Pericarditis Model Research Articles

Discovery of clinical candidate GS8-164, a highly potent oral NLRP3 inflammasome inhibitor for inflammation disorders

Abstract The NLRP3 inflammasome is a component of the innate immune system that plays a crucial role in the pathophysiology of multiple metabolic diseases. But so far, no marketed drugs specifically targeting NLRP3 have been approved. Here, we report the characterization of GS8-164, a potent and selective NLRP3 inflammasome inhibitor with a new phthalazine skeleton. In vitro, GS8-164 displayed potent inhibition of IL-1b production in THP-1, human PBMC and human whole blood assays without inhibiting either IL-6 or TNF-α. In vivo, GS8-164 strongly inhibited production of IL-1β in an acute mouse peritonitis model, and attenuated pathological progress and production of IL-1β in a rat acute pericarditis model. GS8-164 has a good ADME and toxicology profile. In 14-day rat and dog toxicology studies, GS8-164 displayed good tolerance, excellent PK profile and a good safety window (>50 fold). GS8-164 is under IND-enabling study and the clinical development is planned towards early 2025.

Atrial Fibrosis and Inflammation in Postoperative Atrial Fibrillation: Comparative Effects of Amiodarone, Colchicine, or Exosomes

BackgroundExtracellular vesicles (EVs) isolated from human heart-derived cells have shown promise in suppressing inflammation and fibroblast proliferation. However, their precise benefits in atrial fibrillation (AF) prevention and the role of their antifibrotic/anti-inflammatory properties remain unclear. ObjectivesThe purpose of this study was to conduct a head-to-head comparison of antiarrhythmic strategies to prevent postoperative AF using a rat model of sterile pericarditis. Specifically, we aimed to assess the efficacy of amiodarone (a classic antiarrhythmic drug), colchicine (an anti-inflammatory agent), and EVs derived from human heart-derived cells, which possess anti-inflammatory and antifibrotic properties, on AF induction, inflammation, and fibrosis progression. MethodsHeart-derived cells were cultured from human atrial appendages under serum-free xenogen-free conditions. Middle-aged Sprague Dawley rats were randomized into different groups, including sham operation, sterile pericarditis with amiodarone treatment, sterile pericarditis with colchicine treatment (2 dose levels), and sterile pericarditis with intra-atrial injection of EVs or vehicle. Invasive electrophysiological testing was performed 3 days after surgery before sacrifice. ResultsSterile pericarditis increased the likelihood of inducing AF. Colchicine and EVs exhibited anti-inflammatory effects, but only EV treatment significantly reduced AF probability, whereas colchicine showed a positive trend without statistical significance. EVs and high-dose colchicine reduced atrial fibrosis by 46% ± 2% and 26% ± 2%, respectively. Amiodarone prevented AF induction but had no effect on inflammation or fibrosis. ConclusionsIn this study, both amiodarone and EVs prevented AF, whereas treatment with colchicine was ineffective. The additional anti-inflammatory and antifibrotic effects of EVs suggest their potential as a comprehensive therapeutic approach for AF prevention, surpassing the effects of amiodarone or colchicine.

Nonpharmacologic rate control of postoperative atrial fibrillation in the canine sterile pericarditis model.

Postoperative atrial fibrillation (POAF) is common following open heart surgery, and is associated with significant morbidity. Medications used for ventricular rate control of POAF may not be effective in controlling rapid ventricular rates during the postoperative period because of increased sympathetic tone. The purpose of this study was to develop nonpharmacologic rate control of POAF by atrioventricular node (AVN) fat pad stimulation using clinically available temporary pacing wires in the canine sterile pericarditis model. We studied 10 sterile pericarditis dogs in the closed-chest state on postoperative days 1-3. The AVN fat pad stimulation (amplitude 2-15 mA; frequency 20 Hz; pulse width 0.03-0.2 ms) was performed during sustained POAF (>5 min). We measured ventricular rate and inefficient ventricular contractions during sustained POAF and compared it with and without AVN fat pad stimulation. Also, the parameters of AVN fat pad stimulation to achieve a rate control of POAF were measured over the postoperative days. Eleven episodes of sustained POAF were induced in 5/10 sterile pericarditis dogs in the closed-chest state on postoperative days 1-2. During POAF, the AVN fat pad stimulation decreased the ventricular rate from 178 ± 52 bpm to 100 ± 8 bpm in nine episodes. Nonpharmacologic rate control therapy successfully controlled the ventricular rate and eliminated inefficient ventricular contractions during POAF for the duration of the AVN fat pad stimulation. The AVN fat pad stimulation output remained relatively stable over the postoperative days. During sustained POAF, nonpharmacologic rate control by AVN fat pad stimulation effectively and safely controlled rapid ventricular rates throughout the postoperative period.

