scholarly journals Influence of Distal Resistance and Proximal Stiffness on Hemodynamics and RV Afterload in Progression and Treatments of Pulmonary Hypertension: A Computational Study with Validation Using Animal Models

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Zhenbi Su ◽  
Wei Tan ◽  
Robin Shandas ◽  
Kendall S. Hunter
Keyword(s):  
Pulmonary Hypertension ◽  
Ex Vivo ◽  
Computational Study ◽  
Vascular Wall ◽  
Patient Specific ◽  
Model Parameters ◽  
Theoretical Treatment ◽  
Pulmonary Hemodynamics ◽  
Mean Pulmonary Arterial Pressure

We develop a simple computational model based on measurements from a hypoxic neonatal calf model of pulmonary hypertension (PH) to investigate the interplay between vascular and ventricular measures in the setting of progressive PH. Model parameters were obtained directly fromin vivoandex vivomeasurements of neonatal calves. Seventeen sets of model-predicted impedance and mean pulmonary arterial pressure (mPAP) show good agreement with the animal measurements, thereby validating the model. Next, we considered a predictive model in which three parameters, PVR, elastic modulus (EM), and arterial thickness, were varied singly from one simulation to the next to study their individual roles in PH progression. Finally, we used the model to predict the individual impacts of clinical (vasodilatory) and theoretical (compliance increasing) PH treatments on improving pulmonary hemodynamics. Our model (1) displayed excellent patient-specific agreement with measured global pulmonary parameters; (2) quantified relationships between PVR and mean pressure and PVS and pulse pressure, as well as studiying the right ventricular (RV) afterload, which could be measured as a hydraulic load calculated from spectral analysis of pulmonary artery pressure and flow waves; (3) qualitatively confirmed the derangement of vascular wall shear stress in progressive PH; and (4) established that decreasing proximal vascular stiffness through a theoretical treatment of reversing proximal vascular remodeling could decrease RV afterload.

scholarly journals Direct conversion of human fibroblasts into therapeutically active vascular wall-typical mesenchymal stem cells

2019 ◽  
Vol 77 (17) ◽  
pp. 3401-3422 ◽  
Author(s):  
Jennifer Steens ◽  
Kristian Unger ◽  
Lea Klar ◽  
Anika Neureiter ◽  
Karolin Wieber ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Ex Vivo ◽  
Vascular Wall ◽  
Direct Conversion ◽  
Vascular Damage ◽  
Patient Specific ◽  
Programming Approach

Abstract Cell-based therapies using adult stem cells are promising options for the treatment of a number of diseases including autoimmune and cardiovascular disorders. Among these, vascular wall-derived mesenchymal stem cells (VW-MSCs) might be particularly well suited for the protection and curative treatment of vascular damage because of their tissue-specific action. Here we report a novel method for the direct conversion of human skin fibroblasts towards MSCs using a VW-MSC-specific gene code (HOXB7, HOXC6 and HOXC8) that directs cell fate conversion bypassing pluripotency. This direct programming approach using either a self-inactivating (SIN) lentiviral vector expressing the VW-MSC-specific HOX-code or a tetracycline-controlled Tet-On system for doxycycline-inducible gene expressions of HOXB7, HOXC6 and HOXC8 successfully mediated the generation of VW-typical MSCs with classical MSC characteristics in vitro and in vivo. The induced VW-MSCs (iVW-MSCs) fulfilled all criteria of MSCs as defined by the International Society for Cellular Therapy (ISCT). In terms of multipotency and clonogenicity, which are important specific properties to discriminate MSCs from fibroblasts, iVW-MSCs behaved like primary ex vivo isolated VW-MSCs and shared similar molecular and DNA methylation signatures. With respect to their therapeutic potential, these cells suppressed lymphocyte proliferation in vitro, and protected mice against vascular damage in a mouse model of radiation-induced pneumopathy in vivo, as well as ex vivo cultured human lung tissue. The feasibility to obtain patient-specific VW-MSCs from fibroblasts in large amounts by a direct conversion into induced VW-MSCs could potentially open avenues towards novel, MSC-based therapies.

