Biomedical subjects

Kathleen McEntee

Publications and source records attributed to Kathleen McEntee.

6 recordsLinked to original sources

PubMed2006

Pretreatment of adult bone marrow mesenchymal stem cells with cardiomyogenic growth factors and repair of the chronically infarcted myocardium.

The in vivo cardiac differentiation and functional effects of unmodified adult bone marrow mesenchymal stem cells (MSCs) after myocardial infarction (MI) is controversial. We postulated that ex vivo pretreatment of autologous MSCs using cardiomyogenic growth factors will lead to cardiomyogenic specification and will result in superior biological and functional effects on cardiac regeneration of chronically infarcted myocardium. We used a chronic dog MI model generated by ligation of the coronary artery (n = 30). Autologous dog bone marrow MSCs were isolated, culture expanded, and specified into a cardiac lineage by adding growth factors, including basic FGF, IGF-1, and bone morphogenetic protein-2. Dogs underwent cell injection >8 wk after the infarction and were randomized into two groups. Group A dogs (n = 20) received MSCs specified with growth factors (147 +/- 96 x 10(6)), and group B (n = 10) received unmodified MSCs (168 +/- 24 x 10(6)). After the growth factor treatment, MSCs stained positive for the early muscle and cardiac markers desmin, antimyocyte enhancer factor-2, and Nkx2-5. In group A dogs, prespecified MSCs colocalized with troponin I and cardiac myosin. At 12 wk, group A dogs showed a significantly larger increase in regional wall thickening of the infarcted territory (from 22 +/- 8 to 32 +/- 6% in group A; P < 0.05 vs. baseline and group B, and from 19 +/- 7 to 21 +/- 7% in group B, respectively) and a decrease in the wall motion score index (from 1.60 +/- 0.05 to 1.35 +/- 0.03 in group A; P < 0.05 vs. baseline and group B, and from 1.58 +/- 0.07 vs. 1.56 +/- 0.08 in group B, respectively). The biological ex vivo cardiomyogenic specification of adult MSCs before their transplantation is feasible and appears to improve their in vivo cardiac differentiation as well as the functional recovery in a dog model of the chronically infarcted myocardium.

Adult Stem Cells↗

PubMed2006

Analytical, physiologic, and clinical validation of a radioimmunoassay for measurement of procollagen type III amino terminal propeptide in serum and bronchoalveolar lavage fluid obtained from dogs.

OBJECTIVE: To validate a radioimmunoassay for measurement of procollagen type III amino terminal propeptide (PIIINP) concentrations in canine serum and bronchoalveolar lavage fluid (BALF) and investigate the effects of physiologic and pathologic conditions on PIIINP concentrations. SAMPLE POPULATION: Sera from healthy adult (n = 70) and growing dogs (20) and dogs with chronic renal failure (CRF; 10), cardiomyopathy (CMP; 12), or degenerative valve disease (DVD; 26); and sera and BALF from dogs with chronic bronchopneumopathy (CBP; 15) and healthy control dogs (10 growing and 9 adult dogs). PROCEDURE: A radioimmunoassay was validated, and a reference range for serum PIIINP (S-PIIINP) concentration was established. Effects of growth, age, sex, weight, CRF, and heart failure on S-PIIINP concentration were analyzed. In CBP-affected dogs, S-PIIINP and BALF-PIIINP concentrations were evaluated. RESULTS: The radioimmunoassay had good sensitivity, linearity, precision, and reproducibility and reasonable accuracy for measurement of S-PIIINP and BALF-PIIINP concentrations. The S-PIIINP concentration reference range in adult dogs was 8.86 to 11.48 mug/L. Serum PIIINP concentration correlated with weight and age. Growing dogs had significantly higher S-PIIINP concentrations than adults, but concentrations in CRF-, CMP-, DVD-, or CBP-affected dogs were not significantly different from control values. Mean BALF-PIIINP concentration was significantly higher in CBP-affected dogs than in healthy adults. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, renal or cardiac disease or CBP did not significantly affect S-PIIINP concentration; dogs with CBP had high BALF-PIIINP concentrations. Data suggest that the use of PIIINP as a marker of pathologic fibrosis might be limited in growing dogs.

Animals↗

PubMed2005

Endothelin receptor antagonists.

Endothelin receptor antagonists (ERAs) have been developed to block the effects of endothelin-1 (ET-1) in a variety of cardiovascular conditions. ET-1 is a powerful vasoconstrictor with mitogenic or co-mitogenic properties, which acts through the stimulation of 2 subtypes of receptors [endothelin receptor subtype A (ETA) and endothelin receptor subtype B (ETB) receptors]. Endogenous ET-1 is involved in a variety of conditions including systemic and pulmonary hypertension (PH), congestive heart failure (CHF), vascular remodeling (restenosis, atherosclerosis), renal failure, cancer, and cerebrovascular disease. The first dual ETA/ETB receptor blocker, bosentan, has already been approved by the Food and Drug Administration for the treatment of pulmonary arterial hypertension (PAH). Trials of endothelin receptor antagonists in heart failure have been completed with mixed results so far. Studies are ongoing on the effects of selective ETA antagonists or dual ETA/ETB antagonists in lung fibrosis, cancer, and subarachnoid hemorrhage. While non-peptidic ET-1 receptor antagonists suitable for oral intake with excellent bioavailability have become available, proven efficacy is limited to pulmonary hypertension, but it is possible that these agents might find a place in the treatment of several cardiovascular and non-cardiovascular diseases in the coming future.

