Iloprost Treatment Research Articles

Evaluation of changes in cardiac longitudinal strain rate in patients with systemic sclerosis undergoing iloprost treatment: an observational study.

Systemic Sclerosis (SSc) is characterized by widespread microangiopathy and fibrosis of skin and visceral organs. Left ventricle involvement is usually subclinical, characterized by systolic and/or diastolic dysfunction. The global longitudinal strain (GLS), a validated and reliable technique for the measurement of ventricular longitudinal deformation by means of echocardiography, may detect subclinical systolic dysfunction of SSc myocardium. The improvement of myocardial perfusion by means of intravenous Iloprost administration could ameliorate the contractility of SSc heart. Therefore, we aimed to evaluate GLS in a series of SSc patients prior and after Iloprost infusion. Fifteen consecutive SSc patients (age: 54 ± 11 years; 12 females) treated with Iloprost because of the presence/history of digital ulcers underwent echocardiography, including GLS technique. This evaluation was conducted immediately before Iloprost administration and at the end of the 6-h infusion session. Significant improvement in the mean GLS was observed after Iloprost administration (from -13.5 ± 2.5 to -15 ± 3.3; p= 0.011). The echocardiographic data obtained from the four-chamber view showed the best quality for GLS analysis and showed a highly significant improvement of the strain after Iloprost administration (from -13.4 ± 2.2 to -15.6 ± 3; p= 0.001). The degree of GLS improvement did not correlate with any SSc parameters. Iloprost administration improved GLS, suggesting that the increase of myocardial perfusion allowed, at least in part, a correction of left ventricular systolic dysfunction. Further studies are needed to confirm these findings, further exploring the mid/long-term effects of Iloprost on myocardial contraction.

Practice pattern for the use of intravenous iloprost for the treatment of peripheral vasculopathy in systemic sclerosis: A case-control study from the Italian national multicenter "SPRING" (Systemic Sclerosis Progression InvestiGation) Registry.

Intravenous iloprost has been widely used for the treatment of systemic sclerosis peripheral vasculopathy. No agreement has been found on the regimen and the dosage of intravenous iloprost in different scleroderma subset conditions. This study aimed to evaluate the modalities of intravenous iloprost administration within a large cohort of systemic sclerosis patients from the SPRING Registry and to identify any associated clinical-demographic, instrumental or therapeutic data. Data of systemic sclerosis patients treated with intravenous iloprost for at least 1 year (case group) were retrospectively analyzed, including different timing and duration of intravenous iloprost session, and compared with those of untreated patients (control group). Out of 1895 analyzed patients, 937 (49%) received intravenous iloprost treatment, while 958 (51%) were assigned to the control group. Among cases, about 70% were treated every 4 weeks, 24% with an interval of more than 4 weeks, and only 6% of less than 4 weeks. Most patients receiving the treatment every 4 weeks, or less, underwent infusion cycle for 1 day only, while if it was scheduled with an interval of more than 4 weeks, a total number of 5 consecutive days of infusions was the preferred regimen. The comparison between the two groups revealed that patients treated with intravenous iloprost had a higher frequency of DUs (p < 0.001), pitting scars (p < 0.001), diffuse cutaneous involvement (p < 0.001), interstitial lung disease (p < 0.002), as well as higher rates of anti-topoisomerase I, "late" scleroderma pattern at nailfold videocapillaroscopy. These findings were confirmed by multivariate analysis. Our data provide a picture on the Italian use of intravenous iloprost among systemic sclerosis patients and showed that it was usually employed in patients with a more aggressive spectrum of the disease. The disparity of intravenous iloprost treatment strategies in the different centers suggests the need of a rational therapeutical approach based on the clinical characteristics of different patients' subsets.