Antibacterial activity of isopropoxy benzene guanidine against Riemerella anatipestifer.

Introduction: Riemerella anatipestifer (R. anatipestifer) is an important pathogen in waterfowl, leading to substantial economic losses. In recent years, there has been a notable escalation in the drug resistance rate of R. anatipestifer. Consequently, there is an imperative need to expedite the development of novel antibacterial medications to effectively manage the infection caused by R. anatipestifer. Methods: This study investigated the in vitro and in vivo antibacterial activities of a novel substituted benzene guanidine analog, namely, isopropoxy benzene guanidine (IBG), against R. anatipestifer by using the microdilution method, time-killing curve, and a pericarditis model. The possible mechanisms of these activities were explored. Results and Discussion: The minimal inhibitory concentration (MIC) range of IBG for R. anatipestifer was 0.5-2μg/mL. Time-killing curves showed a concentration-dependent antibacterial effect. IBG alone or in combination with gentamicin significantly reduced the bacterial load of R. anatipestifer in the pericarditis model. Serial-passage mutagenicity assays showed a low probability for developing IBG resistance. Mechanistic studies suggested that IBG induced membrane damage by binding to phosphatidylglycerol and cardiolipin, leading to an imbalance in membrane potential and the transmembrane proton gradient, as well as the decreased of intracellular adenosine triphosphate. In summary, IBG is a potential antibacterial for controlling R. anatipestifer infections.

Inactivation of the NLRP3 inflammasome mediates exosome-based prevention of atrial fibrillation.

Rationale: Extracellular vesicles (EVs) from human explant-derived cells injected directly into the atria wall muscle at the time of open chest surgery reduce atrial fibrosis, atrial inflammation, and atrial fibrillation (AF) in a rat model of sterile pericarditis. Albeit a promising solution to prevent postoperative AF, the mechanism(s) underlying this effect are unknown and it is not clear if this benefit is dependent on EV dose. Methods: To determine the dose-efficacy relationship of EVs from human explant-derived cells in a rat model of sterile pericarditis. Increasing doses of EVs (106, 107, 108 or 109) or vehicle control were injected into the atria of middle-age male Sprague-Dawley rats at the time of talc application. A sham control group was included to demonstrate background inducibility. Three days after surgery, all rats underwent invasive electrophysiological testing prior to sacrifice. Results: Pericarditis increased the likelihood of inducing AF (p<0.05 vs. sham). All doses decreased the probability of inducing AF with maximal effects seen after treatment with the highest dose (109, p<0.05 vs. vehicle). Pericarditis increased atrial fibrosis while EV treatment limited the effect of pericarditis on atrial fibrosis with maximal effects seen after treatment with 108 or 109 EVs. Increasing EV dose was associated with progressive decreases in pro-inflammatory cytokine content, inflammatory cell infiltration, and oxidative stress. EVs decreased NLRP3 (NACHT, LRR, and PYD domains-containing protein-3) inflammasome activation though a direct effect on resident atrial fibroblasts and macrophages. This suppressive effect was exclusive to EVs produced by heart-derived cells as application of EVs from bone marrow or umbilical cords did not alter NLRP3 activity. Conclusions: Intramyocardial injection of incremental doses of EVs at the time of open chest surgery led to progressive reductions in atrial fibrosis and inflammatory markers. These effects combined to render atria resistant to the pro-arrhythmic effects of pericarditis which is mechanistically related to suppression of the NLRP3 inflammasome.

Validation of a new species for studying postoperative atrial fibrillation: Swine sterile pericarditis model.

