scholarly journals Lack of elevation in plasma levels of pro-inflammatory cytokines in common rodent models of pulmonary arterial hypertension: questions of construct validity for human patients

2017 ◽  
Vol 7 (2) ◽  
pp. 476-485 ◽  
Author(s):  
Kenny Schlosser ◽  
Mohamad Taha ◽  
Yupu Deng ◽  
Baohua Jiang ◽  
Lauralyn A McIntyre ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Inflammatory Cytokines ◽  
Plasma Levels ◽  
Rodent Models ◽  
Plasma Cytokine ◽  
Cytokine Levels ◽  
Pulmonary Arterial ◽  
Pro Inflammatory Cytokines

Translational research depends on the relevance of animal models and how well they replicate human disease. Here, we investigated plasma levels of three important pro-inflammatory cytokines (TNFα, IL-6, and MCP-1), known to be elevated in human pulmonary arterial hypertension (PAH), and systematically assessed their levels in PAH patients compared to five different rodent models of pulmonary hypertension (PH). A consistent immunoassay platform (Luminex xMAP) and source (Millipore) was used to measure all specimens. PAH patients (n = 29) exhibited significant elevations in all three cytokines (median [IQR] pg/mL; TNFα, 7.0 [4.8–11.7]; IL-6, 9.2 [3.8–17.2]; MCP-1, 109 [65–142]) versus healthy participants (n = 20) (median [IQR] pg/mL; TNFα, 3.0 [2.0–3.6]; IL-6, 1.7 [0.5–7.2]; MCP-1, 79 [49–93]. In contrast, mice with PH established after three weeks of hypoxia (n = 18) or SU5416 plus hypoxia (n = 20) showed no significant change in their plasma cytokine levels versus controls (n = 16), based on three to four independent experiments per group. Similarly, plasma cytokine levels were not elevated in rats with PH established three weeks after monocrotaline (n = 23), eight weeks after SU5416 alone (n = 10) or six to eight weeks after SU5416 plus hypoxia (n = 21) versus controls (n = 36 rats), based on three to eight independent experiments per group. Positive biologic control specimens from sepsis patients (n = 9), cecal-ligation and puncture (CLP)-induced septic mice (n = 6), and lipopolysaccharide-induced septic rats (n = 4) showed robust elevations in all three cytokines. This study suggests that animal models commonly used for the development of novel diagnostic and therapeutic approaches for PAH may have limited construct validity with respect to markers of systemic immune activation seen in human patients.

The Clinical Phenotype of Myelofibrosis Encompasses a Chronic Inflammatory State That Is Favorably Altered by INCB018424, a Selective Inhibitor of JAK1/2

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2804-2804 ◽  
Author(s):  
Ayalew Tefferi ◽  
Hagop M Kantarjian ◽  
Animesh D. Pardanani ◽  
Ruben A. Mesa ◽  
Robert C Newton ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Plasma Levels ◽  
Inflammatory Cytokine ◽  
Cytokine Profile ◽  
Current Evidence ◽  
Plasma Cytokine ◽  
Markers Of Inflammation ◽  
Cytokine Levels ◽  
Inflammatory State ◽  
Pro Inflammatory Cytokines