Cyclooxygenase-2 inhibition prevents renal toxicity but not hypertension during sunitinib treatment

BackgroundAnticancer angiogenesis inhibitors cause hypertension and renal injury. Previously we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and-2) was superior to low-dose aspirin (blocking COX-1 only) to prevent these side-effects during treatment with the angiogenesis inhibitor sunitinib, suggesting a role for COX-2. High-dose aspirin additionally prevented the rise in COX-derived prostacyclin (PGI2). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI2 during angiogenesis inhibition. MethodsMale WKY rats received vehicle, sunitinib ((SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day) or a PGI2 analogue (iloprost, 100 μg/kg/day) for 8 days (n = 8–9 per group). Mean arterial pressure (MAP) was measured via radiotelemetry, biochemical measurements were performed via ELISA and vascular function was assessed via wire myography. ResultsSU increased MAP (17±1mmHg versus 3±1mmHg after vehicle on day 4, P < 0.002), which could not be significantly blunted by celecoxib (+12±3mmHg on day 4, P = 0.247), but was temporarily attenuated by iloprost (treatment days 1 + 2 only). Urinary PGI2 (996 ± 112 versus 51 ± 11ng/24h after vehicle, P < 0.001), but not circulating PGI2 increased during SU, which remained unaffected by celecoxib and iloprost. Celecoxib reduced sunitinib-induced albuminuria (0.36 ± 0.05 versus 0.58 ± 0.05mg/24h after SU, P = 0.005). Wire myography demonstrated increased vasoconstriction to endothelin-1 after SU (Emax P = 0.005 versus vehicle), which remained unaffected by celecoxib or iloprost. ConclusionSelective COX-2 inhibition ameliorates albuminuria during angiogenesis inhibition with sunitinib, which most likely acts independently of PGI2. To combat angiogenesis inhibitor-induced hypertension, dual rather than selective COX-1/2 blockade seems preferential.

MiR-520a-5p regulates Frizzled 9 expression and mediates effects of cigarette smoke and iloprost chemoprevention

Expression of Frizzled 9 (FZD9) is critical to the activity of the lung cancer chemoprevention agent and prostacyclin analogue, iloprost. FZD9 is required in lung epithelial cells for iloprost to activate peroxisome proliferator activated receptor gamma (PPARG) and related anti-tumor signaling. We aimed to investigate which miRNA regulate FZD9 in the context of cigarette smoke exposure and iloprost treatment. We found that miR-520a-5p binds the FZD9 3’UTR in lung cell lines and alters activity and expression of FZD9 downstream targets. Cigarette smoke condensate (CSC) increases expression of miR-520a-5p, while iloprost decreases expression. Cancer promoting effects of a miR-520a-5p mimic were rescued with iloprost treatment, and effects of cigarette smoke were partially rescued with a miR-520a-5p inhibitor. Here we confirm miR-520a-5p as a regulator of FZD9 activity and a mediator of CSC and iloprost effects in the lung. Targeting miR-520a-5p could be an approach to restoring FZD9 expression and improving response to iloprost lung cancer chemoprevention.

Intranasal Iloprost Prevents Tumors in a Murine Lung Carcinogenesis Model.

Lung cancer chemoprevention with the prostacyclin analogue iloprost is the most promising approach to date for intercepting progression of premalignant lung lesions in former smokers. Previous preclinical studies of iloprost used oral delivery, but a study modeling delivery directly to the target organ was needed. In vivo and in vitro studies have identified gene expression changes following iloprost treatment, including increased e-cadherin and Ppargγ and decreased COX2 and vimentin. We used tumor counts and gene expression to demonstrate the effectiveness of intranasal delivery of iloprost in a murine model of premalignant adenomas. Intranasal delivery of iloprost reduced adenoma multiplicity 14 weeks after urethane exposure in FVB/N mice compared with untreated urethane controls. Intranasal iloprost reversed urethane-induced gene expression changes in tumors and whole lung. These results correspond to previous studies of oral iloprost and in vitro treatment of human bronchial epithelial cells. This study demonstrates that intranasal delivery of iloprost in a mouse model of lung premalignant lesions is effective chemoprevention. This will be an essential tool for exploring mechanisms and outcomes of iloprost chemoprevention, along with supporting ongoing clinical trials of inhaled iloprost chemoprevention. PREVENTION RELEVANCE: Iloprost is a promising chemoprevention agent for lung cancer and this work describes a new delivery approach in vivo.

