Lung Transplant ForumsPulmonary hypertension: pathophysiology as a basis for clinical decision making
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Pulmonary vascular disease in patients with congenital heart defects
Congenital heart defects with left-to-right shunts characterized by high pulmonary blood flow and high pressure induce increasing pulmonary hypertension related to progressive structural abnormalities1 associated with impaired growth of the pulmonary arteries. First observed is extension of muscle into peripheral, normally non-muscular, arteries (morphometric grade A) (Figure 1). Ultrastructural studies of lung biopsy tissue2 showed that this change is due to precocious differentiation of
Mechanisms underlying the reactive pulmonary circulation
There are many factors that could contribute to the hyper-reactive pulmonary circulation. Endothelial changes on scanning and transmission electron microscopy suggest a potential for altered function as well as increased interaction with circulating blood elements, such as platelets and leukocytes.19, 20, 21, 22, 23 This could result in a release of thromboxanes21 and other mediators causing pulmonary vasoconstriction. In addition, alterations in the subendothelium reflected in fragmentation of
Nature of the vascular lesions
Our recent immunohistochemical studies carried out in lung biopsy tissue from patients with congenital heart defects have shown that there is a progressive increase in the deposition of the glycoproteins tenascin and fibronectin in the media and neointima (Figure 7). 33 We have previously related increased expression of TN-C to vascular smooth muscle cell proliferation34, 35 and, in fact, there is co-localization of tenascin with proliferating smooth muscle cells and with expression of growth
Pathophysiology of pulmonary vascular disease
In experimental studies, aortopulmonary shunts surgically created in growing piglets were associated with a progressive increase in pulmonary artery pressure and with the development of structural changes; specifically, extension of muscle into peripheral arteries, medial hypertrophy of muscular arteries, and reduced arterial number.42 Several different experimental models of high-flow congenital heart defects have been studied, e.g., lambs with a ventricular septal defect,43 aortopulmonary
Mechanism of induction of elastase activity
To investigate how an increase in elastase might occur, and how it might cause the proliferative and obliterative changes that accompany progressive pulmonary hypertension cell culture, studies were carried out (Figure 10). We hypothesized that in response to a perturbing stimulus, structural and functional alterations in endothelium would lead to the loss of barrier properties, and as a consequence, a serum factor would accumulate in the subendothelium, inducing activity of this EVE in
Elastase activity linked to smooth muscle cell proliferation
Expression of EVE activity leads to the release of smooth muscle cell mitogens58 as has been shown for other serine proteinases.59, 60 Both human leukocyte elastase and EVE induced by serum-treated elastin liberate fibroblast growth factor 2 (FGF-2) from the extracellular matrices of smooth muscle cells. In order for cells to respond optimally to growth factors, receptors must be available and in some way “primed.” Attachment of cells to the specific glycoprotein tenascin enhances their
Fibronectin in pulmonary vascular pathobiology
Increased elastase activity also appears to underlie the mechanism of smooth muscle cell migration associated with neointimal formation and occlusive pulmonary vascular disease. We had previously shown increased expression of the matrix glyocoprotein fibronectin with neointimal formation in the lamb ductus arteriosus in late gestation and in coronary arteries as a result of experimental heterotopic heart transplantation. In lung biopsy tissue from patients with congenital heart defects and
Vasoactive agents are important modulators of structural remodeling
Nitric oxide donors reduce the serum stimulation of elastase in pulmonary artery smooth muscle cells, suggesting how nitric oxide might also suppress the vascular remodeling associated with pulmonary hypertension.74 On the other hand, nitric oxide donors, perhaps via peroxynitite production, increase fibronectin production and therefore can be expected to stimulate smooth muscle cell migration.75 Previous reports have also shown that increased expression of endothelin is associated with
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2016, Smith's Anesthesia for Infants and Children, Ninth EditionHypoxia and lymphangiogenesis in tumor microenvironment and metastasis
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2012, Heart Failure ClinicsCitation Excerpt :Most of the pathophysiologic processes in PAH-CHD seem similar to the pathogenesis implicated in the development of other forms of PAH. The pathogenesis of PAH is explained by a persistent high flow and pressure in the pulmonary vasculature that causes endothelial damage, leading to loss of endothelial barrier function and imbalance of vasoactive mediators that favor vasoconstriction, inflammation, thrombosis, cell proliferation, apoptosis, and fibrosis and result in pulmonary vascular remodeling and irreversible PAH.37 A more detailed description of the mechanisms involved in the development of PAH helps to understand current and potential future therapeutic interventions.
Cardiovascular Physiology
2011, Smith's Anesthesia for Infants and ChildrenImportance of adhesion molecules for children with congenital heart disease
2013, Cardiology in the Young