The canine sterile pericarditis model associated with atrial inflammation is an experimental counterpart of postoperative atrial fibrillation (POAF). However, the use of canines for research is restricted by ethics committees in many countries, and social acceptance is declining. To validate the feasibility of the swine sterile pericarditis model as an experimental counterpart to study POAF. Seven domestic pigs (35-60kg) underwent initial pericarditis surgery. On two or more postoperative days in the closed-chest state, we performed electrophysiological measurements of pacing threshold and atrial effective refractory period (AERP) while pacing from the right atrial appendage (RAA) and the posterior left atrium (PLA). The inducibility of POAF(>5min) by burst pacing was determined in both the conscious and anesthetized closed-chest state. These data were compared to previously published canine sterile pericarditis data for validation. The pacing threshold increased from day 1 to day 3 (2±0.1 to 3.3±0.6mA in the RAA, 2.5±0.1 to 4.8±0.2mA in the PLA). Also, the AERP increased from day 1 to day 3 (118±8 to 157±16ms in the RAA; 98±4 to 124±2ms in the PLA, both p<.05). Induction of sustained POAF occurred in 43% (POAF CL range 74-124ms). All electrophysiologic data from the swine model were consistent with the canine model with respect to (1) the range of both pacing threshold and AERP; (2) the progressive increase in threshold and AERP over time; (3) a 40%-50% incidence of POAF. A newly developed swine sterile pericarditis model demonstrated electrophysiologic properties consistent with the canine model and patients after open heart surgery.

Novel Pathophysiological, Diagnostic and Therapeutic Concepts in Acute and Recurrent Pericarditis.

Acute pericarditis is the most frequent pericardial disease characterized by inflammation of the pericardial layers resulting in pain, dyspnea and fatigue. Often limited to an isolated event, up to 30% of patients experience one or more recurrences. There is limited knowledge about the pathophysiology of this disease, possibly due to the limited availability of animal models. More recently, following seminal clinical trials with colchicine and interleukin-1 (IL-1) blockers and a novel murine model of acute pericarditis using zymosan A, it has become clear that the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome/IL-1 axis plays a central role in driving acute pericardial inflammation and in sustaining this process during recurrences. Diagnostic management of pericarditis has been implemented with multimodality imaging including echocardiography, cardiac computed tomography, and cardiac magnetic resonance. These imaging modalities provide essential diagnostic and pathogenetic information, and are able to characterize pericardial inflammation, allowing to refine risk stratification and personalize treatment. Recent acquisitions yield relevant implications with regard to the therapeutic management of acute and recurrent pericarditis. Non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are cornerstone therapies either for acute and recurrent pericarditis. However, the benefits of targeted agents, such as anakinra - a recombinant human IL-1 receptor antagonist - and rilonacept - an IL-1 /IL-1 trap, are being increasingly recognized. To this end, phenotyping patients with pericarditis and addressing such therapies to those presenting with auto-inflammatory features (elevated C-reactive protein, sustained pericardial and systemic inflammation, multiple recurrences) is of utmost importance to identify patients who might be more likely to benefit from NLRP3 inflammasome/IL-1 pathway blockade.

Recurrent Pericarditis: a Stubborn Opponent Meets New Treatments in 2022.

Purpose of ReviewOur goal in writing this review was to provide a comprehensive appraisal of current therapies for idiopathic recurrent pericarditis with a particular focus on the newest therapeutic agents. We sought to understand the role of the inflammasome in the pathophysiology of pericarditis and how it informs the use of interleukin-1 (IL-1)-directed therapies.Recent FindingsThe latest research on this topic has focused on the critical role of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein) inflammasome. Very recently, components of the NLRP3 inflammasome were detected by immune staining in pericardial tissue from patients with recurrent idiopathic pericarditis. In a mouse model of pericarditis, anti-IL-1 agents anakinra and rilonacept reduced NLRP3 immunostaining. Subsequent study of these drugs in human subjects with idiopathic recurrent pericarditis demonstrated their efficacy.SummaryRecurrent idiopathic pericarditis, while relatively rare, poses a continued treatment challenge and contributes to a diminished quality of life for those patients who are afflicted. Recent developments, including an animal model of the disease and the use of IL-1-directed therapies, represent an exciting leap forward in our understanding of treatment targets. These advances offer not only new tools in our fight against this disease, but also the promise of earlier intervention and attenuation of disease morbidity. As our experience with these new agents expands, we can address questions about the ideal timing of introduction of anti-IL-1 therapy and duration of therapy and better understand the potential side effect profile. Supplementary InformationThe online version contains supplementary material available at 10.1007/s11886-022-01719-z.