Definitions, pathogenesis, and pharmacological options for bone marrow lesions: an updated review

The term “Bone Marrow Lesions” (BMLs) identifies a pathological state characterized by a structural degeneration of the osteochondral unit (OCU) and by an alteration of the biochemical balance existing between articular cartilage and subchondral bone. These lesions, if they do not resolve spontaneously and if not adequately treated, can give rise to chronic degenerative diseases such as osteoarthritis and, in the most serious cases, evolve into stress fractures. The technique considered to be the gold standard for the detection of BMLs is Magnetic Resonance Imaging (MRI), to which BMLs appear as an area of ill-defined hyperintensity (high signal) in subchondral bone in fat-suppressed T2-weighted sequences, and hypointense areas (low signal) in T1-weighted sequences. There are several pharmacological intervention strategies for the treatment of BMLs, primarily the administration of bisphosphonates, but in recent years Iloprost treatment is also proving to be an effective therapeutic strategy. The aim of this review is to provide further evidence on the sequence of clinical-biological events leading to the appearance of these lesions, and on the current treatment strategies with the best outcome, in order to shed light on the importance of conducting further research in this field, since BMLs are part of a pathological picture characterised by numerous variables.

Digital Tracking of Physical Activity, Heart Rate, and Inhalation Behavior in Patients With Pulmonary Arterial Hypertension Treated With Inhaled Iloprost: Observational Study (VENTASTEP).

BackgroundPulmonary arterial hypertension restricts the ability of patients to perform routine physical activities. As part of pulmonary arterial hypertension treatment, inhaled iloprost can be administered via a nebulizer that tracks inhalation behavior. Pulmonary arterial hypertension treatment is guided by intermittent clinical measurements, such as 6-minute walk distance, assessed during regular physician visits. Continuous digital monitoring of physical activity may facilitate more complete assessment of the impact of pulmonary arterial hypertension on daily life. Physical activity tracking with a wearable has not yet been assessed with simultaneous tracking of pulmonary arterial hypertension medication intake.ObjectiveWe aimed to digitally track the physical parameters of patients with pulmonary arterial hypertension who were starting treatment with iloprost using a Breelib nebulizer. The primary objective was to investigate correlations between changes in digital physical activity measures and changes in traditional clinical measures and health-related quality of life over 3 months. Secondary objectives were to evaluate inhalation behavior, adverse events, and changes in heart rate and sleep quality.MethodsWe conducted a prospective, multicenter observational study of adults with pulmonary arterial hypertension in World Health Organization functional class III who were adding inhaled iloprost to existing pulmonary arterial hypertension therapy. Daily distance walked, step count, number of standing-up events, heart rate, and 6-minute walk distance were digitally captured using smartwatch (Apple Watch Series 2) and smartphone (iPhone 6S) apps during a 3-month observation period (which began when iloprost treatment began). Before and at the end of the observation period (within 2 weeks), we also evaluated 6-minute walk distance, Borg dyspnea, functional class, B-type natriuretic peptide (or N-terminal pro–B-type natriuretic peptide) levels, health-related quality of life (EQ-5D questionnaire), and sleep quality (Pittsburgh Sleep Quality Index).ResultsOf 31 patients, 18 were included in the full analysis (observation period: median 91.5 days, IQR 88.0 to 92.0). Changes from baseline in traditional and digital 6-minute walk distance were moderately correlated (r=0.57). Physical activity (daily distance walked: median 0.4 km, IQR –0.2 to 1.9; daily step count: median 591, IQR −509 to 2413) and clinical measures (traditional 6-minute walk distance: median 26 m, IQR 0 to 40) changed concordantly from baseline to the end of the observation period. Health-related quality of life showed little change. Total sleep score and resting heart rate slightly decreased. Distance walked and step count showed short-term increases after each iloprost inhalation. No new safety signals were identified (safety analysis set: n=30).ConclusionsOur results suggest that despite challenges, parallel monitoring of physical activity, heart rate, and iloprost inhalation is feasible in patients with pulmonary arterial hypertension and may complement traditional measures in guiding treatment; however, the sample size of this study limits generalizability.Trial RegistrationClinicalTrials.gov NCT03293407; https://clinicaltrials.gov/ct2/show/NCT03293407International Registered Report Identifier (IRRID)RR2-10.2196/12144

Clinical efficacy, safety, tolerability, and survival outcome of long-term inhaled iloprost treatment in the management of pulmonary arterial hypertension: Data from prospective multicenter observational OPTION study.

