Elastin metabolism in the vessel wall during pulmonary hypertension

The elastic fibre is critical for lung gas exchange and circulation. The compliant properties of elastin provide recoil both to restore normal alveolar structure after inspiration and to maintain vascular pressure in the face of pulsatile flow. Elastin destruction is characteristic of pulmonary emphysema, while elastin accumulation is evident in clinical and experimental pulmonary hypertension (PH). The predominant source of elastin in the vessel wall is the smooth muscle cell, although responses to injury may recruit cells capable of producing elastin. During pulmonary hypertension net synthesis of elastin occurs in vessels; however, several lines of evidence point to turnover of elastin as another hallmark of vascular changes. The unique elastin cross-links, desmosine and isodesmosine, and immunoreactive elastin peptides (EP) serve as specific markers of elastin degradation in biological fluids. EP levels in lung lymph rise rapidly with the onset of PH brought about by air embolism in the sheep, while data in other PH models also suggest a role for elastolysis. Recent studies in a sheep model of PH indicate that secretory leucoprotease inhibitor can reduce the rise in pulmonary vascular resistance and flux of lymph EP. Taken together, such studies suggest that considerable elastin turnover or remodelling accompanies the net accumulation of elastin that is characteristic of PH. The mediators of elastin synthesis and turnover are uncertain. Sequestration of granulocytes, endothelial injury and inflammation are inciting events, and the action of mononuclear cells and granulocytes are likely to be contributing factors. In the sheep model, both insulin-like growth factor-I and transforming growth factor-β (TGF-β) reach maximum levels prior to the visible accumulation of elastic fibres. We have detected agents in lymph of hypertensive sheep that stimulate elastin production by smooth muscle cells 3-6 fold. This activity was neutralized by antibodies to TGF-β suggesting this agent may be involved. Mechanical force or vessel wall stress is capable of inducing elastin expression in cells and tissues, and this signal could activate proteolytic pathways. Although elastin deposition is generally regarded as an irreversible and delayed event in tissue development or repair, the observed rates of accretion and resorption in the vessel wall, together with the net accumulation that occurs in spite of excretion of elastin degradation products, suggest that the adult pulmonary vasculature is very dynamic with respect to elastin metabolism.