Effect of inhibition of 5-lipoxygenase metabolism of arachidonic acid on response to endotoxemia in sheep

1988 ◽  
Vol 65 (3) ◽  
pp. 1351-1359 ◽  
Author(s):  
J. W. Coggeshall ◽  
B. W. Christman ◽  
P. L. Lefferts ◽  
W. E. Serafin ◽  
I. A. Blair ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Whole Blood ◽  
Ex Vivo ◽  
Calcium Ionophore ◽  
Lung Mechanics ◽  
Gas Chromatography Mass Spectrometry ◽  
Lipoxygenase Inhibitor ◽  
Pulmonary Hemodynamics ◽  
Lung Lymph

We studied the effects of a 5-lipoxygenase inhibitor, L-651,192, on the pulmonary dysfunction caused by endotoxemia in chronically instrumented unanesthetized sheep. The efficacy and selectivity of L-651,392 were tested by measuring in vivo production of leukotriene B4 (LTB4) and cyclooxygenase products of arachidonic acid after endotoxemia before and after pretreatment with L-651,392 and ex vivo from granulocytes and whole blood stimulated with calcium ionophore from sheep before and 24 h after pretreatment with L-651,392. A novel assay for LTB4 by high-performance liquid chromatography/gas chromatography/mass spectrometry techniques was developed as a measure of 5-lipoxygenase metabolism of arachidonic acid. L-651,392 proved to be an effective in vivo 5-lipoxygenase inhibitor in sheep. L-651,392 blocked the increase in LTB4 observed in lung lymph after endotoxemia in vivo in sheep as well as inhibited by 80% the ex vivo production of LTB4 by granulocytes removed from sheep treated 24 h earlier with L-651,392. Although L-651,392 blocked the increase in cyclooxygenase products of arachidonic acid observed in lung lymph after endotoxemia in vivo in sheep, the drug probably did not function directly as a cyclooxygenase inhibitor. L-651,392 did not attenuate the ex vivo production of thromboxane B2 by whole blood from sheep treated 24 h earlier with the drug. L-651,392 attenuated the alterations in pulmonary hemodynamics, lung mechanics, oxygenation, and lung fluid and solute exchange observed after endotoxemia in sheep. We speculate that 5-lipoxygenase products are a major stimulus for cyclooxygenase metabolism of arachidonic acid after endotoxemia in sheep.

Computational Study on the Effects of Peripheral Vessel Network on Blood Flow in the Arterial Circle of Willis

2007 ◽  
Author(s):  
Shigefumi Tokuda ◽  
Takeshi Unemura ◽  
Marie Oshima
Keyword(s):  
Numerical Simulation ◽  
Blood Flow ◽  
Boundary Conditions ◽  
Vascular System ◽  
Computational Study ◽  
Circulatory System ◽  
Biological Data ◽  
Patient Specific ◽  
Peripheral Vessel

Cerebrovascular disorder such as subarachnoid hemorrhage (SAH) is 3rd position of the cause of death in Japan [1]. Its initiation and growth are reported to depend on hemodynamic factors, particularly on wall shear stress or blood pressure induced by blood flow. In order to investigate the information on the hemodynamic quantities in the cerebral vascular system, the authors have been developing a computational tool using patient-specific modeling and numerical simulation [2]. In order to achieve an in vivo simulation of living organisms, it is important to apply appropriate physiological conditions such as physical properties, models, and boundary conditions. Generally, the numerical simulation using a patient-specific model is conducted for a localized region near the research target. Although the analysis region is only a part of the circulatory system, the simulation has to include the effects from the entire circulatory system. Many studies have carried out to derive the boundary conditions to model in vivo environment [3–5]. However, it is not easy to obtain the biological data of cerebral arteries due to head capsule.

