Vascular remodelling in the lung.

In the 1960s, studies on lungs of normal, high altitude dwelling natives demonstrated distinct structural differences in the pulmonary vasculature, compared to native sea level dwellers, accompanied by mild pulmonary hypertension [1]. ARIAS-STELLA and SALDANA [2] reported an increase in medial muscle mass in the distal segments of the pulmonary arterial tree. This was considered not to be due to medial hypertrophy of muscular arteries but to the development of a muscular media in pulmonary arterioles. Similar changes have been observed in native high altitude animals, animals exposed to experimental high altitude and in man suffering from a variety of chronic lung diseases [1]. The type and extent of the structural changes, termed "vascular remodelling" ("remodeling" in the USA), are dependent on the aetiology of the pulmonary hypertension (PH) which includes hypoxia, lung injury, high blood flow, chronic embolisation and venous obstruction. PH of unknown cause is referred to as primary pulmonary hypertension. Hypoxia is the major stimulus for PH at high altitude and in chronic lung disease. Although the structural changes are generally considered secondary to hypoxic vasoconstriction, other factors may play a role. The changes include extension of longitudinal muscle into the intima as well as medial hypertrophy, in both arterioles and, to a lesser extent venules. The consequences of remodelling, namely restriction of the vascular bed, will exacerbate pulmonary hypertension. Thus, therapeutic relief of PH depends on the reversibility of both the vasoconstriction and the remodelling. The muscular changes are essentially reversible but other irreversible changes such as intimal fibrosis and vascular ablation may occur [3]; the successful reversibility of PH in the high altitude native brought down to sea level being consistent with the lack of irreversible intimal fibrosis [1]. The study of pulmonary vascular disease has become an area of intense research over the last decade. Although it is argued that mild PH may not be relevant clinically, severe PH is indicative of poor prognosis in disease. A recent conference held in London in September 1992 entitled "The Pulmonary Vasculature in Health and Disease" brought together clinicians, pathologists, physiologists, molecular biologists, biophysicists and others, to pool the current knowledge on the pathophysiology of pulmonary vascular remodelling associated with pulmonary hypertension. "State of the art" lectures covered vascular physiology and pathology, relevance of animal models and clinical aspects of pulmonary hypertension. The concepts of cellular and inflammatory regulation of pulmonary vascular remodelling were discussed, along with the influence of mechanical force on vessel structure and function. Major papers from this conference have recently been published in the European Respiratory Review [4] which is reviewed in this article. In the foetus, pulmonary vascular resistance is high and blood flow is minimal; the vascular lumen being obstructed both by vasoconstriction and wall architecture. After birth, expansion of the lung (with accompanying oxygenation) is rapidly followed by a dramatic fall in pulmonary artery pressure (Ppa) occurring within 2–3 min, and a marked increase in pulmonary blood flow. Pressure continues to fall gradually, stabilising within 2–3 days at the low level which, in the normal lung, will persist throughout life. Remodelling of the pulmonary vasculature begins immediately. HAWORTH [5] reported that within 30 mins after birth the endothelial cells, which in the foetal state are cuboidal and bulge into the lumen, flatten and brick-like immature smooth muscle cells (SMC) spread out, thus increasing lumen diameter and reducing vascular resistance. The size of the vascular bed increases as new blood vessels develop with an increase in vascular innervation. There is no loss of vascular smooth muscle, as was originally thought [5]. Cellular phenotypic changes occur, with SMC synthesising the matrix proteins, elastin and collagen. A combination of mechanical, neural and chemical influences such as prostacyclin and nitric oxide (NO), identified as an endothelial derived relaxant factor, may well be involved in both the vasodilatation and stimulation of the cellular changes. Occasionally the neonatal pulmonary circulation fails to adapt to extra-uterine conditions and pulmonary vascular resistance and pressure remain high, termed "persistent pulmonary hypertension of the newborn". STENMARK et al. [6] considered that there may be a failure of the transition from foetal to adult vascular cell phenotype. Further muscularisation of this "immature" pulmonary vasculature occurs, which includes migration of adventitial fibroblasts into the media and SMC into the intima. An increase in matrix proteins may fix the vessel wall in an incomplete dilated state. Pathophysiological changes associated with development of PH in the adult lung are complex [7]. In the adult, development of PH is accompanied by vascular remodelling to what may be considered a foetal-like structure (but probably not reversion to a foetal pattern); EDITORIAL