To evaluate clinical efficacy, safety and tolerability of long-term inhaled iloprost treatment in the daily practice for the management of pulmonary arterial hypertension (PAH). A total of 115 patients with PAH on inhaled iloprost treatment were included. New York Heart Association (NYHA) functional class, brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and 6-minute walk distance (6MWD) were recorded at baseline and at 3rd to 24th month visits. Safety and tolerability of iloprost treatment were also evaluated during follow-up, as were the survival, clinical worsening, and the related risk factors. The treatment was associated with an increase in the percentage NYHA functional class II (from 0.0% at enrolment to 36.2% at 24th month visit) patients but no significant difference was noted in 6MWD values. Clinical worsening was observed in 63.5% patients, while survival rate was 69.6%. NT-proBNP levels were significantly higher in non-survivors than in survivors (p=0.042). Cox regression analysis revealed the association of female sex [odds ratio (OR)=0.318; 95% confidence interval (CI), 0.128-0.792; p=0.014] and scleroderma-related PAH (OR=0.347; 95% CI, 0.140-0.860; p=0.022) with significantly lower risk (3.14 fold and 2.88 fold, respectively) of mortality. Our findings indicate favorable efficacy, safety, and tolerability of long-term iloprost treatment in the management of PAH, whereas improved NYHA functional class was not accompanied with a significant change in 6MWD values. Patient age was a risk factor for clinical worsening, while female sex, scleroderma subtype, and lower NT-proBNP levels were associated with significantly lower mortality risk.

Abstract 2569: miR520a inhibits Fzd9 in bronchial epithelial cells and NSCLC

Abstract Non-small cell lung cancer (NSCLC) continues to be the most diagnosed cancer type worldwide and has the highest mortality rate. Treatment is highly researched, but 5 year survival remains around 20%. Chemoprevention could combat the development of lung cancer in individuals who are at high risk, such as former cigarette smokers. Iloprost is a prostacyclin analogue demonstrated to reduce the presence of endobronchial dysplasia in former smokers. Increased Frizzled-9 (Fzd9) expression is induced by Iloprost, resulting in activation of peroxisome proliferator activated receptor γ (PPARγ) and inhibition of transformed growth. The goal of this study is to elucidate the relationship of cigarette smoke, NSCLC, and miRNA regulation of Fzd9 expression. We hypothesized that miRNA regulate Fzd9 expression when NSCLC cells are exposed to both cigarette smoke condensate (CSC) and Iloprost. miR520a5p was predicted in silico to bind Fzd9 and we validated binding with a miR520a5p mimic and Fzd9 3'UTR luciferase in an immortalized human bronchial epithelial cell line (HBEC) and NSCLC cell lines. A549 and H322 NSCLC cells and HBEC were exposed to cigarette smoke condensate (CSC) and Iloprost. CSC increased miR520a expression, while the opposite was observed in Iloprost treated cells. We also measured Fzd9 3'UTR activity and demonstrated that CSC decreases both Fzd9 3'UTR and PPRE activity, while Iloprost does the opposite. We investigated the effect of miR520a5p on targets downstream of Fzd9, including PPARγ response element (PPRE), a direct measure of PPARγ activity, and epithelial to mesenchymal transition (EMT) gene expression, including Cox2, E-cadherin, and CRB3. We found that when Fzd9 is inhibited by miR520a5p, PPRE activity and epithelial gene expression are inhibited, while mesenchymal gene expression is stimulated. Rescue experiments combining CSC with a miR520a5p inhibitor or iloprost with a miR520a5p mimic supported a role for miR-520a-5p in inhibition of Fzd9 in a CSC carcinogenic pathway in lung epithelial cells that is reversed with iloprost treatment. Overall, these findings suggest a mechanism for miRNA regulation of Fzd9 in lung epithelial cells exposed to cigarette smoke and a potential chemoprevention target. Citation Format: Alex J. Smith, Paulina Do, Kayla M. Sompel, Alamelu Elango. miR520a inhibits Fzd9 in bronchial epithelial cells and NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2569.