Abstract Background: Current evidence links some of the disease manifestations in myelofibrosis (MF) to abnormal cytokines, likely produced by clonally involved megakaryocytes and monocytes. Furthermore, the recent discovery of JAK2/MPL mutations in MF suggests the contribution of abnormal JAK-STAT signaling to both clonal myeloproliferation and cytokine-driven debility. In order to gain additional pathogenetic insight regarding cytokine-phenotype correlations in MF, we looked into the plasma cytokine profile of MF before and after treatment with INCB018424, a selective JAK1/2 inhibitor. Methods: The current study includes subjects with MF enrolled in an ongoing phase 1–2 study of oral INCB018424 (doses ranging from 25 mg/day to 50 mg BID). Plasma samples were obtained prior to treatment and at intervals of 2 weeks, 1 month and 2 months following INCB018424 dosing. Samples were submitted to Rules Based Medicine Human MAP multiplexed immunoassay system to obtain plasma levels on a range of protein analytes. Results: Plasma cytokine levels in MF patients (n=53) vs. normal healthy volunteers (n=15): Compared to normal controls, plasma levels of pro-inflammatory cytokines and markers of inflammation were significantly increased in MF patients (Table; mean +/− SD values). Furthermore, the observed inflammatory cytokine levels in MF were often higher than those seen in patients with rheumatoid arthritis or cancer-associated cachexia (data to be presented at the meeting). Correlation of plasma cytokine levels in MF with JAK2 V617F mutational status, MF subtype and/or constitutional symptoms/cachexia: Comparison of JAK2V617F positive (n=40) and negative (n=13) MF cases suggested significantly (p<0.01) higher IL-1RA (mean +/− SD = 5575 +/− 917 vs. 1291 +/− 359 pg/ml) and CRP (17.4 +/− 1.6 vs. 6.7 +/− 1.9 μg/ml) levels for the former whereas the other cytokines were elevated to a similar extent. Plasma cytokine levels in PMF (n=30) vs. post-PV MF (n=15) vs. post-ET MF (n=8) were not significantly different. The presence of prior splenectomy did not appear to alter the specific MF cytokine profile (Table 1); the abnormal cytokine profile in MF is, therefore, not necessarily a consequence of marked splenomegaly. There was a direct correlation between the levels of pro-inflammatory cytokines and the presence or absence of constitutional symptoms/cachexia (Figure). Similarly, increased inflammatory cytokine levels in MF were accompanied with significantly decreased leptin levels, a surrogate for nutritional status (Table). Post-INCB018424 treatment cytokine levels: Treatment with INCB018424 induced a rapid decrease in MF-associated inflammatory cytokine levels, in parallel with the observed clinical benefit of both reduced splenomegaly and improvement in constitutional symptoms/cachexia (data to be presented at the meeting). Conclusion: The plasma cytokine profile of MF is reminiscent of a chronic inflammatory state with levels of pro-inflammatory cytokines that are possibly higher than those seen in other inflammatory/malignant conditions. Furthermore, the current study suggests a fundamental link between these cytokines and MF-associated constitutional symptoms/cachexia. Cytokine modulation through JAK-STAT inhibition appears to be a mechanism of action for INCB018424 in MF. Cytokine Normal volunteer (N = 15) MF with splenectomy (N = 6) MF without splenectomy (N = 47) IL-1b (pg/ml) 0.6 +/− 0.04 44 +/− 36 41 +/− 25 IL-1RA (pg/ml) 103 +/− 10 7759 +/− 3939 4111 +/− 763 IL-6 (pg/ml) 0 9.7 +/− 3.3 53.6 +/− 22.5 IL-8 (pg/ml) 7.6 +/− 1.17 1618 +/− 1165 2376 +/− 451 TNFa (pg/ml) 2.6 +/− 0.21 38 +/− 6.8 45 +/− 8.8 TNFRII (ng/ml) 3.1 +/− 0.12 27.3 +/− 7.4 24.7 +/− 2.5 CRP (mg/ml) 1.5 +/− 0.49 21.7 +/− 4.5 13.9 +/− 1.6 Leptin (ng/ml) 10.8 +/− 3.5 3.8 +/− 0.9 2.74 +/− 0.6

scholarly journals Impact of Nutrition on Pulmonary Arterial Hypertension

Nutrients ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 169
Author(s):  
María Callejo ◽  
Joan Albert Barberá ◽  
Juan Duarte ◽  
Francisco Perez-Vizcaino
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Gut Microbiota ◽  
Arterial Hypertension ◽  
Case Reports ◽  
Host Immune System ◽  
Dietary Polyphenols ◽  
Pulmonary Arterial ◽  
Near Future

Pulmonary arterial hypertension (PAH) is characterized by sustained vasoconstriction, vascular remodeling, inflammation, and in situ thrombosis. Although there have been important advances in the knowledge of the pathophysiology of PAH, it remains a debilitating, limiting, and rapidly progressive disease. Vitamin D and iron deficiency are worldwide health problems of pandemic proportions. Notably, these nutritional alterations are largely more prevalent in PAH patients than in the general population and there are several pieces of evidence suggesting that they may trigger or aggravate disease progression. There are also several case reports associating scurvy, due to severe vitamin C deficiency, with PAH. Flavonoids such as quercetin, isoflavonoids such as genistein, and other dietary polyphenols including resveratrol slow the progression of the disease in animal models of PAH. Finally, the role of the gut microbiota and its interplay with the diet, host immune system, and energy metabolism is emerging in multiple cardiovascular diseases. The alteration of the gut microbiota has also been reported in animal models of PAH. It is thus possible that in the near future interventions targeting the nutritional status and the gut dysbiosis will improve the outcome of these patients.

scholarly journals Circulating Plasma Metabolomic Profiles Differentiate Rodent Models of Pulmonary Hypertension and Idiopathic Pulmonary Arterial Hypertension Patients

2019 ◽  
Vol 32 (11) ◽  
pp. 1109-1117
Author(s):  
Jun-Han Zhao ◽  
Yang-Yang He ◽  
Shan-Shan Guo ◽  
Yi Yan ◽  
Zhe Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Progressive Disease ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Rodent Models ◽  
Preclinical Models ◽  
Metabolic Dysregulation ◽  
Pulmonary Arterial ◽  
Significant Pathway

