PATHOBIOLOGY OF PULMONARY HYPERTENSION: Extracellular Matrix
Section snippets
CHANGES IN THE EXTRACELLULAR MATRIX IN LUNG BIOPSY TISSUE
Studies of lung biopsy tissue in patients with pulmonary hypertension associated with congenital heart defects first led to the identification of changes in the extracellular matrix and an understanding of their potential pathophysiologic role. 42, 61 The author and others initially described alterations related to abnormal growth of the peripheral arteries. Extension of muscle into peripheral arteries occurs early in the evolution of the disease and is attributable to precocious
EXTRACELLULAR MATRIX AND HYPOXIA-INDUCED PULMONARY VASCULAR DISEASE
In patients living at high altitudes, chronic elevation in PA pressure is associated with vessels that are more muscular than normal.3 The pulmonary hypertension is almost completely reversible upon return to room air but there may be a deficit with exercise, suggesting some residual abnormalities, perhaps related to loss of small arteries. In addition, Meyrick and Reid41 observed an increase in the relative proportion of elastin in rat PAs following recovery from hypoxia. Increased elastin and
INFLAMMATORY CHANGES IN THE EXTRACELLULAR MATRIX
There may be many pathophysiologic similarities between the immune inflammatory reaction leading to postcardiac-transplant coronary artery disease and the pulmonary hypertensive changes associated with collagen vascular disease. The author has shown experimentally that the neointimal formation seen in the coronary arteries is mediated by an increase in serine elastase activity, 51 which, together with an increase in cytokine release, 10, 11 induces the production or release of gene products,
PATHOLOGY OF UNEXPLAINED PULMONARY HYPERTENSION
After all known causes of pulmonary hypertension have been ruled out, the diagnosis becomes that of idiopathic or unexplained pulmonary hypertension. A structural abnormality is always found in the arteries or the veins and rarely with a familial tendency. In young children, the pathobiology suggests failure of the neonatal vasculature to open and a striking reduction in arterial number.69 In older children, intimal hyperplasia and occlusive changes are found in the PAs and plexiform lesions.
EXPERIMENTAL MODELS OF INFLAMMATION AND EXTRACELLULAR MATRIX CHANGES
Models of chronic inflammation, such as repeated injections of endotoxin40 and tumor necrosis factor, 68 also have been associated with the development of pulmonary vascular changes in association with proteolysis and increased expression of growth factors. Whereas in these models, there is at least a transient inflammatory response, in models of chronic air embolization53 and thoracic irradiation, 52 in which pulmonary hypertension and vascular changes are produced, endothelial injury is the
REVERSIBILIY OF EXPERIMENTAL PULMONARY HYPERTENSION
Studies in organ culture suggest that stress unloading of PAs in which hypertrophy was induced by the toxin monocrotaline results in repression of elastase and associated matrix proteinase activity and tenascin expression, leading to apoptosis and resorption of the extracellular matrix and regression of disease.18 In fact, elastase and matrix metalloproteinase inhibitors also induce regression of PA hypertrophy directly.19 Transplanting a hypertensive lung harvested from a rat following
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Address reprint requests to Marlene Rabinovitch, MD, Division of Cardiovascular Research, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, MSGIX8 Canada e-mail: [email protected]