Neonatal calves develop airflow limitation due to chronic hypobaric hypoxia

1991 ◽  
Vol 70 (1) ◽  
pp. 384-390 ◽  
Author(s):  
S. C. Inscore ◽  
K. R. Stenmark ◽  
C. Orton ◽  
C. G. Irvin
Keyword(s):  
Pulmonary Hypertension ◽  
Hypobaric Hypoxia ◽  
Fibrous Tissue ◽  
Lung Compliance ◽  
Airflow Limitation ◽  
Mean Pulmonary Arterial Pressure ◽  
Neonatal Calves ◽  
Dynamic Lung Compliance

Neonates and infants presenting with pulmonary hypertension and chronic hypoxia often exhibit airway obstruction. To investigate this association, we utilized a system in which neonatal calves are exposed to chronic hypobaric hypoxia and develop severe pulmonary hypertension. For the present study, one of each pair of six age-matched pairs of neonatal calves was continuously exposed to hypobaric hypoxia at 4,500 m (CH); the other remained at 1,500 m. At 2 wk of age, mean pulmonary arterial pressure (MPAP), dynamic lung compliance (Cdyn), resistance (RL), and static respiratory system compliance (Crs) were measured at 4,500 m in both CH and control calves exposed acutely to hypoxia (C). These measurements were repeated after cumulative administrations of nebulized methacholine (MCh). Tissues were removed for histological examination and assessment of bronchial ring contractility to MCh and KCl. After 2 wk of hypobaric hypoxia, MPAP (C 35 +/- 1.7 vs. CH 120 +/- 7 mmHg, P less than 0.001) and RL (C 2.64 +/- 0.16 vs CH 4.99 +/- 0.47 cmH2O.l-1s, P less than 0.001) increased. Cdyn (C 0.100 +/- 0.01 vs. CH 0.082 +/- 0.007 l/cmH2O) and Crs (CH 0.46 +/- 0.003 vs. C 0.59 +/- 0.009 l/cmH2O) were not significantly different. Compared with airways of C calves, airways of CH animals did not exhibit in vivo or in vitro MCh hyperresponsiveness; however, in vitro contractility to KCl of airways from CH animals was significantly increased. Histologically, airways from the CH calves showed increases in airway fibrous tissue and smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Selected Contribution: Pulmonary hypertension in mice following intermittent hypoxia

2001 ◽  
Vol 90 (6) ◽  
pp. 2502-2507 ◽  
Author(s):  
Karen A. Fagan
Keyword(s):  
Pulmonary Hypertension ◽  
Sleep Apnea ◽  
Intermittent Hypoxia ◽  
Systolic Pressure ◽  
Genetically Engineered ◽  
Systemic Hypertension ◽  
Pulmonary Hemodynamics ◽  
Genetically Engineered Mice ◽  
The Relationship

Sleep apnea (intermittent periods of hypoxia with or without hypercapnia) is associated with systemic hypertension and increased mortality from cardiovascular disease, but the relationship to pulmonary hypertension is uncertain. Previous studies on intermittent hypoxia (IH) in rats that demonstrated pulmonary hypertension utilized relatively long periods of hypoxia. Recent studies that utilized brief periods of hypoxia have conflicting reports of right ventricular (RV) hypertrophy. In addition, many studies have not measured pulmonary hemodynamics to asses the severity of pulmonary hypertension in vivo. Given the increasing availability of genetically engineered mice and the need to establish a rodent model of IH-induced pulmonary hypertension, we studied the effect of IH (2-min cycles of 10% and 21% O2, 8 h/day, 4 wk) on wild-type mice, correlating in vivo measurements of pulmonary hypertension with RV mass and pulmonary vascular remodeling. RV systolic pressure was increased after IH (36 ± 0.9 mmHg) compared with normoxia (29.5 ± 0.6) but was lower than continuous hypoxia (44.2 ± 3.4). RV mass [RV-to-(left ventricle plus septum) ratio] correlated with pressure measurements (IH = 0.27 ± 0.02, normoxia = 0.22 ± 0.01, and continuous hypoxia = 0.34 ± 0.01). Hematocrits were also elevated after IH and continuous hypoxia (56 ± 1.6 and 54 ± 1.1 vs. 44.3 ± 0.5%). Evidence of neomuscularization of the distal pulmonary circulation was found after IH and continuous hypoxia. We conclude that mice develop pulmonary hypertension following IH, representing a possible animal model of pulmonary hypertension in response to the repetitive hypoxia-reoxygenation of sleep apnea.