Periferik Vasküler Hastalığın Tedavisinde İloprost’tun Nitrik Oksit, Asimetrik Dimetilarjinin ve Serotonin’e Etkisi

Aim: In this study, it is aimed to investigate the efficacy of iloprost use in peripheral artery disease patients on the parameters involved in endothelial functions such as circulating acetyl dimethyl arginine (ADMA), serotonin and nitric oxide (NO).&#x0D; Patients and Methods: 30 patients (19 male, 11 female, age interval 60.7 ± 13.7) who were followed-up with the diagnosis of Fontaine III-IV disease and decided to receive a medical treatment were included in the study. Iloprost infusion was initiated as a 16-hour intravenous infusion at the dose of 0.5-1.5 ng / kg / min from the forearm veins and was given for 7 days. Blood was taken for ADMA, Serotonin and NO results before and after the treatment (8th day). Total nitrite (nitrite + nitrate) concentration was measured by the modified cadmium reduction method, ADMA and serotonin levels were measured by High Performance Liquid Chromotography (HPLC) method.&#x0D; Results: ADMA value before and after the iloprost treatment was decreased after the treatment and while this was statistically significant (p=0.001), the changes in serotonin (p=0.82) and NO (P= 0.16) values were found statistically insignificant. &#x0D; Conclisions: Peripheral arterial disease may be a parameter that can be taken into account in the evaluation of treatment for peripheral arterial disease and ADMA, which is considered to be an endothelial dysfunction indicator after iloprost treatment.

Prostacyclin facilitates vascular smooth muscle cell phenotypic transformation via activating TP receptors when IP receptors are deficient.

By activating prostacyclin receptors (IP receptors), prostacyclin (PGI2 ) exerts cardiovascular protective effects such as vasodilation and inhibition of vascular smooth muscle cell (VSMC) proliferation. However, IP receptors are dysfunctional under pathological conditions, and PGI2 produces detrimental effects that are opposite to its physiological protective effects via thromboxane-prostanoid (TP) receptors. This attempted to investigate whether or not IP receptor dysfunction facilitates the shift of PGI2 action. The effects of PGI2 and its stable analog iloprost on VSMC phenotypic transformation and proliferation were examined in A10 cells silencing IP receptors, in human aortic VSMCs (HAVSMCs) knocked down IP receptor by CRISPR-Cas9, or in HAVSMCs transfected with a dysfunctional mutation of IP receptor IPR212C . PGI2 /iloprost treatment stimulated cell proliferation, upregulated synthetic proteins and downregulated contractile proteins, suggesting that PGI2 /iloprost promotes VSMC phenotypic transformation in IP-deficient cells. The effect of PGI2 /iloprost was prevented by TP antagonist S18886 or TP knockdown, indicating that the VSMC detrimental effect of PGI2 is dependent on TP receptor. RNA sequencing and Western blotting results showed that RhoA/ROCKs, MEK1/2 and JNK signalling cascades were involved. Moreover, IP deficiency increased the distribution of TP receptors at the cell membrane. PGI2 induces VSMC phenotypic transformation when IP receptors are impaired. This is attributed to the activation of TP receptor and its downstream signaling cascades, and to the increased membrane distribution of TP receptors. The VSMC detrimental effect of PGI2 medicated by IP dysfunction and TP activation might probably exacerbate vascular remodelling, accelerating cardiovascular diseases.

Analysis of the Efficacy of Iloprost Treatment in Amputations Due to Burn.

The aim of our study was to demonstrate the decrease in amputation rates with iloprost treatment in patients who develop vascular injury due to burns. The data of 366 adult burn patients who were admitted to the emergency department of our hospital between 2016 and 2019 were analyzed. Demographic characteristics, burn factors, vascular examination findings, medical treatments, amputation rates, and levels were recorded. The amputation rates of the patients who were treated with iloprost and who were not treated with iloprost were compared. The mean age of 366 adult patients treated for burns was 37.8 ± 16.4 years, and of these patients, 220 (59.9%) were under 40 years of age. Although heat burns (n = 331.85%) were the most common burn etiology, it was found that the incidence of vascular injury was higher in burns caused by electricity (11.7%) and cold (3.3%) (P < 0.001). Vascular injury was detected in 60 (16.3%) of the patients and 21 (35%) of these patients were treated with iloprost. Amputation was observed in 20 (5.5%) of all burn patients, but only one of the patients treated with iloprost underwent amputation (P < .001). The individual and social impacts of amputations caused by burns are unquestionable. The authors are of the opinion that iloprost treatment is effective in reducing amputations due to burns.

