Elsevier

Clinics in Chest Medicine

Volume 22, Issue 3, 1 September 2001, Pages 433-449
Clinics in Chest Medicine

PATHOBIOLOGY OF PULMONARY HYPERTENSION: Extracellular Matrix

https://doi.org/10.1016/S0272-5231(05)70282-3Get rights and content

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

First page preview

First page preview
Click to open first page preview

References (87)

  • S.S. Arcot et al.

    Basic fibroblast growth factor alterations during development of monocrotaline-induced pulmonary hypertension in rats

    Growth Factors

    (1995)
  • J. Arias-Stella et al.

    The terminal portion of the pulmonary arterial tree in people native to high altitude

    Circulation

    (1963)
  • M.D. Botney et al.

    Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-β

    Am J Pathol

    (1994)
  • M.D. Botney et al.

    Extracellular matrix protein gene expression in atherosclerotic hypertensive pulmonary arteries

    Am J Pathol

    (1992)
  • M.D. Botney et al.

    Active collagen synthesis by pulmonary arteries in human primary pulmonary hypertension

    Am J Pathol

    (1993)
  • I. Chazova et al.

    Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension

    Am J Pathol

    (1995)
  • S.J. Chen et al.

    Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats

    J Appl Physiol

    (1995)
  • N. Clausell et al.

    Upregulation of fibronectin synthesis by interleukin-1β in coronary artery smooth muscle cells is associated with the development of the post-cardiac transplant arteriopathy in piglets

    J Clin Invest

    (1992)
  • N. Clausell et al.

    Increased interleukin-1β and fibronectin expression are early features of the development of the post-cardiac transplant coronary arteriopathy in piglets

    Am J Pathol

    (1993)
  • N. Clausell et al.

    In vivo blockade of tumor necrosis factor in cholesterol-fed rabbits after cardiac transplant inhibits acute coronary artery neointimal formation

    Circulation

    (1994)
  • A.H. Cohen et al.

    Inhibition of cyclic 3′–5′-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats

    J Clin Invest

    (1996)
  • D.N. Cornfield et al.

    Oxygen causes fetal pulmonary vasodilation through activation of a calcium dependent potassium channel

    Proc Natl Acad Sci USA

    (1996)
  • B. Cowan et al.

    Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits following heterotopic cardiac transplantation

    J Clin Invest

    (1996)
  • K.N. Cowan

    Regression of vascular thickening is mediated by loss of smooth muscle cell β3 integrin ligation to survival factors, induction of apoptosis and caspase-mediated resorption of extracellular matrix [abstract]

    Circulation

    (2000)
  • K.N. Cowan et al.

    Reversal of severe pulmonary hypertension by a serine elastase inhibitor

    Nat Med

    (2000)
  • K.N. Cowan et al.

    Regression of hypertrophied rat pulmonary arteries in organ culture is associated with suppression of proteolytic activity, inhibition of tenascin-C and smooth muscle cell apoptosis

    Circ Res

    (1999)
  • K.N. Cowan et al.

    Elastase and matrix metalloproteinase inhibitors induce regression and tenascin-C antisense prevents progressive vascular disease [abstract]

    J Clin Invest

    (2000)
  • E.C. Dempsey et al.

    Insulin-like growth factor I and protein kinase C activation stimulate pulmonary artery smooth muscle cell proliferation through separate but synergistic pathways

    J Cell Physiol

    (1990)
  • A.G. Durmowicz et al.

    Persistence, re-expression, and induction of pulmonary arterial fibronectin, tropoelastin, and type I procollagen mRNA expression in neonatal hypoxic pulmonary hypertension

    Am J Pathol

    (1994)
  • R.L. Geggel et al.

    Von Willebrand factor abnormalities in primary pulmonary hypertension

    Am Rev Respir Dis

    (1987)
  • A. Giaid et al.

    Expression of endothelin-1 in the lungs of patients with pulmonary hypertension

    New Engl J Med

    (1993)
  • D. Heath et al.

    The pathology of hypertensive vascular disease

    Circulation

    (1958)
  • P.L. Jones et al.

    Tenascin-C is induced with progressive pulmonary vascular disease in rats is functionally related to increased smooth muscle cell proliferation

    Circ Res

    (1996)
  • P.L. Jones et al.

    Induction of tenascin and fibronectin are features associated with increased smooth muscle cell proliferation during the development of progressive pulmonary hypertension in children

    Am J Pathol

    (1997)
  • P.L. Jones et al.

    Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the avβ3 integrin to promote epidermal growth factor receptor phosphorylation and growth

    J Cell Biol

    (1997)
  • P.L. Jones et al.

    Denatured type I collagen induction of vascular smooth muscle cell tenascin-C gene expression is dependent upon a β3 integrin-mediated mitogen-activated protein kinase pathway and a 122 bp promoter element

    J Cell Sci

    (1999)
  • J. Kobayashi et al.

    Serum-induced vascular smooth muscle cell elastolytic activity through tyrosine kinase intracellular signalling

    J Cell Physiol

    (1994)
  • C. Kouyoumdjian et al.

    Continuous inhalation of nitric oxide protects against development of pulmonary hypertension in chronically hypoxic rats

    J Clin Invest

    (1994)
  • J.I. LaBourene et al.

    Alterations in elastin and collagen related to the mechanism of progressive pulmonary venous obstruction in a piglet model. A hemodynamic, ultrastructural, and biochemical study

    Circ Res

    (1990)
  • K.B. Lane et al.

    Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension

    Nat Genet

    (2000)
  • H. Li et al.

    Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia

    J Appl Physiol

    (1994)
  • M.J. Liptay et al.

    Neointimal macrophages colocalize with extracellular matrix gene expression in human atherosclerotic pulmonary arteries

    J Clin Invest

    (1993)
  • K. Maruyama et al.

    Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity

    Am J Physiol

    (1991)
  • Cited by (84)

    View all citing articles on Scopus

    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]

    View full text