Animals↗

PubMed2003

Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension.

BACKGROUND: The dual endothelin-receptor antagonist bosentan has been reported to improve pulmonary arterial hypertension, but the role of endothelins in the pathogenesis of the condition remains uncertain. We investigated the roles of endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and tenascin in overcirculation-induced pulmonary hypertension in piglets, as a model of early pulmonary arterial hypertension, with or without bosentan therapy. METHODS AND RESULTS: Thirty 3-week-old piglets were randomized to placebo or to bosentan 15 mg/kg BID after the anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Chronic systemic-to-pulmonary shunting increased circulating plasma ET-1, pulmonary mRNA for ET-1, ET(B) receptor, inducible NO synthase, VEGF, and pulmonary ET-1 and VEGF proteins. There were increases in myocardial mRNA for ET(A) receptor and VEGF and in myocardial VEGF protein. Pulmonary and myocardial tissue mRNA for tenascin did not change. Normalized-flow pulmonary artery pressure increased from 20 (2) to 33 (1) mm Hg [mean (SEM)], arteriolar medial thickness increased on average by 83%, and these changes were completely prevented by bosentan therapy. Right ventricular end-systolic elastance increased in proportion to pulmonary arterial elastance with or without bosentan. CONCLUSIONS: Experimental overcirculation-induced pulmonary arterial hypertension appears to be causally related to an activation of the pulmonary ET-1 system and as such is completely prevented by the dual endothelin receptor antagonist bosentan.

Animals↗

PubMed2003

Early activation of cardiac and renal endothelin systems in experimental heart failure.

We investigated the time course of the expression of cardiac and renal endothelin systems in tachycardia-induced heart failure in dogs. Eleven beagles underwent rapid pacing at a progressively increased rate over a period of 5 wk, with a weekly clinical examination, echocardiography, measurement of circulating and urinary endothelin-1 (ET-1), and myocardial and renal tissue biopsies. Real-time quantitative PCR was used for determinations of tissue prepro-ET-1 (ppET-1), ET-1-converting enzyme (ECE-1), and ETA and ETB receptor mRNA. Cardiac and renal tissue ET-1 contents were evaluated by immunostaining and measured by radioimmunoassay at autopsy. Rapid pacing caused a progressive increase in end-systolic and end-diastolic ventricular volumes (P < 0.05) from week 2 together with a decrease in ejection fraction and in mean velocity of circumferential shortening (P < 0.05) from week 1. These changes were tightly correlated to myocardial ppET-1 and renal ETA receptor mRNA and less so to myocardial ECE-1 mRNA, and they occurred before any increase in plasma and urinary ET-1 (P < 0.05 from week 4) and clinical signs of heart failure. Renal ppET-1 did not change. Both cardiac and renal ET-1 peptide contents were increased at autopsy. We conclude that tachycardia-induced heart failure in dogs is characterized by an early activation of the cardiac and renal tissue endothelin systems, which occurs before any changes in circulating and urinary ET-1 and is closely related to altered ventricular function.

Animals↗

PubMedDate not supplied

An immunologic investigation of canine eosinophilic bronchopneumopathy.

Immunologic variables in dogs with eosinophilic bronchopneumopathy (EBP) have not been extensively evaluated. The aim of this study was to determine immunoglobulin (Ig) concentrations and to perform phenotypic subtyping of lymphocytes in the bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) of 12 dogs with EBP at the time of diagnosis (TD) and to compare these data with those obtained in healthy dogs, as well as in EBP dogs after antibiotic therapy (TAB) and during corticosteroid treatment (TM). Matched samples of serum and BALF were used to determine Ig concentrations (IgG, IgM, and IgA) by capture enzyme-linked immunosorbent assay (ELISA), from which a secretory index (SI) was calculated. Lymphocyte subpopulations were studied in the BALF and PB by flow cytometry. Log values of BALF IgM and IgA were significantly higher (0.64+/-0.05 and 1.06+/-0.13, respectively) in EBP dogs at TD than in controls and then tended to decrease at TM (0.55+/-0.03 and 1.02+/-0.17, respectively). A calculated SI for IgA was not significantly increased. In the BALF of dogs with EBg the CD4: CD8 was significantly (P < .05) higher (22.6+/-30.3) than in controls (3.2+/-1.9), due to significantly higher CD4+ T cells and lower CD8+ T cells. At TM, the BALF T-cell percentages returned to normal (2.4+/-0.6). We propose that the influx of eosinophils into the airway of dogs with EBP is at least in part mediated by cytokines derived from CD4+ T cells. Further studies of canine cytokines and chemokines will help determine whether canine EBP involves type I hypersensitivity mechanisms regulated by Th2 lymphocytes.

Animals↗