scholarly journals Population Pharmacokinetic/Pharmacodynamic Analysis of the Bactericidal Activities of Sutezolid (PNU-100480) and Its Major Metabolite against Intracellular Mycobacterium tuberculosis inEx VivoWhole-Blood Cultures of Patients with Pulmonary Tuberculosis

2014 ◽  
Vol 58 (6) ◽  
pp. 3306-3311 ◽  
Author(s):  
Tong Zhu ◽  
Sven O. Friedrich ◽  
Andreas Diacon ◽  
Robert S. Wallis
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hollow Fiber ◽  
Ex Vivo ◽  
Parent Compound ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Model Parameters ◽  
Data Set ◽  
Content Type

ABSTRACTSutezolid (PNU-100480 [U-480]) is an oxazolidinone antimicrobial being developed for the treatment of tuberculosis. An active sulfoxide metabolite (PNU-101603 [U-603]), which reaches concentrations in plasma several times those of the parent, has been reported to drive the killing of extracellularMycobacterium tuberculosisby sutezolid in hollow-fiber culture. However, the relative contributions of the parent and metabolite against intracellularM. tuberculosisin vivoare not fully understood. The relationships between the plasma concentrations of U-480 and U-603 and intracellular whole-blood bactericidal activity (WBA) inex vivocultures were examined using a direct competitive population pharmacokinetic (PK)/pharmacodynamic 4-parameter sigmoid model. The data set included 690 PK determinations and 345 WBA determinations from 50 tuberculosis patients enrolled in a phase 2a sutezolid trial. The model parameters were solved iteratively. The median U-603/U-480 concentration ratio was 7.1 (range, 1 to 28). The apparent 50% inhibitory concentration of U-603 for intracellularM. tuberculosiswas 17-fold greater than that of U-480 (90% confidence interval [CI], 9.9- to 53-fold). Model parameters were used to simulatein vivoactivity after oral dosing with sutezolid at 600 mg twice a day (BID) and 1,200 mg once a day (QD). Divided dosing resulted in greater cumulative activity (−0.269 log10per day; 90% CI, −0.237 to −0.293 log10per day) than single daily dosing (−0.186 log10per day; 90% CI, −0.160 to −0.208 log10per day). U-480 accounted for 84% and 78% of the activity for BID and QD dosing, respectively, despite the higher concentrations of U-603. Killing of intracellularM. tuberculosisby orally administered sutezolid is mainly due to the activity of the parent compound. Taken together with the findings of other studies in the hollow-fiber model, these findings suggest that sutezolid and its metabolite act on different mycobacterial subpopulations.

scholarly journals EXPRESS: Mouse Model of Experimental Pulmonary Hypertension: Lung Angiogram and Right Heart Catheterization

2021 ◽  
pp. 204589402110415
Author(s):  
Jason X.-J. Yuan ◽  
Mingmei Xiong ◽  
Pritesh Prakash Jain ◽  
Jiyuan Chen ◽  
Aleksandra Babicheva ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Ex Vivo ◽  
Systolic Pressure ◽  
Right Heart Catheterization ◽  
Mouse Lung ◽  
Heart Catheterization ◽  
Right Heart ◽  
Pulmonary Hemodynamics ◽  
Pulmonary Vascular Remodeling

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease and rodents with experimental pulmonary hypertension (PH) are often used to study pathogenic mechanisms, identify therapeutic targets, and develop novel drugs for treatment. Here we describe a hands-on set of experimental approaches including ex vivo lung angiography and histology and in vivo right heart catheterization (RHC) to phenotypically characterize pulmonary hemodynamics and lung vascular structure in normal mice and mice with experimental PH. We utilized Microfil polymer as contrast in our ex vivo lung angiogram to quantitatively examine pulmonary vascular remodeling in mice with experimental PH, and lung histology to estimate pulmonary artery wall thickness. The peripheral lung vascular images were selected to determine the total length of lung vascular branches, the number of branches and the number of junctions in a given area (mm-2). We found that the three parameter determined by angiogram were not significantly different among the apical, middle and basal regions of the mouse lung from normal mice, and were not influenced by gender (no significant difference between female and male mice). We conducted RHC in mice to measure right ventricular systolic pressure (RVSP), a surrogate measure for pulmonary artery (PA) systolic pressure and right ventricle (RV) contractility (RV-±dP/dtmax) to estimate RV function. RHC, a short time (4-6 min) procedure, did not alter the lung angiography measurements. In summary, utilizing ex vivo angiogram to determine peripheral vascular structure and density in the mouse lung and utilizing in vivo RHC to measure pulmonary hemodynamics are reliable readouts to phenotype normal mice and mice with experimental PH. Lung angiogram and RHC are also reliable approaches to examine pharmacological effects of new drugs on pulmonary vascular remodeling and hemodynamics.