PO-617-04 A DOSE ESCALATION STUDY USING EXTRACELLULAR VESICLES TO REDUCE ATRIAL FIBROSIS, INFLAMMATION, AND FIBRILLATION

Extracellular vesicles (EVs) from human Explant-Derived Cells delivered directly to the atria at the time of open chest surgery reduce atrial fibrosis/inflammation and AF in a rat model of sterile pericarditis. But the minimally effective dose is not known, nor is it clear if this benefit is dependent on EV dose.

PO-676-07 A DIRECT COMPARISON OF TWO ANTI-INFLAMMATORY STRATEGIES TO PREVENT POST-OPERATIVE ATRIAL FIBRILLATION REVEALS SUPERIOR ANTI-FIBROTIC AND ANTIARRHYTHMIC EFFICACY WITH EXTRACELLULAR VESICLES

Extracellular vesicles (EVs) from human Explant-Derived Cells delivered directly to the atria at the time of open chest surgery reduce atrial fibrosis/inflammation and AF in a rat model of sterile pericarditis. But the minimally effective dose is not known, nor is it clear if this benefit is dependent on EV dose.

Reliable pace termination of postoperative atrial fibrillation in the canine sterile pericarditis model: Implications for atypical atrial flutter.

BackgroundWe have identified a reentrant circuit in the pulmonary vein region, which drives the atria, producing fibrillatory conduction, as one mechanism of postoperative atrial fibrillation (POAF) in the canine sterile pericarditis model.ObjectiveIn this model, we tested the hypothesis that overdrive pacing from a site at or near such a reentrant circuit would interrupt it and thereby terminate POAF.MethodsWe studied 11 sterile pericarditis dogs on postoperative days 1–4. Atrial electrograms (AEGs) were recorded during POAF, overdrive pacing, and pace termination from 3 sites simultaneously: Bachmann's bundle, posterior left atrium, and right atrial appendage. When recorded AEGs demonstrated regular activation, pace termination was attempted at that site by delivering a drive train starting with 4 consecutive beats at a cycle length (CL) of 2–5 ms shorter than that of the intrinsic CL.ResultsSixteen episodes of sustained POAF (>5 minutes) diagnosed by electrocardiogram were induced. During all episodes of POAF, AEGs recorded from the left atrium exhibited regular activation, ie, constant AEG morphology and CL. When capture of the reentrant circuit by overdrive pacing occurred (mean 13 ± 5, range 5–23 beats), all 16 POAF episodes were successfully terminated. In all termination episodes, at the end of pacing but prior to the return of sinus rhythm, there was disorganized atrial activation in the previously organized sites (mean 2 seconds, range 0.1–8 seconds). However, these beats did not sustain POAF in the absence of a reentrant circuit (“driver”).ConclusionOverdrive pacing from a site demonstrating regular activation during sustained POAF terminated the POAF by interrupting the reentrant circuit.

Structure and function of the ventricular tachycardia isthmus.

Catheter ablation of postinfarction reentrant ventricular tachycardia (VT) has received renewed interest owing to the increased availability of high-resolution electroanatomic mapping systems that can describe the VT circuits in greater detail, and the emergence and need to target noninvasive external beam radioablation. These recent advancements provide optimism for improving the clinical outcome of VT ablation in patients with postinfarction and potentially other scar-related VTs. The combination of analyses gleaned from studies in swine and canine models of postinfarction reentrant VT, and in human studies, suggests the existence of common electroanatomic properties for reentrant VT circuits. Characterizing these properties may be useful for increasing the specificity of substrate mapping techniques and for noninvasive identification to guide ablation. Herein, we describe properties of reentrant VT circuits that may assist in elucidating the mechanisms of onset and maintenance, as well as a means to localize and delineate optimal catheter ablation targets.