Iloprost-treated dendritic cells promote antigen-specific regulatory T cell differentiation in mice

Abstract Iloprost, a stable prostaglandin I2 (PGI2) analog, can inhibit allergic inflammation in an OVA-induced asthma model via inhibition of airway dendritic cell (DC) function. However, the underlying mechanism of PGI2 signaling-mediated immunosuppression remains unclear. This study explored whether iloprost-treated DCs can suppress inflammation by promoting antigen-specific regulatory T cell (Treg) differentiation. We established an allergic lung inflammation model using a hydrogel biomaterial delivery system and observed that iloprost significantly suppressed OVA-induced Th2 lung inflammation and increased the frequency of OVA-specific Tregs in vivo. We further observed that iloprost-treated DCs displayed tolerogenic characteristics, including low inflammatory cytokine (IL-12p70, TNF-α, IL-6, IL-23) expression levels, high anti-inflammatory cytokine (IL-10) production, and a semimature phenotype. In addition, iloprost-treated DCs increased OVA-specific CD4+Foxp3+ T cell differentiation from naïve T cells in vitro and in vivo. Blocking experiments showed that iloprost-treated DCs promoted Treg differentiation, at least in part, through PD-L1. Furthermore, iloprost treatment suppressed DC-mediated airway inflammation and increased the frequency of OVA-specific Tregs through PD-L1 in vivo. Taken together, these results show that PGI2 signaling in DCs may lead to immune tolerance, suggesting that the PGI2 analog has the potential to be applied therapeutically for tolerogenic DC immunotherapy in autoimmune diseases or allergic asthma.

Therapeutic iloprost for the treatment of acute respiratory distress syndrome (ARDS) (the ThIlo trial): a prospective, randomized, multicenter phase II study

BackgroundAcute respiratory distress syndrome (ARDS) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. The treatment of ARDS to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. Several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ARDS, iloprost treatment resulted in improved oxygenation. Therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ARDS.MethodsThe Therapeutic Iloprost during ARDS trial (ThIlo trial) is a multicenter, randomized, single blinded, clinical phase II trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ARDS in critically ill patients. One hundred fifty critically ill patients suffering from acute ARDS will be treated either by nebulized iloprost or NaCl 0.9% for 5 days. Blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. Mechanical ventilation will be standardized. In follow-up visits at days 28 and 90 as well as 6 months after enrollment, functional status according to the Barthel Index and a health care-related questionnaire, and frailty (Vulnerable Elders Survey) will be evaluated. The primary endpoint is the improvement of oxygenation, defined as the ratio of PaO2/FiO2. Secondary endpoints include 90-day all-cause mortality, Sequential Organ Failure Assessment scores during the study period up to day 90, the duration of mechanical ventilation, the length of intensive care unit (ICU) stay, ventilator-associated pneumonia, delirium, ICU-acquired weakness, and discharge localization. The study will be conducted in three university ARDS centers in Germany.DiscussionThe results of the ThIlo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ARDS, resulting in the improvement of outcome parameters in patients with ARDS.Trial registrationEUDRA-CT: 2016-003168-37. Registered on 12 April 2017. ClinicalTrials.gov: NCT03111212. Registered on 4 June 2017.

Dendritic cells treated with a prostaglandin I2 analog, iloprost, promote antigen-specific regulatory T cell differentiation in mice

Iloprost, a stable prostaglandin I2 (PGI2) analog, can inhibit allergic inflammation in an ovalbumin (OVA)-induced asthma model via inhibition of airway dendritic cell (DC) function. However, the underlying mechanism of PGI2 signaling-mediated immunosuppression remains unclear. This study explored whether iloprost-treated DCs can suppress inflammation by promoting antigen-specific regulatory T cell (Treg) differentiation through PGI2-G-protein-coupled receptor (IP). We established an allergic lung inflammation model using a hydrogel biomaterial delivery system and observed that iloprost significantly suppressed OVA-induced Th2 lung inflammation and increased the frequency of OVA-specific Tregs in vivo. We further observed that iloprost-treated DCs displayed tolerogenic characteristics, including low inflammatory cytokine (IL-12, TNF-α, IL-6, IL-23) expression levels, high anti-inflammatory cytokine (IL-10) production, and a semimature phenotype. In addition, iloprost-treated DCs increased OVA-specific CD4+Foxp3+ T cell differentiation from naïve T cells in an IP-dependent pathway in vitro and in vivo. Blocking experiments showed that iloprost-treated DCs promoted Treg differentiation, at least in part, through programmed death ligand 1 (PD-L1), whereas iloprost-induced PD-L1 expression in DCs was through the IP receptor. Furthermore, iloprost treatment suppressed DC-mediated airway inflammation and increased the frequency of OVA-specific Tregs through PD-L1 in vivo. Taken together, these results show that PGI2-IP signaling mediated by iloprost in DCs may lead to immune tolerance, suggesting that the PGI2 analog has the potential to be applied therapeutically for tolerogenic DC immunotherapy in autoimmune diseases or allergic asthma.