Abstract BACKGROUND Pulmonary arterial hypertension (PAH) is a severe progressive disease with systemic metabolic dysregulation. Monocrotaline (MCT)-induced and hypoxia-induced pulmonary hypertension (PH) rodent models are the most widely used preclinical models, however, whether or not these preclinical models recapitulate metabolomic profiles of PAH patients remain unclear. METHODS In this study, a targeted metabolomics panel of 126 small molecule metabolites was conducted. We applied it to the plasma of the 2 preclinical rodent models of PH and 30 idiopathic pulmonary arterial hypertension (IPAH) patients as well as 30 healthy controls to comparatively assess the metabolomic profiles of PAH patients and rodent models. RESULTS Significantly different metabolomics profiling and pathways were shown among the 2 classical rodent models and IPAH patients. Pathway analysis demonstrated that methionine metabolism and urea cycle metabolism were the most significant pathway involved in the pathogenesis of hypoxia-induced PH model and MCT-induced model, respectively, and both of them were also observed in the dysregulated pathways in IPAH patients. CONCLUSIONS These 2 models may develop PAH through different metabolomic pathways and each of the 2 classical PH model resembles IPAH patients in certain aspects.

Circulating Plasma Levels of Bone Morphogenic Protein Antagonist Gremlin-1 Are Increased in Patients with Pulmonary Arterial Hypertension

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5189-5189
Author(s):  
Jasmin Wellbrock ◽  
Jan K. Hennigs ◽  
Björn Schulz ◽  
Gabi Vohwinkel ◽  
Hans Jörg Baumann ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Plasma Levels ◽  
Research Funding ◽  
Bmp Signaling ◽  
Pulmonary Arterial ◽  
Bmp Antagonist ◽  
Minute Walk Distance ◽  
Gremlin 1

Abstract Abstract 5189 Background: Pulmonary arterial hypertension (PAH) is a severe and life-threatening disease. It is characterized by excessive growth of pulmonary artery endothelial and smooth muscle cells leading to a profound pulmonary artery remodeling and consequently increased pulmonary artery pressure and vascular resistance. Most patients with the heritable form of PAH harbor a mutation in the bone morphogenic protein (BMP) receptor 2 (BMPR2) resulting in dysregulated BMP signaling. In addition, aberrant BMP signaling was also observed in the idiopathic form of PAH although the underlying molecular mechanisms have not been elucidated. Recently, it was shown that BMP antagonist Gremlin-1 was elevated in pulmonary vessels of mice during development of hypoxic pulmonary hypertension (Cahill et al, Circulation. 2012;125(7):920–30). Methods and Results: The aim of this prospective study was to investigate the plasma levels of Gremlin-1 in PAH patients (Dana point classification group I) and to correlate Gremlin-1 levels to clinical and hemodynamic parameters. Thirty subjects were included in the study (19 patients with PAH treated at the PH clinics of the University Medical Center Hamburg-Eppendorf, Germany and 11 healthy volunteers) after giving informed consent. The mean Gremlin-1 plasma level was 2. 6-fold increased with 333 ± 160 ng/ml, in patients with pulmonary arterial hypertension compared to those of healthy control subjects with a mean Gremlin-1 plasma level of 118 ± 115 ng/ml (p=0. 001 in t-test). Gremlin-1 plasma levels of PAH patients were correlated to demographic, clinical and hemodynamic parameters including age, sex, 6-minute walk distance, systemic and pulmonary blood pressure & vascular resistance, lung function testing, NT-proBNP (N terminal pro-brain natriuretic peptide) and NYHA/WHO functional classification. A positive correlation between Gremlin-1 plasma levels and NT-proBNP plasma levels was observed (Spearman Rho 0. 809 with p<0. 001). Furthermore, a negative correlation was observed between the Gremlin-1 levels and the 6-minute walk distance (Spearman Rho −0. 522 with p=0. 032). Conclusion: The plasma levels of BMP antagonist Gremlin-1 are significantly elevated in patients with pulmonary arterial hypertension and may serve as new serological marker. Gremlin-1 might mirror the state of BMP dysregulation and represent a potential follow up marker under a future targeted therapy. Furthermore, since Gremlin-1 was shown to induce proliferative effects on both endothelial as well as smooth muscle cells, it might also contribute directly to the aberrant vessel growth observed in PAH. Gremlin-1 plasma levels of patients with pulmonary hypertension (n=19) were analyzed in an enzyme-linked immunosorbent assay. Compared to healthy subjects (n=11), mean plasma levels of Gremlin-1 were 2. 6-fold increased in PH patients (t-test p=0. 001). Box plots show the median (center horizontal line), the 25th to the 75th percentile (box) and the range (whiskers).** indicates p<0. 01. Disclosures: Hennigs: Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Actelion: Research Funding; GlaxoSmithKline: Honoraria; Novartis: Honoraria. Fiedler:Pfizer Inc. : Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

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