Abstract 6970: Extracellular Vesicles Prevent Post-Operative Atrial Fibrillation

Half of patients recovering from cardiac surgery experience a malignant form of atrial fibrillation that results from inflammation in the pericardial space surrounding the heart. Given that post-operative atrial fibrillation (POAF) increases mortality, effective measures to prevent or treat POAF are highly desirable. In this study, we built on previous work to see if extracellular vesicles (EVs) isolated from human atrial explant-derived cell conditioned media can prevent POAF. Hypothesis: Human EVs will reduce AF inducibility in a rat model of sterile pericarditis by reducing inflammation and the malignant pro-fibrillatory transformation of atrial fibroblasts. Methods and Results: Middle aged female and male Sprague-Dawley rats (6 months old) were randomized to sham operation (n=24; 12 females, 12 males) or induction of sterile pericarditis followed by intra-atrial injection of 10 8 human EVs (n=34; 17 females, 17 males) or vehicle (n=34; 17 females, 17 males). Three days later, all rats underwent invasive electrophysiological testing prior to sacrifice. As expected, pericarditis increased the probability of inducing AF (Figure Panel A). EV treatment reduced the probability of AF. Recipient sex did not alter this effect. Analysis of atrial tissue histology (H&amp;E staining) and lysate (Luminex assays for IL-2, Il-18, MCP-1 and PDGF-AB) revealed that EV treatment abrogated the pro-inflammatory effects of pericarditis. As shown in Panel B, pericarditis increased both atrial fibrosis and mass while EV treatment limited the effect of pericarditis on atrial fibrosis and mass. These effects were attributable to the anti-fibrotic effect of EV treatment on atrial fibroblast proliferation profiled using in-vitro cultures exposed to pro-fibrillatory stimuli (i.e., IL-6 and TGFβ1). Conclusion: Intramyocardial injection of EVs at the time of open chest surgery may provide a facile acellular strategy to prevent POAF by reducing inflammation and fibrosis.

Interleukin-1 and the NLRP3 Inflammasome in Pericardial Disease.

Purpose of ReviewPericarditis is a generally benign disease, although complications and/or recurrences may occur in up to 30% of cases. New evidence on the pathophysiology of the disease has accumulated in recent years.Recent FindingsRecently, it has been shown that the activation of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome is central in the pathophysiology of pericarditis. These findings derive from clinical data, an experimental animal model of acute pericarditis supporting a role for the NLRP3 inflammasome in pericarditis, and from indirect evidence of inhibitors of NLRP3 inflammasome in clinical trials.SummaryPericarditis is regarded as a stereotypical response to an acute damage of the mesothelial cells of the pericardial layers. NLRP3 inflammasome, a macromolecular structure sensing damage and releasing pro-inflammatory cytokines, is centrally involved as it releases interleukin (IL)-1β, whose auto-induction feeds an autoinflammatory disease, mostly responsible for recurrences. Colchicine, an inhibitor of NLRP3 inflammasome formation, and IL-1-targeted therapies, such as anakinra and rilonacept, were found to effectively blunt the acute inflammation and reduce the risk for recurrences.

The Role of NLRP3 Inflammasome in Pericarditis: Potential for Therapeutic Approaches

Human samples of patients with chronic pericarditis and appropriate control subjects were stained for the inflammasome components. A mouse model of pericarditis was developed through the intrapericardial injection of zymosan A. Different inflammasome blockers were tested in the mouse model. Patients with pericarditis presented an intensification of the inflammasome activation compared with control subjects. The experimental model showed the pathological features of pericarditis. Among inflammasome blockers, NLRP3 inflammasome inhibitor, anakinra, and interleukin-1 trap were found to significantly improve pericardial alterations. Colchicine partially improved the pericardial inflammation. An intense activation of the inflammasome in pericarditis was demonstrated both in humans and in mice.

MiR-146a mediates TLR-4 signaling pathway to affect myocardial fibrosis in rat constrictive pericarditis model.