Mitral Kapak Cerrahisinde İloprost Kullanımının Pulmoner Arter Hipertansiyonu Üzerine Klinik Etkisi

Introduction: Pulmonary arterial hypertension (PAH) is an important risk factor for increased mortality and morbidity during mitral valve surgery. In this study, we analysed the haemodynamic effects of the prostaglandin analogue iloprost in patients with PAH. Patients and Methods: We retrospectively analysed patients with PAH who were undergoing mitral valve surgery and had received intravenous iloprost therapy at our hospital from 1 January 2003 to 31 March 2013. Systemic and pulmonary arterial pressures were measured with catheterisation. The haemodynamic parameters were administered preoperatively and at 0 hours and 24 hours postoperatively. Results: A total of 135 patients had undergone mitral valve operations, of whom 78 patients were administered iloprost during the study period. Of all the cases, 29.9% were male and the average patient age was 54.45 ± 12.48 years. A comparison of the preoperative, hour 0 and hour 24 baseline parameters showed that pulmonary artery pressure and blood pressure statistically significantly decreased at postoperative hour 24 (p< 0.05). Age, preoperative EF and revisions were found to be statistically significant risk factors for mortality (p< 0.0001). Pulmonary pressures did not affect mortality and were not classified as risk factors. Conclusion: Iloprost treatment might improve postoperative outcomes in patients with high pulmonary arterial pressures and with decreasing pulmonary arterial pressures in the early postoperative period. Treatment with iloprost during the mitral valve replacement decreases high pulmonary arterial pressures and the peroperative mortality risk.

Effects of iloprost on human mature osteoblasts in vitro

Bone marrow oedema is a multifactorial conditioned illness. Alongside any strain relief of an affected joint, treatment with Iloprost also belongs to the choice of cures. In past studies, a modulatory effect on bone could be shown. The hypothesis of the present work is that Iloprost has a growth-stimulating effect on osteoblasts in vitro. Human osteoblasts were isolated and cultivated. Subsequently, the cells were treated with Iloprost in bioavailable concentrations. Alterations of the cell structure were examined by means of light microscopy. A regulation of the number of vital cells was carried out by using a CASY cell counter. Possible cell impairment after Iloprost treatment was analysed by means of XTT Elisa as well as FDA and PI staining via fluorescence microscopy. Using light microscopy, no changes in cell structure could be observed. With the CASY cell counter, no increase in the numbers of osteoblasts appeared after Iloprost treatment. Also, XTT Elisas and fluorescence microscopy did not reveal any cell impairment due to Iloprost. Our results could not confirm a modulatory effect in mature osteoblasts. On the basis of the present work we could not verify any growth-stimulating effect by Iloprost in mature osteoblasts in vitro. Admittedly, effects had been shown previously during osteogenesis, but we do exclude an effect on mature osteoblasts which have already differentiated.

Effects of iloprost and sildenafil treatment on elabela, apelin-13, nitric oxide, and total antioxidant and total oxidant status in experimental enzyme-positive acute coronary syndrome in rats

ABSTRACTDespite significant advances in medicine, mortality due to cardiovascular disease is not yet preventable. We investigated the amounts of elabela (ELA) and apelin, synthesized by cardiomyocytes, and changes of these compounds in cardiac tissue and circulation after administration of iloprost (ILO) and sildenafil (SIL) in rats with induced myocardial ischemia (MI). We also investigated a connection with circulating troponin-I, creatine kinase (CK), creatine kinase-myocardial band (CK-MB) and nitric oxide (NO), and total anti-oxidant (TAS)/total oxidant status (TOS). We established eight study groups of five rats each. Group 1, sham, was given only physiologic serum; group 2, ILO; group 3, SIL; group 4, ILO + SIL; group 5, MI; group 6, MI + ILO; group 7, MI + SIL; group 8, MI + ILO + SIL. Troponin-I, CK, CK-MB and TAS-TOS were investigated using an autoanalyzer. NO, ELA and apelin were analyzed by ELISA. Tissue apelin and ELA expressions and localizations were determined by immunohistochemistry. The MI group compared to the control (sham) group showed that ELA, apelin, troponin-I, CK, CK-MB, NO and TOS levels were elevated significantly. Concentrations of these factors increased in MI, but decreased after ILO and SIL administration. The largest decrease of TOS was identified in the ILO + SIL group. ELA and apelin may be novel indicators of MI and administration of ILO and SIL, individually or together, may be useful for treating MI.

