MMPs have been extensively involved in pulmonary diseases, including interstitial lung disease, emphysema, asthma, and in the context of this review, pulmonary hypertension. Pulmonary hypertension concerns the elevation of pulmonary artery pressures above 25mmHg mean pulmonary artery pressures. Pulmonary hypertension may occur as an idiopathic disease, known historically as primary pulmonary hypertension (or, currently, as idiopathic pulmonary hypertension), or associated with underlying clinical conditions such as congenital heart malformations with left-to-right shunting, collagen vascular diseases, HIV infection, liver diseases, interstitial lung processes, or chronic obstructive pulmonary disease. Clinically, pulmonary hypertension can be divided as mild to moderate, when the pulmonary artery pressures rise to levels not more than 40 to 45 mmHg, and severe, if the pressures are equivalent to those in the systemic circulation. The severe forms of pulmonary hypertension ultimately kill as a result of right heart failure. The underlying morphological basis of pulmonary hypertension is an alteration in the number or size of medial, smooth muscle cells (hyperplasia or hypertrophy, respectively), and in growth of myofibroblasts into the intima. In a selected group of patients with severe disease, endothelial cells undergo growth, forming plexiform lesions. In aggregate, these cellular alterations are known as pulmonary vascular remodeling.
Degradation of components of ECM releases matrix-bound growth factors or creates fragments originated from degraded matrix proteins, resulting in biologically active mediators. The integrated action of these growth factors or active protein fragments may induce vascular cell growth and vascular remodeling. Increased elastolytic activity in pulmonary arteries was postulated as a potential mechanism leading to pulmonary vascular remodeling. Experimental pulmonary hypertension caused by monocrotaline, an alkaloid that causes pulmonary artery endothelial cell injury and pulmonary hypertension, was associated with enhanced elastolytic activity. Similar observations were then extended to the chronic hypoxia model of pulmonary hypertension. The mediator of this elastolytic activity appeared to be a serine protease called endogenous vascular elastase, and if blocked with an elastase inhibitor, pulmonary hypertension was prevented .
The interaction between the action of the vascular elas-tase and MMps was further dissected in studies employing pulmonary arteries of pulmonary hypertensive lungs caused by monocrotaline, grown in organ cultures. These explants demonstrated increased gelatinase activity (mostly MMP2), which could be blocked by treatment with the broad-spectrum MMP inhibitor GM6001. GM6001 also inhibited tenascin (a growth factor for smooth muscle cells) expression, increased vascular cell apoptosis, decreased cell proliferation, and finally, caused a reduction of medial thickness . This line of work agrees with other hypotheses. It is proposed that, during chronic hypoxia, pulmonary arteries undergo cycles of extracellular collagen synthesis and degradation, ultimately contributing to pulmonary vascular remodeling. pulmonary vascular oxidative stress with formation of peroxynitrite can induce MMP activation, such as of MMP-1, -2, -8, and -9. There is evidence of oxidative stress in experimental hypoxic pulmonary hypertension and in pulmonary arteries of patients with idiopathic pulmonary hypertension . Also, there is evidence that chronic hypoxia activates MMP-2 and MMP-13, which might degrade elastin and fibrillar collagen, respectively. The corollary of this paradigm is the protection against pulmonary hypertension and pulmonary vascular remodeling afforded by the MMP inhibitor Batismat. In summary, these data ascribe a pathogenetic role for serine proteases and MMPs in the process of pulmonary vascular remodeling, which is most pertinent to the monocrotaline model of pulmonary hypertension.
However, other investigations revealed a diametrically opposite function for MMPs in pulmonary vascular remodeling associated with pulmonary hypertension. Armed with the rationale that regression of pulmonary vascular remodeling requires proteolytic processing of the ECM in pulmonary arteries, Vieillard-Baron et al. demonstrated that TIMP-1 inhibition of MMPs worsened hypoxia-induced pulmonary hypertension. It is difficult to pinpoint the cause of this discrepancy with regard to the pathobiological importance of matrix proteases in pulmonary vascular remodeling, but it is conceivable that TIMP-1 may have an unforeseen effect on pulmonary vascular remodeling that is independent of its MMP-inhibitory effect.
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Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...