BackgroundMyocardial fibrosis (MF) is thought to be associated with constrictive pericarditis (CP). miR-146a has been reported to be related to the survival of myocardial fibroblasts and related signal transduction pathways. The aim of this study was to investigate the expression of miR-146a in CP with MF and the activation of the Toll-like receptor 4 (TLR-4) signaling pathway, to understand the molecular mechanism of MF involvement in CP.MethodsThirty rats with different disease duration were randomly divided into three groups: an 8-week model group (CP-8W group), a 16-week model group (CP-16W group) model, and a normal control group (N group). After the CP model was established in the rats, the myocardial tissues were collected. The expression of miR-146a, the key factors of TLR-4 signaling pathway, including IL-1 receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), nuclear factor-κB (NF-κB) and p-NF-κB, and the MF indicator α-SMA in myocardial tissue were detected. After treatment with lipopolysaccharide (LPS), primary cultured rat cardiac fibroblasts (CFs) were transfected with miR-146a. RT-PCR and western blot were used to detect the expression of downstream effectors to further verify the function of miRNA-146a in regulating MF via the TLR-4 signaling pathway.ResultsmiR-146a was increased in the CP-8W group but not in the CP-16W group. IRAK1 and TRAF6 in the CP-16W group were found to be higher than in the N group and CP-8W group. α-SMA in the model groups was higher than in the N group. Compared with the CP-8W group, α-SMA in the CP-16W model group was further increased. In the experiments using CFs, the expression of IRAK1, TRAF6, p-NF-κB and α-SMA increased in the LPS-treated group compared with the N group. After transfection of CFs with the miR-146a mimics, the expression of IRAK1, TRAF6, p-NF-κB and α-SMA decreased compared with the LPS-treated group. Following transfection of CFs with miR-146a inhibitors, the expression of IRAK1, TRAF6, p-NF-κB and α-SMA increased compared with the LPS-treated group.ConclusionsThe expression of miR-146a demonstrated a dynamic change in the CP model; it was increased at the early time point (CP-8W) and then decreased at the 16W time point. miR-146a suppressed MF by inhibiting the target genes TRAF6 and IRAK1 via the TLR-4 signaling pathway.

A novel model of constrictive pericarditis associated with myocardial fibrosis in rats.

An efficient animal model is fundamental for studies on the underlying mechanisms of constrictive pericarditis (CP). A novel CP rat model was established by pericardial injection composing of lipopolysaccharides (LPS) and talcum powder without thoracotomy. Pathological changes were confirmed by histological staining. E-flow Doppler of mitral valve, tissue Doppler E' in the medial mitral annular (E'sep ) and the lateral mitral annular (E'lat ) were measured to assess ventricular filling function. Circumferential, longitudinal, and radial strains (SC, SL and SR) and the respective strain rates (SrC, SrL and SrR) were analyzed in interventricular septum (IVS) and left ventricular free wall (LVFW). Rat cardiac fibroblasts (CFs) were treated with LPS. The activation of transforming growth factor β1 (TGF-β1) was confirmed by Q-PCR and western blot assays. Thickening of pericardium and fibrosis in pericardium and subepicardial myocardium were showed in the model group. Diastolic dysfunction in the CP group was indicated by decreased E'lat and E'lat /E'sep , increased E/E'lat , decreased EFW of SrC and SrL, increased AIVS and decreased E/A of SrC, SrL and SrR. Systolic dysfunction was indicated by decreased SCFW and SLFW in CP rats. The levels of TGF-β1, p-Smad2/3, α-smooth muscle actin (α-SMA), and collagen-I/III (COL-I/III) were increased in the CP group. The increased TGF-β1 that induced by LPS activated and phosphorylated Smad2/3 resulting in the secretion of α-SMA and COL-I/III. This model is of vital importance in studying the pathogenesis of CP.

Colchicine prevents atrial fibrillation promotion by inhibiting IL-1β-induced IL-6 release and atrial fibrosis in the rat sterile pericarditis model

