T cells in the lung tissue and mediastinal lymph nodes. Interestingly, such challenge also induced production of IgG autoantibodies directed against lung tissue lysate, alveolar epithelial cell proteins and elastin fragment, while putrescine, one of metabolites generated by the bacterium, might play an important role in the autoantibody production. Furthermore, all of these effects were partly but significantly abrogated in mice with deletion of the IL-33 receptor ST2. Collectively, these data support the hypothesis that COPD is progressed at least partly by airways microbiota such as E. tarda initiating autoimmune attack of the airways epithelium mediated at least partly through the IL-33-ST2 axis.

Abstract We055: Role of Classical Dendritic Cells in the Sterile Inflammatory Response Following Myocardial Infarction

Myocardial infarction and the subsequent development of chronic ischemic cardiomyopathy is the most common cause of congestive heart failure. Infarction is associated with an intense sterile inflammatory response which can lead to adverse remodeling over the long term. Dendritic cells (DCs) are antigen presenting cells that function as a bridge between innate and adaptive immunity. Precursor DCs give rise to several distinct classical DC (cDC) subsets that mediate a variety of functions. The cDC1 subset is essential for cross-presentation of antigens to CD8 + T cells, while the cDC2 lineage is a potent inducer of CD4 + T cell proliferation. The aim of the study was to characterize the profile of the cDC populations present during the various stages of the development of chronic ischemic cardiomyopathy. We hypothesized that cDCs are essential mediators of chronic LV remodeling in the period following ischemic myocardial injury. We sought to determine which specific cDC subtype (cDC1 vs cDC2) forms the predominant population in the heart and secondary lymphoid tissues following ischemic injury. Adult male C57BL/6 (WT) mice underwent non-perfused myocardial infarction by ligating the left anterior descending artery (LAD) to induce sterile injury, with sham operated mice used as controls. Left ventricular (LV) remodeling was assessed by echocardiography at 1 w and 8 w following surgery. Alterations in cDC1 (CD45+CD11c+CD103-XCR1-) and cDC2 (CD45+CD11c+CD103+XCR1+) profile were examined by flow cytometry. When compared with the sham operated mice, mice with ischemic cardiomyopathy following LAD ligation exhibited the following features. There is an initial influx of cDC2 into the myocardium 1 w after MI (mean of 3.0% vs 0.26% of CD45 + leukocytes, p=0.02). This is followed by a subsequent influx of cDC1 into the myocardium 4 weeks after MI (mean of 1.98% vs 0.16% of CD45 + leukocytes, p=0.001). This influx of cDC into the heart is accompanied by an egress of cDC from the spleen (mean of 0.37% vs 0.76% of CD45 + leukocytes, P=0.001) at 4 weeks following MI. In conclusion, the findings of our study suggest that there is an initial influx of cDC2 followed by a more sustained influx of cDC1 into the myocardium in the weeks following an infarct. Antigen presentation by cDC likely plays a critical role in driving the inflammatory response and inducing chronic LV remodeling in the period following MI.

Advanced meta-analysis on therapeutic strategies of mesenchymal derived exosome for diabetic chronic wound healing and tissue remodeling

BackgroundExosome (EXOs) are rapidly being identified as key mediators of cell-to-cell communication. They convey biologically active molecules to target cells, serve important roles in a range of physiological and pathological processes, and have enormous potential as novel therapeutic strategies. MethodsPreclinical research published between 2019 and 2023 provided the study's data searched on different medline search engine, and clinicaltrials.gov was searched for clinical data. These papers were chosen because they are relevant to the research of mesenchymal stem cell-derived exosomes (MSC-EXOs). Thematic synthesis and meta-analysis were used to perform the meta-analysis of diabetic wound healing. ResultsFor data extraction, a total of 18 preclinical and 4 clinical trials were selected. Preclinical investigations involving EXOs across various animal wound healing models showed promising potential for treatment. Specifically, following EXO treatment, there was a notable correlation with wound closure rates, with a pooled proportion of 46 % (95 % CI: 0.34; 0.59) and τ2 of 0.0593 after 3 ± 2 days, 54 % (95 % CI: 0.43; 0.65) and τ2 of 0.0465 after 7 ± 2 days, and 69 % (95 % CI: 0.62; 0.76) and τ2 of 0.0221 after 14 ± 2 days, with an egger's test p-value of <0.01. Further investigation into heterogeneity was conducted through subgroup analysis based on the source of EXO and the animal model utilized in the study. ConclusionsEXOs are proving to be viable platforms for the treatment of a wide range of disorders in clinical trials. MSC-EXOs exhibited significant diabetic wound healing capabilities across diverse outcomes including wound closure, increase angiogenesis, immunomodulatory ability and skin regeneration with its typical structure and functions.