scholarly journals Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
David Osuna de la Peña ◽  
Sara Maria David Trabulo ◽  
Estelle Collin ◽  
Ying Liu ◽  
Shreya Sharma ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Human Cancer ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Patient Specific ◽  
In Vivo Models ◽  
Mesenchymal Transition ◽  
Matrix Deposition ◽  
Tumour Biology

AbstractPatient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.

scholarly journals Patient-specific logic models of signaling pathways from screenings on cancer biopsies to prioritize personalized combination therapies

2018 ◽  
Author(s):  
Federica Eduati ◽  
Patricia Jaaks ◽  
Christoph A. Merten ◽  
Mathew J. Garnett ◽  
Julio Saez- Rodriguez
Keyword(s):  
Signaling Pathways ◽  
Large Scale ◽  
Dynamic Models ◽  
Ex Vivo ◽  
Response To Therapy ◽  
Mechanistic Modeling ◽  
Patient Specific ◽  
Model Parameters ◽  
Specific Response ◽  
Tumor Stages

AbstractMechanistic modeling of signaling pathways mediating patient-specific response to therapy can help to unveil resistance mechanisms and improve therapeutic strategies. Yet, creating such models for patients, in particular for solid malignancies, is challenging. A major hurdle to build these models is the limited material available, that precludes the generation of large-scale perturbation data. Here, we present an approach that couples ex vivo high-throughput screenings of cancer biopsies using microfluidics with logic-based modeling to generate patient-specific dynamic models of extrinsic and intrinsic apoptosis signaling pathways. We used the resulting models to investigate heterogeneity in pancreatic cancer patients, showing dissimilarities especially in the PI3K-Akt pathway. Variation in model parameters reflected well the different tumor stages. Finally, we used our dynamic models to efficaciously predict new personalized combinatorial treatments. Our results suggest our combination of microfluidic experiments and mathematical model can be a novel tool toward cancer precision medicine.

scholarly journals Organ-Chip Models: Opportunities for Precision Medicine in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4487
Author(s):  
Muhammad R. Haque ◽  
Trevor H. Rempert ◽  
Taslim A. Al-Hilal ◽  
Chengyao Wang ◽  
Abhinav Bhushan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Ex Vivo ◽  
Primary Response ◽  
Ductal Adenocarcinoma ◽  
Study Patient ◽  
Patient Specific ◽  
Molecular Heterogeneity ◽  
Cellular Interactions ◽  
Organ On A Chip

Pancreatic Ductal Adenocarcinoma (PDAC) is an expeditiously fatal malignancy with a five-year survival rate of 6–8%. Conventional chemotherapeutics fail in many cases due to inadequate primary response and rapidly developing resistance. This treatment failure is particularly challenging in pancreatic cancer because of the high molecular heterogeneity across tumors. Additionally, a rich fibro-inflammatory component within the tumor microenvironment (TME) limits the delivery and effectiveness of anticancer drugs, further contributing to the lack of response or developing resistance to conventional approaches in this cancer. As a result, there is an urgent need to model pancreatic cancer ex vivo to discover effective drug regimens, including those targeting the components of the TME on an individualized basis. Patient-derived three-dimensional (3D) organoid technology has provided a unique opportunity to study patient-specific cancerous epithelium. Patient-derived organoids cultured with the TME components can more accurately reflect the in vivo tumor environment. Here we present the advances in organoid technology and multicellular platforms that could allow for the development of “organ-on-a-chip” approaches to recapitulate the complex cellular interactions in PDAC tumors. We highlight the current advances of the organ-on-a-chip-based cancer models and discuss their potential for the preclinical selection of individualized treatment in PDAC.

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