A few clinical trials have recently reported the potential effect of colchicine in preventing post-operative atrial fibrillation (POAF) and early atrial fibrillation (AF) recurrence after catheter pulmonary vein isolation. However, the molecular mechanisms through which colchicine inhibits AF remain unclear. We aim to assess the anti-AF effect of colchicine in the rat sterile pericarditis (SP) model and to investigate its molecular mechanisms. SP was induced in Sprague-Dawley rats by the epicardial application of sterile talc. Treatment with colchicine or vehicle began 1 d before pericardiotomy. AF was induced by transesophageal burst pacing on day 3 after surgery. Treatment with colchicine reduced the duration of AF and the probability of induction of AF in SP rats. The dose of 0.5 mg kg−1·day−1 had the best effect. Such treatment also reduced neutrophil infiltration, the mRNA expression of IL-6, TGF-β, and TNF-α, atrial fibrosis, fibrosis related genes, and signal molecules (STAT3, P38, and AKT). Meanwhile, the release of IL-1β (4−24 h) and IL-6 (4−72 h) in atria after surgery was significantly inhibited by colchicine. In cultured rat cardiac fibroblasts, colchicine treatment inhibited IL-1β-induced expression of IL-6, which was accompanied by significantly decreased phosphorylation of P38, AKT, JNK, and NFκB. Interestingly, the supplementation of IL-6 abolished the anti-AF effect of colchicine in SP rats. Colchicine prevents AF in SP rats through the inhibition of IL-1β-induced IL-6 release and subsequent atrial fibrosis. However, further studies are required to investigate whether colchicine inhibits POAF through other mechanisms.

The role of innate lymphoid cells in the heart and cardiac inflammation

Abstract Studies have shown the diverse role of innate lymphoid cells (ILCs) in mucosal organs, however, the role of ILCs in the heart has not been studied. The aim of the work was to examine the role of group 2 innate lymphoid cells (ILC2s) in the heart and inflammatory heart diseases. To study the role of ILCs in the heart, we used a pericarditis model where IL-33 treatment induces pericarditis in mice. In this model, diastolic dysfunction was observed in the heart of IL-33-treated mice and eosinophils were heavily infiltrated into the heart. We found that the number of ILC2s was increased in the heart after IL-33 administration. We hypothesized that IL-33 induces cardiac ILC2s to produce IL-5 and IL-13, which drives pericarditis development. To examine whether ILCs are required for pericarditis development, we treated WT, Rag2−/− and Rag2−/−γc−/− mice with IL-33. Rag2−/−γc−/− mice which are deficient in all lymphoid cells including ILCs were completely protected from developing pericarditis, while WT and Rag2−/− mice developed pericarditis, indicating the adaptive immunity is not required for the development of IL-33-induced pericarditis. This data suggests that ILCs might play a pathogenic role in the heart. To determine the function of ILC2s, we analyzed cytokine production by ILC2s in the heart. Cardiac ILC2s were a major producer of IL-5 and IL-13. With anti-IL-5 treatment, the number of eosinophils in the heart was reduced, which prevented the heart from developing pericarditis. IL-13−/− mice showed less severe pericarditis upon IL-33 treatment than WT mice. Collectively, our data suggest that ILCs play a critical role in pericarditis, and could provide insight into novel strategies for treating this disease.

The role of innate lymphoid cells in the cardiac inflammation

Abstract To investigate the role of innate lymphoid cells (ILCs) in the heart, we have established a pericarditis model in which mice develop pericarditis upon IL-33 injections. Studies have shown the role of group 2 innate lymphoid cells (ILC2s) mostly in mucosal organs such as lung and gut, however, the role of ILC2s in the heart has been overlooked. We found that the number of ILC2s increases in the heart after IL-33 treatment. The aim of this work is to examine the role of ILC2s in inflammatory heart disease using the IL-33-induced pericarditis model. We hypothesize that IL-33 induces cardiac resident ILCs to become activated ILC2s to produce large amounts of IL-5 and IL-13, driving the development of pericarditis. To determine whether ILCs are required for pericarditis development, we compared WT mice to Rag2−/− mice and to Rag2−/−γc−/− mice which lack all of lymphoid cells including ILCs. Whereas Rag2−/− mice developed pericarditis, Rag2−/−γc−/− mice were completely protected. This indicates that the adaptive immune response is not required for the development of IL-33-induced pericarditis, but ILCs may play a pathogenic role. We assessed cytokine production by ILC2s in pericarditis to determine the function of ILC2s in the heart. Cardiac ILC2s were a major source of IL-5 and IL-13. The number of eosinophils in the heart was significantly reduced by anti-IL-5 treatment, which prevented the development of pericarditis. In addition, IL-13−/− mice developed less severe pericarditis compared to WT mice. These data suggest that ILCs play a critical role in inflammatory heart diseases. The pathogenic mechanism of ILC2s in the heart could provide insight into novel therapeutic strategies for treating cardiac inflammation including pericarditis.