PROSTACYCLIN IS A NOVEL HEMATOPOIETIC STEM CELL REGULATOR ENRICHED IN THE ENDOSTEAL BONE MARROW NICHE

Potent functional HSCs are enriched at the endosteal bone marrow (BM), which comprises ∼10% of total BM. To identify novel niche factors that regulate HSCs, we performed a gene expression microarray seeking genes overexpressed in the endosteal relative to central BM. Prostacyclin/prostaglandin I2 (PGI2) synthase (Ptgis) was one of the highest enriched genes in the endosteal versus central BM (27-fold). PTGIS is the sole enzyme for biosynthesis of PGI2. PGI2 has no reported roles in HSC regulation in the BM and was chosen for further investigation. We found PGI2 analogue iloprost treatment of sorted BM lineage- Kit+ Sca1- (LKS+) cells in vitro for 7 days potently reduced proliferation and differentiation compared to vehicle control. BM cells pulse treated ex vivo with iloprost for 1 hour also resulted in 14-fold increased multilineage reconstitution potential compared to vehicle controls in competitive transplant assay. Iloprost administration in vivo partially rescued BM HSC reconstitution potential in mice sub-lethally (6.5 Gy) irradiated or administered pro-inflammatory granulocyte colony stimulating factor (G-CSF) for 3 days. These data suggest that PGI2 protects HSC from stress. Mechanistically, we found iloprost pulse treatment in vitro was associated with increased pSTAT3 and cell cycle progression in HSCs. Additionally, we found ∼4-fold greater proportion of untreated LKS+ HSPC homing to the BM of recipients co-administered iloprost + G-CSF compared to vehicle + G-CSF at 4 hours post-transplant. We found that G-CSF administration also decreased Scf and Cxcl12 mRNA expression in BM, which were partially rescued with iloprost co-administration. These data suggest that PGI2 protects HSC during stress by acting directly on HSCs and indirectly to preserve BM niche functions. In summary, we identified PGI2 as a novel HSC niche factor abundant in the endosteal BM.

Iloprost treatment on top of infrapopliteal angioplasty accelerates wound healing in critical leg ischemia

Objectives This study aimed to examine the efficacy of the concomitant use of infrapopliteal drug-eluting balloon angioplasty and a medical treatment (iloprost) in the treatment of critical leg ischemia. Methods Eighty-seven patients that underwent infrapopliteal drug-eluting balloon angioplasty for critical leg ischemia were included in this retrospective study. For analyses, patients were allocated into one of the two groups: 55 patients that underwent drug-eluting balloon angioplasty alone (drug-eluting balloon Group), and 32 patients that received intravenous iloprost for one week after drug-eluting balloon (DEB-I Group). Demographic, perioperative and follow-up clinical data were extracted retrospectively and analyzed. Results Duration of hospitalization was significantly longer in the DEB-I group (9.7 vs. 3.1 days, p &lt; 0.001); however, the two groups were similar in terms of other clinical outcomes including early postoperative mortality, and primary patency, wound healing, reintervention, mortality, and amputation rates at one year ( p &gt; 0.05 for all). Primary patency was similar across groups. Wound healing occurred earlier in the DEB-I group when compared to drug-eluting balloon group, in the subgroup of patients with ischemic wound at baseline. Mean time to wound healing was 3.0 ± 0.6 and 4.4 ± 0.6 months in DEB-I and drug-eluting balloon groups, respectively ( p = 0.037). Conclusions Iloprost add-on treatment in patients undergoing drug-eluting balloon angioplasty for critical limb ischemia seems to have additional benefits, at least in terms of accelerated wound healing. Further large prospective studies are warranted.